ID   A4_HUMAN                Reviewed;         770 AA.
AC   P05067; B2R5V1; B4DII8; D3DSD1; D3DSD2; D3DSD3; P09000; P78438; Q13764;
AC   Q13778; Q13793; Q16011; Q16014; Q16019; Q16020; Q6GSC0; Q8WZ99; Q9BT38;
AC   Q9UC33; Q9UCA9; Q9UCB6; Q9UCC8; Q9UCD1; Q9UQ58;
DT   13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1991, sequence version 3.
DT   28-JAN-2026, entry version 318.
DE   RecName: Full=Amyloid-beta precursor protein {ECO:0000312|HGNC:HGNC:620};
DE            Short=APP {ECO:0000312|HGNC:HGNC:620};
DE   AltName: Full=ABPP;
DE   AltName: Full=APPI;
DE   AltName: Full=Alzheimer disease amyloid A4 protein homolog;
DE   AltName: Full=Alzheimer disease amyloid protein;
DE   AltName: Full=Amyloid precursor protein {ECO:0000305};
DE   AltName: Full=Amyloid-beta (A4) precursor protein {ECO:0000250|UniProtKB:P12023};
DE   AltName: Full=Amyloid-beta A4 protein;
DE   AltName: Full=Cerebral vascular amyloid peptide;
DE            Short=CVAP;
DE   AltName: Full=PreA4;
DE   AltName: Full=Protease nexin-II;
DE            Short=PN-II;
DE   Contains:
DE     RecName: Full=N-APP;
DE   Contains:
DE     RecName: Full=Soluble APP-alpha {ECO:0000303|PubMed:10656250};
DE              Short=S-APP-alpha {ECO:0000303|PubMed:10656250};
DE   Contains:
DE     RecName: Full=Soluble APP-beta {ECO:0000303|PubMed:10656250};
DE              Short=S-APP-beta {ECO:0000303|PubMed:10656250};
DE   Contains:
DE     RecName: Full=C99;
DE     AltName: Full=Beta-secretase C-terminal fragment {ECO:0000303|PubMed:10656250};
DE              Short=Beta-CTF {ECO:0000303|PubMed:10656250};
DE   Contains:
DE     RecName: Full=Amyloid-beta protein 42 {ECO:0000303|PubMed:8886002};
DE              Short=Abeta42;
DE     AltName: Full=Beta-APP42;
DE   Contains:
DE     RecName: Full=Amyloid-beta protein 40 {ECO:0000303|PubMed:8886002};
DE              Short=Abeta40;
DE     AltName: Full=Beta-APP40;
DE   Contains:
DE     RecName: Full=C83;
DE     AltName: Full=Alpha-secretase C-terminal fragment {ECO:0000303|PubMed:10656250};
DE              Short=Alpha-CTF {ECO:0000303|PubMed:10656250};
DE   Contains:
DE     RecName: Full=P3(42);
DE   Contains:
DE     RecName: Full=P3(40);
DE   Contains:
DE     RecName: Full=C80;
DE   Contains:
DE     RecName: Full=Gamma-secretase C-terminal fragment 59;
DE     AltName: Full=Amyloid intracellular domain 59;
DE              Short=AICD-59;
DE              Short=AID(59);
DE     AltName: Full=Gamma-CTF(59);
DE   Contains:
DE     RecName: Full=Gamma-secretase C-terminal fragment 57;
DE     AltName: Full=Amyloid intracellular domain 57;
DE              Short=AICD-57;
DE              Short=AID(57);
DE     AltName: Full=Gamma-CTF(57);
DE   Contains:
DE     RecName: Full=Gamma-secretase C-terminal fragment 50;
DE     AltName: Full=Amyloid intracellular domain 50;
DE              Short=AICD-50;
DE              Short=AID(50);
DE     AltName: Full=Gamma-CTF(50);
DE   Contains:
DE     RecName: Full=C31;
DE   Flags: Precursor;
GN   Name=APP {ECO:0000312|HGNC:HGNC:620};
GN   Synonyms=A4 {ECO:0000303|PubMed:2881207}, AD1 {ECO:0000312|HGNC:HGNC:620};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC   TISSUE=Brain;
RX   PubMed=2881207; DOI=10.1038/325733a0;
RA   Kang J., Lemaire H.-G., Unterbeck A., Salbaum J.M., Masters C.L.,
RA   Grzeschik K.-H., Multhaup G., Beyreuther K., Mueller-Hill B.;
RT   "The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-
RT   surface receptor.";
RL   Nature 325:733-736(1987).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP751).
RC   TISSUE=Brain;
RX   PubMed=2893289; DOI=10.1038/331525a0;
RA   Ponte P., Gonzalez-Dewhitt P., Schilling J., Miller J., Hsu D.,
RA   Greenberg B., Davis K., Wallace W., Lieberburg I., Fuller F., Cordell B.;
RT   "A new A4 amyloid mRNA contains a domain homologous to serine proteinase
RT   inhibitors.";
RL   Nature 331:525-527(1988).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP695).
RX   PubMed=2783775; DOI=10.1093/nar/17.2.517;
RA   Lemaire H.-G., Salbaum J.M., Multhaup G., Kang J., Bayney R.M.,
RA   Unterbeck A., Beyreuther K., Mueller-Hill B.;
RT   "The PreA4(695) precursor protein of Alzheimer's disease A4 amyloid is
RT   encoded by 16 exons.";
RL   Nucleic Acids Res. 17:517-522(1989).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP770).
RX   PubMed=2110105; DOI=10.1016/0378-1119(90)90310-n;
RA   Yoshikai S., Sasaki H., Doh-ura K., Furuya H., Sakaki Y.;
RT   "Genomic organization of the human amyloid beta-protein precursor gene.";
RL   Gene 87:257-263(1990).
RN   [5]
RP   ERRATUM OF PUBMED:2110105.
RX   PubMed=1908403; DOI=10.1016/0378-1119(91)90093-q;
RA   Yoshikai S., Sasaki H., Doh-ura K., Furuya H., Sakaki Y.;
RL   Gene 102:291-292(1991).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM L-APP733).
RC   TISSUE=Leukocyte;
RX   PubMed=1587857; DOI=10.1016/s0021-9258(19)50090-4;
RA   Koenig G., Moenning U., Czech C., Prior R., Banati R., Schreiter-Gasser U.,
RA   Bauer J., Masters C.L., Beyreuther K.;
RT   "Identification and differential expression of a novel alternative splice
RT   isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes
RT   and brain microglial cells.";
RL   J. Biol. Chem. 267:10804-10809(1992).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP770).
RX   PubMed=9108164; DOI=10.1093/nar/25.9.1802;
RA   Hattori M., Tsukahara F., Furuhata Y., Tanahashi H., Hirose M., Saito M.,
RA   Tsukuni S., Sakaki Y.;
RT   "A novel method for making nested deletions and its application for
RT   sequencing of a 300 kb region of human APP locus.";
RL   Nucleic Acids Res. 25:1802-1808(1997).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP639), AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=12859342; DOI=10.1046/j.1460-9568.2003.02731.x;
RA   Tang K., Wang C., Shen C., Sheng S., Ravid R., Jing N.;
RT   "Identification of a novel alternative splicing isoform of human amyloid
RT   precursor protein gene, APP639.";
RL   Eur. J. Neurosci. 18:102-108(2003).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS APP770 AND 11).
RC   TISSUE=Cerebellum, and Hippocampus;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [10]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-501.
RG   NIEHS SNPs program;
RL   Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10830953; DOI=10.1038/35012518;
RA   Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA   Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA   Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA   Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA   Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA   Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA   Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA   Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA   Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA   Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA   Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT   "The DNA sequence of human chromosome 21.";
RL   Nature 405:311-319(2000).
RN   [12]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS APP305 AND APP751).
RC   TISSUE=Eye, and Pancreas;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [14]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 1-10.
RC   TISSUE=Liver;
RX   PubMed=3140222; DOI=10.1093/nar/16.19.9351;
RA   Schon E.A., Mita S., Sadlock J., Herbert J.;
RT   "A cDNA specifying the human amyloid beta precursor protein (ABPP) encodes
RT   a 95-kDa polypeptide.";
RL   Nucleic Acids Res. 16:9351-9351(1988).
RN   [15]
RP   ERRATUM OF PUBMED:3140222, AND SEQUENCE REVISION.
RA   Schon E.A., Mita S., Sadlock J., Herbert J.;
RL   Nucleic Acids Res. 16:11402-11402(1988).
RN   [16]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-75.
RX   PubMed=2538123; DOI=10.1016/0006-291x(89)92437-6;
RA   La Fauci G., Lahiri D.K., Salton S.R., Robakis N.K.;
RT   "Characterization of the 5'-end region and the first two exons of the beta-
RT   protein precursor gene.";
RL   Biochem. Biophys. Res. Commun. 159:297-304(1989).
RN   [17]
RP   PROTEIN SEQUENCE OF 18-50.
RC   TISSUE=Fibroblast;
RX   PubMed=3597385; DOI=10.1016/s0021-9258(18)47443-1;
RA   van Nostrand W.E., Cunningham D.D.;
RT   "Purification of protease nexin II from human fibroblasts.";
RL   J. Biol. Chem. 262:8508-8514(1987).
RN   [18]
RP   PROTEIN SEQUENCE OF 18-40.
RC   TISSUE=Platelet;
RX   PubMed=12665801; DOI=10.1038/nbt810;
RA   Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R.,
RA   Vandekerckhove J.;
RT   "Exploring proteomes and analyzing protein processing by mass spectrometric
RT   identification of sorted N-terminal peptides.";
RL   Nat. Biotechnol. 21:566-569(2003).
RN   [19]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 286-366.
RX   PubMed=2893290; DOI=10.1038/331528a0;
RA   Tanzi R.E., McClatchey A.I., Lamperti E.D., Villa-Komaroff L.,
RA   Gusella J.F., Neve R.L.;
RT   "Protease inhibitor domain encoded by an amyloid protein precursor mRNA
RT   associated with Alzheimer's disease.";
RL   Nature 331:528-530(1988).
RN   [20]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 287-367.
RX   PubMed=2893291; DOI=10.1038/331530a0;
RA   Kitaguchi N., Takahashi Y., Tokushima Y., Shiojiri S., Ito H.;
RT   "Novel precursor of Alzheimer's disease amyloid protein shows protease
RT   inhibitory activity.";
RL   Nature 331:530-532(1988).
RN   [21]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 507-770.
RC   TISSUE=Brain cortex;
RX   PubMed=2893379; DOI=10.1073/pnas.85.3.929;
RA   Zain S.B., Salim M., Chou W.G., Sajdel-Sulkowska E.M., Majocha R.E.,
RA   Marotta C.A.;
RT   "Molecular cloning of amyloid cDNA derived from mRNA of the Alzheimer
RT   disease brain: coding and noncoding regions of the fetal precursor mRNA are
RT   expressed in the cortex.";
RL   Proc. Natl. Acad. Sci. U.S.A. 85:929-933(1988).
RN   [22]
RP   PROTEIN SEQUENCE OF 523-555, AND DOMAIN COLLAGEN-BINDING.
RX   PubMed=8576160; DOI=10.1074/jbc.271.3.1613;
RA   Beher D., Hesse L., Masters C.L., Multhaup G.;
RT   "Regulation of amyloid protein precursor (APP) binding to collagen and
RT   mapping of the binding sites on APP and collagen type I.";
RL   J. Biol. Chem. 271:1613-1620(1996).
RN   [23]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 655-737, AND VARIANTS AD1 GLY-717; ILE-717
RP   AND PHE-717.
RX   PubMed=8476439; DOI=10.1006/bbrc.1993.1386;
RA   Denman R.B., Rosenzcwaig R., Miller D.L.;
RT   "A system for studying the effect(s) of familial Alzheimer disease
RT   mutations on the processing of the beta-amyloid peptide precursor.";
RL   Biochem. Biophys. Res. Commun. 192:96-103(1993).
RN   [24]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 656-737.
RX   PubMed=2675837; DOI=10.1016/0006-291x(89)91112-1;
RA   Johnstone E.M., Chaney M.O., Moore R.E., Ward K.E., Norris F.H.,
RA   Little S.P.;
RT   "Alzheimer's disease amyloid peptide is encoded by two exons and shows
RT   similarity to soybean trypsin inhibitor.";
RL   Biochem. Biophys. Res. Commun. 163:1248-1255(1989).
RN   [25]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 672-723, AND VARIANT AD1 ASN-678.
RX   PubMed=15201367; DOI=10.1136/jnnp.2003.010611;
RA   Wakutani Y., Watanabe K., Adachi Y., Wada-Isoe K., Urakami K., Ninomiya H.,
RA   Saido T.C., Hashimoto T., Iwatsubo T., Nakashima K.;
RT   "Novel amyloid precursor protein gene missense mutation (D678N) in probable
RT   familial Alzheimer's disease.";
RL   J. Neurol. Neurosurg. Psych. 75:1039-1042(2004).
RN   [26]
RP   PROTEIN SEQUENCE OF 672-681.
RC   TISSUE=Brain cortex;
RX   PubMed=3312495; DOI=10.1111/j.1471-4159.1987.tb01005.x;
RA   Pardridge W.M., Vinters H.V., Yang J., Eisenberg J., Choi T.B.,
RA   Tourtellotte W.W., Huebner V., Shively J.E.;
RT   "Amyloid angiopathy of Alzheimer's disease: amino acid composition and
RT   partial sequence of a 4,200-dalton peptide isolated from cortical
RT   microvessels.";
RL   J. Neurochem. 49:1394-1401(1987).
RN   [27]
RP   PROTEIN SEQUENCE OF 672-704, AND TISSUE SPECIFICITY.
RX   PubMed=1406936; DOI=10.1038/359325a0;
RA   Seubert P., Vigo-Pelfrey C., Esch F., Lee M., Dovey H., Davis D., Sinha S.,
RA   Schlossmacher M., Whaley J., Swindlehurst C.;
RT   "Isolation and quantification of soluble Alzheimer's beta-peptide from
RT   biological fluids.";
RL   Nature 359:325-327(1992).
RN   [28]
RP   PROTEIN SEQUENCE OF 672-701.
RC   TISSUE=Cerebrospinal fluid;
RX   PubMed=8229004; DOI=10.1111/j.1471-4159.1993.tb09841.x;
RA   Vigo-Pelfrey C., Lee D., Keim P., Lieberburg I., Schenk D.B.;
RT   "Characterization of beta-amyloid peptide from human cerebrospinal fluid.";
RL   J. Neurochem. 61:1965-1968(1993).
RN   [29]
RP   PROTEIN SEQUENCE OF 672-713.
RC   TISSUE=Blood vessel;
RX   PubMed=8248178; DOI=10.1073/pnas.90.22.10836;
RA   Roher A.E., Lowenson J.D., Clarke S., Woods A.S., Cotter R.J., Gowing E.,
RA   Ball M.J.;
RT   "Beta-amyloid-(1-42) is a major component of cerebrovascular amyloid
RT   deposits: implications for the pathology of Alzheimer disease.";
RL   Proc. Natl. Acad. Sci. U.S.A. 90:10836-10840(1993).
RN   [30]
RP   PROTEIN SEQUENCE OF 672-701 AND 707-713.
RX   PubMed=8109908; DOI=10.1002/ana.410350223;
RA   Wisniewski T., Lalowski M., Levy E., Marques M.R.F., Frangione B.;
RT   "The amino acid sequence of neuritic plaque amyloid from a familial
RT   Alzheimer's disease patient.";
RL   Ann. Neurol. 35:245-246(1994).
RN   [31]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 674-770.
RC   TISSUE=Brain;
RX   PubMed=3810169; DOI=10.1126/science.3810169;
RA   Goldgaber D., Lerman M.I., McBride O.W., Saffiotti U., Gajdusek D.C.;
RT   "Characterization and chromosomal localization of a cDNA encoding brain
RT   amyloid of Alzheimer's disease.";
RL   Science 235:877-880(1987).
RN   [32]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 674-703.
RC   TISSUE=Fetal brain;
RX   PubMed=2949367; DOI=10.1126/science.2949367;
RA   Tanzi R.E., Gusella J.F., Watkins P.C., Bruns G.A., St George-Hyslop P.H.,
RA   Van Keuren M.L., Patterson D., Pagan S., Kurnit D.M., Neve R.L.;
RT   "Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage
RT   near the Alzheimer locus.";
RL   Science 235:880-884(1987).
RN   [33]
RP   PROTEIN SEQUENCE OF 609-713, AND GLYCOSYLATION AT THR-633; THR-651;
RP   THR-652; THR-659; THR-663; SER-667 AND TYR-681.
RC   TISSUE=Cerebrospinal fluid;
RX   PubMed=22576872; DOI=10.1002/jms.2987;
RA   Brinkmalm G., Portelius E., Ohrfelt A., Mattsson N., Persson R.,
RA   Gustavsson M.K., Vite C.H., Gobom J., Mansson J.E., Nilsson J., Halim A.,
RA   Larson G., Ruetschi U., Zetterberg H., Blennow K., Brinkmalm A.;
RT   "An online nano-LC-ESI-FTICR-MS method for comprehensive characterization
RT   of endogenous fragments from amyloid beta and amyloid precursor protein in
RT   human and cat cerebrospinal fluid.";
RL   J. Mass Spectrom. 47:591-603(2012).
RN   [34]
RP   PROTEIN SEQUENCE OF 691-698, AND PROTEOLYTIC CLEAVAGE AT PHE-690 BY
RP   THETA-SECRETASE.
RX   PubMed=16816112; DOI=10.1096/fj.05-5632com;
RA   Sun X., He G., Song W.;
RT   "BACE2, as a novel APP theta-secretase, is not responsible for the
RT   pathogenesis of Alzheimer's disease in Down syndrome.";
RL   FASEB J. 20:1369-1376(2006).
RN   [35]
RP   PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP751).
RC   TISSUE=Brain;
RX   PubMed=2569763; DOI=10.1126/science.2569763;
RA   de Sauvage F., Octave J.-N.;
RT   "A novel mRNA of the A4 amyloid precursor gene coding for a possibly
RT   secreted protein.";
RL   Science 245:651-653(1989).
RN   [36]
RP   PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC   TISSUE=Brain;
RX   PubMed=3035574; DOI=10.1073/pnas.84.12.4190;
RA   Robakis N.K., Ramakrishna N., Wolfe G., Wisniewski H.M.;
RT   "Molecular cloning and characterization of a cDNA encoding the
RT   cerebrovascular and the neuritic plaque amyloid peptides.";
RL   Proc. Natl. Acad. Sci. U.S.A. 84:4190-4194(1987).
RN   [37]
RP   SUBCELLULAR LOCATION, SIGNAL SEQUENCE CLEAVAGE SITE, AND TOPOLOGY.
RX   PubMed=2900137; DOI=10.1002/j.1460-2075.1988.tb02900.x;
RA   Dyrks T., Weidemann A., Multhaup G., Salbaum J.M., Lemaire H.-G., Kang J.,
RA   Mueller-Hill B., Masters C.L., Beyreuther K.;
RT   "Identification, transmembrane orientation and biogenesis of the amyloid A4
RT   precursor of Alzheimer's disease.";
RL   EMBO J. 7:949-957(1988).
RN   [38]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, GLYCOSYLATION, SULFATION, AND
RP   OX-2 MOTIF.
RX   PubMed=2649245; DOI=10.1016/0092-8674(89)90177-3;
RA   Weidemann A., Koenig G., Bunke D., Fischer P., Salbaum J.M., Masters C.L.,
RA   Beyreuther K.;
RT   "Identification, biogenesis, and localization of precursors of Alzheimer's
RT   disease A4 amyloid protein.";
RL   Cell 57:115-126(1989).
RN   [39]
RP   IDENTITY OF APP WITH NEXIN-II.
RX   PubMed=2506449; DOI=10.1038/341144a0;
RA   Oltersdorf T., Fritz L.C., Schenk D.B., Lieberburg I., Johnson-Wood K.L.,
RA   Beattie E.C., Ward P.J., Blacher R.W., Dovey H.F., Sinha S.;
RT   "The secreted form of the Alzheimer's amyloid precursor protein with the
RT   Kunitz domain is protease nexin-II.";
RL   Nature 341:144-147(1989).
RN   [40]
RP   PROTEASE-SPECIFICITY OF INHIBITOR DOMAIN.
RX   PubMed=1969731; DOI=10.1016/0006-291x(90)92084-d;
RA   Kido H., Fukutomi A., Schilling J., Wang Y., Cordell B., Katunuma N.;
RT   "Protease-specificity of Kunitz inhibitor domain of Alzheimer's disease
RT   amyloid protein precursor.";
RL   Biochem. Biophys. Res. Commun. 167:716-721(1990).
RN   [41]
RP   EXTRACELLULAR ZINC-BINDING DOMAIN.
RX   PubMed=8344894; DOI=10.1016/s0021-9258(19)85394-2;
RA   Bush A.I., Multhaup G., Moir R.D., Williamson T.G., Small D.H., Rumble B.,
RA   Pollwein P., Beyreuther K., Masters C.L.;
RT   "A novel zinc(II) binding site modulates the function of the beta A4
RT   amyloid protein precursor of Alzheimer's disease.";
RL   J. Biol. Chem. 268:16109-16112(1993).
RN   [42]
RP   INTERACTION WITH G(O).
RX   PubMed=8446172; DOI=10.1038/362075a0;
RA   Nishimoto I., Okamoto T., Matsuura Y., Takahashi S., Okamoto T.,
RA   Murayama Y., Ogata E.;
RT   "Alzheimer amyloid protein precursor complexes with brain GTP-binding
RT   protein G(o).";
RL   Nature 362:75-79(1993).
RN   [43]
RP   PHOSPHORYLATION AT THR-743.
RX   PubMed=8131745; DOI=10.1002/j.1460-2075.1994.tb06360.x;
RA   Suzuki T., Oishi M., Marshak D.R., Czernik A.J., Nairn A.C., Greengard P.;
RT   "Cell cycle-dependent regulation of the phosphorylation and metabolism of
RT   the Alzheimer amyloid precursor protein.";
RL   EMBO J. 13:1114-1122(1994).
RN   [44]
RP   EXTRACELLULAR COPPER-BINDING DOMAIN, AND MUTAGENESIS OF HIS-137; MET-141;
RP   CYS-144; HIS-147 AND HIS-151.
RX   PubMed=7913895; DOI=10.1016/0014-5793(94)00658-x;
RA   Hesse L., Beher D., Masters C.L., Multhaup G.;
RT   "The beta A4 amyloid precursor protein binding to copper.";
RL   FEBS Lett. 349:109-116(1994).
RN   [45]
RP   N-TERMINAL HEPARIN-BINDING DOMAIN, AND MUTAGENESIS OF 99-LYS--ARG-102.
RX   PubMed=8158260; DOI=10.1523/jneurosci.14-04-02117.1994;
RA   Small D.H., Nurcombe V., Reed G., Clarris H., Moir R., Beyreuther K.,
RA   Masters C.L.;
RT   "A heparin-binding domain in the amyloid protein precursor of Alzheimer's
RT   disease is involved in the regulation of neurite outgrowth.";
RL   J. Neurosci. 14:2117-2127(1994).
RN   [46]
RP   CHARACTERIZATION OF L-APP733, AND MUTAGENESIS OF SER-656.
RX   PubMed=7737970; DOI=10.1074/jbc.270.18.10388;
RA   Pangalos M.N., Efthimiopoulos S., Shioi J., Robakis N.K.;
RT   "The chondroitin sulfate attachment site of appican is formed by splicing
RT   out exon 15 of the amyloid precursor gene.";
RL   J. Biol. Chem. 270:10388-10391(1995).
RN   [47]
RP   INTERACTION WITH APP-BP1.
RX   PubMed=8626687; DOI=10.1074/jbc.271.19.11339;
RA   Chow N., Korenberg J.R., Chen X.-N., Neve R.L.;
RT   "APP-BP1, a novel protein that binds to the carboxyl-terminal region of the
RT   amyloid precursor protein.";
RL   J. Biol. Chem. 271:11339-11346(1996).
RN   [48]
RP   INTERACTION WITH APBA1 AND APBB1, AND MUTAGENESIS OF TYR-728; TYR-757;
RP   ASN-759 AND TYR-762.
RX   PubMed=8887653; DOI=10.1128/mcb.16.11.6229;
RA   Borg J.-P., Ooi J., Levy E., Margolis B.;
RT   "The phosphotyrosine interaction domains of X11 and FE65 bind to distinct
RT   sites on the YENPTY motif of amyloid precursor protein.";
RL   Mol. Cell. Biol. 16:6229-6241(1996).
RN   [49]
RP   INTERACTION WITH APBB2.
RX   PubMed=8855266; DOI=10.1073/pnas.93.20.10832;
RA   Guenette S.Y., Chen J., Jondro P.D., Tanzi R.E.;
RT   "Association of a novel human FE65-like protein with the cytoplasmic domain
RT   of the amyloid-beta precursor protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:10832-10837(1996).
RN   [50]
RP   FUNCTION OF AMYLOID-BETA PEPTIDE AS LIPID PEROXIDATION INHIBITOR, AND
RP   MUTAGENESIS OF MET-706.
RX   PubMed=9168929; DOI=10.1006/bbrc.1997.6547;
RA   Walter M.F., Mason P.E., Mason R.P.;
RT   "Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation
RT   as a result of its membrane interactions.";
RL   Biochem. Biophys. Res. Commun. 233:760-764(1997).
RN   [51]
RP   HEPARIN-BINDING DOMAINS.
RX   PubMed=9357988; DOI=10.1016/s0014-5793(97)01146-0;
RA   Mok S.S., Sberna G., Heffernan D., Cappai R., Galatis D., Clarris H.J.,
RA   Sawyer W.H., Beyreuther K., Masters C.L., Small D.H.;
RT   "Expression and analysis of heparin-binding regions of the amyloid
RT   precursor protein of Alzheimer's disease.";
RL   FEBS Lett. 415:303-307(1997).
RN   [52]
RP   INTERACTION OF AMYLOID-BETA PEPTIDE WITH HADH2.
RC   TISSUE=Brain;
RX   PubMed=9338779; DOI=10.1038/39522;
RA   Yan S.D., Fu J., Soto C., Chen X., Zhu H., Al-Mohanna F., Collinson K.,
RA   Zhu A., Stern E., Saido T., Tohyama M., Ogawa S., Roher A., Stern D.;
RT   "An intracellular protein that binds amyloid-beta peptide and mediates
RT   neurotoxicity in Alzheimer's disease.";
RL   Nature 389:689-695(1997).
RN   [53]
RP   COPPER-BINDING, AND DISULFIDE BOND FORMATION.
RX   PubMed=9585534; DOI=10.1021/bi980022m;
RA   Multhaup G., Ruppert T., Schlicksupp A., Hesse L., Bill E., Pipkorn R.,
RA   Masters C.L., Beyreuther K.;
RT   "Copper-binding amyloid precursor protein undergoes a site-specific
RT   fragmentation in the reduction of hydrogen peroxide.";
RL   Biochemistry 37:7224-7230(1998).
RN   [54]
RP   INTERACTION WITH APPBP2, MUTAGENESIS OF TYR-728, AND DOMAIN.
RX   PubMed=9843960; DOI=10.1073/pnas.95.25.14745;
RA   Zheng P., Eastman J., Vande Pol S., Pimplikar S.W.;
RT   "PAT1, a microtubule-interacting protein, recognizes the basolateral
RT   sorting signal of amyloid precursor protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:14745-14750(1998).
RN   [55]
RP   AMYLOID-BETA ZINC-BINDING, AND MUTAGENESIS OF ARG-676; TYR-681 AND HIS-684.
RX   PubMed=10413512; DOI=10.1021/bi990205o;
RA   Liu S.T., Howlett G., Barrow C.J.;
RT   "Histidine-13 is a crucial residue in the zinc ion-induced aggregation of
RT   the A beta peptide of Alzheimer's disease.";
RL   Biochemistry 38:9373-9378(1999).
RN   [56]
RP   PROTEOLYTIC CLEAVAGE AT ASP-197; ASP-219 AND ASP-739 BY CASPASES, AND
RP   MUTAGENESIS OF ASP-739.
RX   PubMed=10319819; DOI=10.1016/s0092-8674(00)80748-5;
RA   Gervais F.G., Xu D., Robertson G.S., Vaillancourt J.P., Zhu Y., Huang J.,
RA   LeBlanc A., Smith D., Rigby M., Shearman M.S., Clarke E.E., Zheng H.,
RA   van der Ploeg L.H.T., Ruffolo S.C., Thornberry N.A., Xanthoudakis S.,
RA   Zamboni R.J., Roy S., Nicholson D.W.;
RT   "Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-
RT   beta precursor protein and amyloidogenic A beta peptide formation.";
RL   Cell 97:395-406(1999).
RN   [57]
RP   IMPORTANCE OF MET-706 IN FREE RADICAL OXIDATIVE STRESS, AND MUTAGENESIS OF
RP   MET-706.
RX   PubMed=10535332; DOI=10.1016/s0361-9230(99)00093-3;
RA   Varadarajan S., Yatin S., Kanski J., Jahanshahi F., Butterfield D.A.;
RT   "Methionine residue 35 is important in amyloid beta-peptide-associated free
RT   radical oxidative stress.";
RL   Brain Res. Bull. 50:133-141(1999).
RN   [58]
RP   SUBCELLULAR LOCATION, PHOSPHORYLATION, AND MUTAGENESIS OF THR-743.
RX   PubMed=10341243; DOI=10.1523/jneurosci.19-11-04421.1999;
RA   Ando K., Oishi M., Takeda S., Iijima K., Isohara T., Nairn A.C., Kirino Y.,
RA   Greengard P., Suzuki T.;
RT   "Role of phosphorylation of Alzheimer's amyloid precursor protein during
RT   neuronal differentiation.";
RL   J. Neurosci. 19:4421-4427(1999).
RN   [59]
RP   INTERACTION WITH APBA2.
RX   PubMed=9890987; DOI=10.1074/jbc.274.4.2243;
RA   Tomita S., Ozaki T., Taru H., Oguchi S., Takeda S., Yagi Y., Sakiyama S.,
RA   Kirino Y., Suzuki T.;
RT   "Interaction of a neuron-specific protein containing PDZ domains with
RT   Alzheimer's amyloid precursor protein.";
RL   J. Biol. Chem. 274:2243-2254(1999).
RN   [60]
RP   SUBCELLULAR LOCATION, ENDOCYTOSIS SIGNAL, AND MUTAGENESIS OF TYR-728;
RP   GLY-756; TYR-757; ASN-759; PRO-760 AND TYR-762.
RX   PubMed=10383380; DOI=10.1074/jbc.274.27.18851;
RA   Perez R.G., Soriano S., Hayes J.D., Ostaszewski B., Xia W., Selkoe D.J.,
RA   Chen X., Stokin G.B., Koo E.H.;
RT   "Mutagenesis identifies new signals for beta-amyloid precursor protein
RT   endocytosis, turnover, and the generation of secreted fragments, including
RT   Abeta42.";
RL   J. Biol. Chem. 274:18851-18856(1999).
RN   [61]
RP   IMPORTANCE OF CYS-144 IN COPPER REDUCTION, AND MUTAGENESIS OF CYS-144 AND
RP   147-HIS--HIS-149.
RX   PubMed=10461923; DOI=10.1046/j.1471-4159.1999.0731288.x;
RA   Ruiz F.H., Gonzalez M., Bodini M., Opazo C., Inestrosa N.C.;
RT   "Cysteine 144 is a key residue in the copper reduction by the beta-amyloid
RT   precursor protein.";
RL   J. Neurochem. 73:1288-1292(1999).
RN   [62]
RP   CLEAVAGE BY BACE1, SUBCELLULAR LOCATION (SOLUBLE APP-BETA), AND
RP   CHARACTERIZATION OF VARIANT AD1 670-LYS-MET-671 DELINS ASN-LEU.
RX   PubMed=10656250; DOI=10.1006/mcne.1999.0811;
RA   Hussain I., Powell D.J., Howlett D.R., Tew D.G., Meek T.D., Chapman C.,
RA   Gloger I.S., Murphy K.E., Southan C.D., Ryan D.M., Smith T.S.,
RA   Simmons D.L., Walsh F.S., Dingwall C., Christie G.;
RT   "Identification of a novel aspartic proteinase (Asp 2) as beta-secretase.";
RL   Mol. Cell. Neurosci. 14:419-427(1999).
RN   [63]
RP   INTERACTION WITH APBB3.
RX   PubMed=10081969; DOI=10.1016/s0304-3940(98)00995-1;
RA   Tanahashi H.;
RT   "Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's
RT   beta-amyloid precursor protein.";
RL   Neurosci. Lett. 261:143-146(1999).
RN   [64]
RP   INTERACTION OF AMYLOID-BETA WITH APOE.
RX   PubMed=10816430; DOI=10.1042/bj3480359;
RA   Tokuda T., Calero M., Matsubara E., Vidal R., Kumar A., Permanne B.,
RA   Zlokovic B., Smith J.D., Ladu M.J., Rostagno A., Frangione B., Ghiso J.;
RT   "Lipidation of apolipoprotein E influences its isoform-specific interaction
RT   with Alzheimer's amyloid beta peptides.";
RL   Biochem. J. 348:359-365(2000).
RN   [65]
RP   INTERACTION OF APP42-BETA WITH CHRNA7.
RX   PubMed=10681545; DOI=10.1074/jbc.275.8.5626;
RA   Wang H.-Y., Lee D.H.S., D'Andrea M.R., Peterson P.A., Shank R.P.,
RA   Reitz A.B.;
RT   "Beta-amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with
RT   high affinity. Implications for Alzheimer's disease pathology.";
RL   J. Biol. Chem. 275:5626-5632(2000).
RN   [66]
RP   IDENTIFICATION OF GAMMA-CTFS BY MASS SPECTROMETRY, MUTAGENESIS OF ASP-739,
RP   AND PROTEOLYTIC CLEAVAGE.
RX   PubMed=12214090; DOI=10.3233/jad-2000-23-408;
RA   Passer B., Pellegrini L., Russo C., Siegel R.M., Lenardo M.J.,
RA   Schettini G., Bachmann M., Tabaton M., D'Adamio L.;
RT   "Generation of an apoptotic intracellular peptide by gamma-secretase
RT   cleavage of Alzheimer's amyloid beta protein precursor.";
RL   J. Alzheimers Dis. 2:289-301(2000).
RN   [67]
RP   REVIEW ON FUNCTION OF AMYLOID-BETA AS ANTIOXIDANT.
RX   PubMed=11775062; DOI=10.1023/a:1012629603390;
RA   Kontush A.;
RT   "Alzheimer's amyloid-beta as a preventive antioxidant for brain
RT   lipoproteins.";
RL   Cell. Mol. Neurobiol. 21:299-315(2001).
RN   [68]
RP   INTERACTION WITH FPR2 (AMYLOID-BETA PROTEIN 42), AND SUBCELLULAR LOCATION
RP   (AMYLOID-BETA PROTEIN 42).
RX   PubMed=11689470; DOI=10.1096/fj.01-0251com;
RA   Yazawa H., Yu Z.-X., Takeda K., Le Y., Gong W., Ferrans V.J.,
RA   Oppenheim J.J., Li C.C.H., Wang J.M.;
RT   "Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled
RT   receptor FPRL1 and forms fibrillar aggregates in macrophages.";
RL   FASEB J. 15:2454-2462(2001).
RN   [69]
RP   INTERACTION WITH BBP.
RX   PubMed=11278849; DOI=10.1074/jbc.m011161200;
RA   Kajkowski E.M., Lo C.F., Ning X., Walker S., Sofia H.J., Wang W., Edris W.,
RA   Chanda P., Wagner E., Vile S., Ryan K., McHendry-Rinde B., Smith S.C.,
RA   Wood A., Rhodes K.J., Kennedy J.D., Bard J., Jacobsen J.S.,
RA   Ozenberger B.A.;
RT   "Beta-amyloid peptide-induced apoptosis regulated by a novel protein
RT   containing a G protein activation module.";
RL   J. Biol. Chem. 276:18748-18756(2001).
RN   [70]
RP   AMYLOID-BETA COPPER AND ZINC-BINDING SITES.
RX   PubMed=11274207; DOI=10.1074/jbc.m100175200;
RA   Curtain C.C., Ali F., Volitakis I., Cherny R.A., Norton R.S.,
RA   Beyreuther K., Barrow C.J., Masters C.L., Bush A.I., Barnham K.J.;
RT   "Alzheimer's disease amyloid-beta binds copper and zinc to generate an
RT   allosterically ordered structure containing superoxide dismutase-like
RT   subunits.";
RL   J. Biol. Chem. 276:20466-20473(2001).
RN   [71]
RP   SUBUNIT.
RX   PubMed=11438549; DOI=10.1074/jbc.m105410200;
RA   Scheuermann S., Hambsch B., Hesse L., Stumm J., Schmidt C., Beher D.,
RA   Bayer T.A., Beyreuther K., Multhaup G.;
RT   "Homodimerization of amyloid precursor protein and its implication in the
RT   amyloidogenic pathway of Alzheimer's disease.";
RL   J. Biol. Chem. 276:33923-33929(2001).
RN   [72]
RP   INTERACTION WITH APBB1, FUNCTION, AND SUBCELLULAR LOCATION (GAMMA-SECRETASE
RP   C-TERMINAL FRAGMENT 59).
RX   PubMed=11544248; DOI=10.1074/jbc.c100447200;
RA   Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.;
RT   "The intracellular domain of the beta-amyloid precursor protein is
RT   stabilized by Fe65 and translocates to the nucleus in a notch-like
RT   manner.";
RL   J. Biol. Chem. 276:40288-40292(2001).
RN   [73]
RP   INTERACTION WITH FBLN1.
RX   PubMed=11238726; DOI=10.1046/j.1471-4159.2001.00144.x;
RA   Ohsawa I., Takamura C., Kohsaka S.;
RT   "Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein
RT   and modulates its physiological function.";
RL   J. Neurochem. 76:1411-1420(2001).
RN   [74]
RP   INTERACTION WITH MAPT, AND FUNCTION.
RX   PubMed=11943163; DOI=10.1016/s0014-5793(02)02376-1;
RA   Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J.,
RA   Johnston J.A., Sharma S.K.;
RT   "Direct interaction of soluble human recombinant tau protein with Abeta 1-
RT   42 results in tau aggregation and hyperphosphorylation by tau protein
RT   kinase II.";
RL   FEBS Lett. 514:263-268(2002).
RN   [75]
RP   INTERACTION WITH MAPK8IP1, AND MUTAGENESIS OF TYR-757.
RX   PubMed=11724784; DOI=10.1074/jbc.m108357200;
RA   Scheinfeld M.H., Roncarati R., Vito P., Lopez P.A., Abdallah M.,
RA   D'Adamio L.;
RT   "Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the
RT   cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein
RT   (APP).";
RL   J. Biol. Chem. 277:3767-3775(2002).
RN   [76]
RP   COPPER-MEDIATED LIPID PEROXIDATION, AND MUTAGENESIS OF HIS-147 AND HIS-151.
RX   PubMed=11784781; DOI=10.1523/jneurosci.22-02-00365.2002;
RA   White A.R., Multhaup G., Galatis D., McKinstry W.J., Parker M.W.,
RA   Pipkorn R., Beyreuther K., Masters C.L., Cappai R.;
RT   "Contrasting species-dependent modulation of copper-mediated neurotoxicity
RT   by the Alzheimer's disease amyloid precursor protein.";
RL   J. Neurosci. 22:365-376(2002).
RN   [77]
RP   REVIEW ON ZINC-BINDING.
RX   PubMed=12032279; DOI=10.1073/pnas.122249699;
RA   Bush A.I., Tanzi R.E.;
RT   "The galvanization of beta-amyloid in Alzheimer's disease.";
RL   Proc. Natl. Acad. Sci. U.S.A. 99:7317-7319(2002).
RN   [78]
RP   PHOSPHORYLATION AT SER-198 AND SER-206 BY CASEIN KINASES, AND MUTAGENESIS
RP   OF SER-198 AND SER-206.
RX   PubMed=8999878; DOI=10.1074/jbc.272.3.1896;
RA   Walter J., Capell A., Hung A.Y., Langen H., Schnoelzer M., Thinakaran G.,
RA   Sisodia S.S., Selkoe D.J., Haass C.;
RT   "Ectodomain phosphorylation of beta-amyloid precursor protein at two
RT   distinct cellular locations.";
RL   J. Biol. Chem. 272:1896-1903(1997).
RN   [79]
RP   CHARACTERIZATION OF CASEIN KINASE PHOSPHORYLATION, AND MUTAGENESIS OF
RP   SER-198 AND SER-206.
RX   PubMed=10806211; DOI=10.1074/jbc.m002850200;
RA   Walter J., Schindzielorz A., Hartung B., Haass C.;
RT   "Phosphorylation of the beta-amyloid precursor protein at the cell surface
RT   by ectocasein kinases 1 and 2.";
RL   J. Biol. Chem. 275:23523-23529(2000).
RN   [80]
RP   PROTEOLYTIC CLEAVAGE BY CASPASES, AND MUTAGENESIS OF ASP-739.
RX   PubMed=10742146; DOI=10.1038/74656;
RA   Lu D.C., Rabizadeh S., Chandra S., Shayya R.F., Ellerby L.M., Ye X.,
RA   Salvesen G.S., Koo E.H., Bredesen D.E.;
RT   "A second cytotoxic proteolytic peptide derived from amyloid beta-protein
RT   precursor.";
RL   Nat. Med. 6:397-404(2000).
RN   [81]
RP   PHOSPHORYLATION, INTERACTION WITH APBB1, AND MUTAGENESIS OF THR-743.
RX   PubMed=11517218; DOI=10.1074/jbc.m104059200;
RA   Ando K., Iijima K., Elliott J.I., Kirino Y., Suzuki T.;
RT   "Phosphorylation-dependent regulation of the interaction of amyloid
RT   precursor protein with Fe65 affects the production of beta-amyloid.";
RL   J. Biol. Chem. 276:40353-40361(2001).
RN   [82]
RP   PROTEOLYTIC CLEAVAGE (AMYLOID-BETA PROTEIN 40 AND AMYLOID-BETA PROTEIN 42).
RX   PubMed=11604391; DOI=10.1074/jbc.m104068200;
RA   Hu J., Igarashi A., Kamata M., Nakagawa H.;
RT   "Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A
RT   beta); retards A beta aggregation, deposition, fibril formation; and
RT   inhibits cytotoxicity.";
RL   J. Biol. Chem. 276:47863-47868(2001).
RN   [83]
RP   PHOSPHORYLATION BY MAPK10, AND MUTAGENESIS OF THR-743.
RX   PubMed=11146006; DOI=10.1046/j.1471-4159.2001.00102.x;
RA   Standen C.L., Brownlees J., Grierson A.J., Kesavapany S., Lau K.-F.,
RA   McLoughlin D.M., Miller C.C.J.;
RT   "Phosphorylation of thr(668) in the cytoplasmic domain of the Alzheimer's
RT   disease amyloid precursor protein by stress-activated protein kinase 1b
RT   (Jun N-terminal kinase-3).";
RL   J. Neurochem. 76:316-320(2001).
RN   [84]
RP   PROTEOLYTIC CLEAVAGE AT MET-671; LYS-687; VAL-711; ALA-713 AND LEU-720.
RX   PubMed=11851430; DOI=10.1021/bi015794o;
RA   Weidemann A., Eggert S., Reinhard F.B.M., Vogel M., Paliga K., Baier G.,
RA   Masters C.L., Beyreuther K., Evin G.;
RT   "A novel epsilon-cleavage within the transmembrane domain of the Alzheimer
RT   amyloid precursor protein demonstrates homology with Notch processing.";
RL   Biochemistry 41:2825-2835(2002).
RN   [85]
RP   PHOSPHORYLATION AT TYR-757, INTERACTION WITH SHC1, AND MUTAGENESIS OF
RP   THR-743 AND TYR-757.
RX   PubMed=11877420; DOI=10.1074/jbc.m110286200;
RA   Tarr P.E., Roncarati R., Pelicci G., Pelicci P.G., D'Adamio L.;
RT   "Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic
RT   tail promotes interaction with Shc.";
RL   J. Biol. Chem. 277:16798-16804(2002).
RN   [86]
RP   REVIEW.
RX   PubMed=12142279; DOI=10.1146/annurev.cellbio.18.020402.142302;
RA   Annaert W., De Strooper B.;
RT   "A cell biological perspective on Alzheimer's disease.";
RL   Annu. Rev. Cell Dev. Biol. 18:25-51(2002).
RN   [87]
RP   INTERACTION WITH APBB2.
RX   PubMed=14527950; DOI=10.1074/jbc.m309561200;
RA   Chang Y., Tesco G., Jeong W.J., Lindsley L., Eckman E.A., Eckman C.B.,
RA   Tanzi R.E., Guenette S.Y.;
RT   "Generation of the beta-amyloid peptide and the amyloid precursor protein
RT   C-terminal fragment gamma are potentiated by FE65L1.";
RL   J. Biol. Chem. 278:51100-51107(2003).
RN   [88]
RP   SUBCELLULAR LOCATION, AND ASSOCIATION OF AMYLOID FIBRILS WITH GCP1.
RX   PubMed=15084524; DOI=10.1096/fj.03-1040fje;
RA   Watanabe N., Araki W., Chui D.H., Makifuchi T., Ihara Y., Tabira T.;
RT   "Glypican-1 as an Abeta binding HSPG in the human brain: its localization
RT   in DIG domains and possible roles in the pathogenesis of Alzheimer's
RT   disease.";
RL   FASEB J. 18:1013-1015(2004).
RN   [89]
RP   INTERACTION WITH ANKS1B.
RX   PubMed=15347684; DOI=10.1074/jbc.m405329200;
RA   Ghersi E., Noviello C., D'Adamio L.;
RT   "Amyloid-beta protein precursor (AbetaPP) intracellular domain-associated
RT   protein-1 proteins bind to AbetaPP and modulate its processing in an
RT   isoform-specific manner.";
RL   J. Biol. Chem. 279:49105-49112(2004).
RN   [90]
RP   PROTEOLYTIC CLEAVAGE (AMYLOID-BETA PROTEIN 40 AND AMYLOID-BETA PROTEIN 42),
RP   AND SUBCELLULAR LOCATION (AMYLOID-BETA PROTEIN 40 AND AMYLOID-BETA PROTEIN
RP   42).
RX   PubMed=16154999; DOI=10.1074/jbc.m508460200;
RA   Hemming M.L., Selkoe D.J.;
RT   "Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme
RT   (ACE) and elevated by an ACE inhibitor.";
RL   J. Biol. Chem. 280:37644-37650(2005).
RN   [91]
RP   GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-542.
RC   TISSUE=Plasma;
RX   PubMed=16335952; DOI=10.1021/pr0502065;
RA   Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA   Smith R.D.;
RT   "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT   hydrazide chemistry, and mass spectrometry.";
RL   J. Proteome Res. 4:2070-2080(2005).
RN   [92]
RP   INTERACTION WITH SORL1, AND SUBCELLULAR LOCATION.
RX   PubMed=16174740; DOI=10.1073/pnas.0503689102;
RA   Andersen O.M., Reiche J., Schmidt V., Gotthardt M., Spoelgen R., Behlke J.,
RA   von Arnim C.A., Breiderhoff T., Jansen P., Wu X., Bales K.R., Cappai R.,
RA   Masters C.L., Gliemann J., Mufson E.J., Hyman B.T., Paul S.M., Nykjaer A.,
RA   Willnow T.E.;
RT   "Neuronal sorting protein-related receptor sorLA/LR11 regulates processing
RT   of the amyloid precursor protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 102:13461-13466(2005).
RN   [93]
RP   INTERACTION WITH SORL1, AND MUTAGENESIS OF 757-TYR--TYR-762.
RX   PubMed=16407538; DOI=10.1523/jneurosci.3882-05.2006;
RA   Spoelgen R., von Arnim C.A., Thomas A.V., Peltan I.D., Koker M., Deng A.,
RA   Irizarry M.C., Andersen O.M., Willnow T.E., Hyman B.T.;
RT   "Interaction of the cytosolic domains of sorLA/LR11 with the amyloid
RT   precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.";
RL   J. Neurosci. 26:418-428(2006).
RN   [94]
RP   FUNCTION.
RX   PubMed=17062754; DOI=10.1073/pnas.0607527103;
RA   Satpute-Krishnan P., DeGiorgis J.A., Conley M.P., Jang M., Bearer E.L.;
RT   "A peptide zipcode sufficient for anterograde transport within amyloid
RT   precursor protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:16532-16537(2006).
RN   [95]
RP   INTERACTION WITH SORL1.
RX   PubMed=17855360; DOI=10.1074/jbc.m705073200;
RA   Schmidt V., Sporbert A., Rohe M., Reimer T., Rehm A., Andersen O.M.,
RA   Willnow T.E.;
RT   "SorLA/LR11 regulates processing of amyloid precursor protein via
RT   interaction with adaptors GGA and PACS-1.";
RL   J. Biol. Chem. 282:32956-32964(2007).
RN   [96]
RP   INTERACTION WITH APBB1.
RX   PubMed=18468999; DOI=10.1074/jbc.m801827200;
RA   Nakaya T., Kawai T., Suzuki T.;
RT   "Regulation of FE65 nuclear translocation and function by amyloid beta-
RT   protein precursor in osmotically stressed cells.";
RL   J. Biol. Chem. 283:19119-19131(2008).
RN   [97]
RP   INTERACTION WITH ITM2C.
RX   PubMed=19366692; DOI=10.1074/jbc.m109.006403;
RA   Matsuda S., Matsuda Y., D'Adamio L.;
RT   "BRI3 inhibits amyloid precursor protein processing in a mechanistically
RT   distinct manner from its homologue dementia gene BRI2.";
RL   J. Biol. Chem. 284:15815-15825(2009).
RN   [98]
RP   RETRACTED PAPER.
RX   PubMed=19225519; DOI=10.1038/nature07767;
RA   Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.;
RT   "APP binds DR6 to trigger axon pruning and neuron death via distinct
RT   caspases.";
RL   Nature 457:981-989(2009).
RN   [99]
RP   CAUTION, AND RETRACTION NOTICE OF PUBMED:19225519.
RX   PubMed=38110576; DOI=10.1038/s41586-023-06943-3;
RA   Nikolaev A., McLaughlin T., O'Leary D.D.M., Tessier-Lavigne M.;
RT   "Retraction Note: APP binds DR6 to trigger axon pruning and neuron death
RT   via distinct caspases.";
RL   Nature 625:204-204(2024).
RN   [100]
RP   FUNCTION, AND INTERACTION WITH AGER.
RX   PubMed=19901339; DOI=10.1073/pnas.0905686106;
RA   Takuma K., Fang F., Zhang W., Yan S., Fukuzaki E., Du H., Sosunov A.,
RA   McKhann G., Funatsu Y., Nakamichi N., Nagai T., Mizoguchi H., Ibi D.,
RA   Hori O., Ogawa S., Stern D.M., Yamada K., Yan S.S.;
RT   "RAGE-mediated signaling contributes to intraneuronal transport of
RT   amyloid-{beta} and neuronal dysfunction.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:20021-20026(2009).
RN   [101]
RP   SUBCELLULAR LOCATION.
RX   PubMed=20580937; DOI=10.1016/j.bbalip.2010.05.010;
RA   Cossec J.C., Simon A., Marquer C., Moldrich R.X., Leterrier C., Rossier J.,
RA   Duyckaerts C., Lenkei Z., Potier M.C.;
RT   "Clathrin-dependent APP endocytosis and Abeta secretion are highly
RT   sensitive to the level of plasma membrane cholesterol.";
RL   Biochim. Biophys. Acta 1801:846-852(2010).
RN   [102]
RP   INTERACTION WITH GSAP.
RX   PubMed=20811458; DOI=10.1038/nature09325;
RA   He G., Luo W., Li P., Remmers C., Netzer W.J., Hendrick J., Bettayeb K.,
RA   Flajolet M., Gorelick F., Wennogle L.P., Greengard P.;
RT   "Gamma-secretase activating protein is a therapeutic target for Alzheimer's
RT   disease.";
RL   Nature 467:95-98(2010).
RN   [103]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [104]
RP   GLYCOSYLATION AT THR-633; THR-651; THR-652; SER-656; THR-663 AND SER-667
RP   PROTEOLYTIC PROCESSING, STRUCTURE OF CARBOHYDRATES, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY.
RX   PubMed=21712440; DOI=10.1073/pnas.1102664108;
RA   Halim A., Brinkmalm G., Ruetschi U., Westman-Brinkmalm A., Portelius E.,
RA   Zetterberg H., Blennow K., Larson G., Nilsson J.;
RT   "Site-specific characterization of threonine, serine, and tyrosine
RT   glycosylations of amyloid precursor protein/amyloid beta-peptides in human
RT   cerebrospinal fluid.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:11848-11853(2011).
RN   [105]
RP   FUNCTION, AND INTERACTION WITH KIF5B.
RX   PubMed=23011729; DOI=10.1088/1478-3975/9/5/055005;
RA   Seamster P.E., Loewenberg M., Pascal J., Chauviere A., Gonzales A.,
RA   Cristini V., Bearer E.L.;
RT   "Quantitative measurements and modeling of cargo-motor interactions during
RT   fast transport in the living axon.";
RL   Phys. Biol. 9:055005-055005(2012).
RN   [106]
RP   INTERACTION WITH S100A9.
RX   PubMed=22457725; DOI=10.1371/journal.pone.0032953;
RA   Zhang C., Liu Y., Gilthorpe J., van der Maarel J.R.;
RT   "MRP14 (S100A9) protein interacts with Alzheimer beta-amyloid peptide and
RT   induces its fibrillization.";
RL   PLoS ONE 7:E32953-E32953(2012).
RN   [107]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-743, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [108]
RP   INTERACTION WITH PLD3.
RX   PubMed=24336208; DOI=10.1038/nature12825;
RG   UK Brain Expression Consortium;
RA   Cruchaga C., Karch C.M., Jin S.C., Benitez B.A., Cai Y., Guerreiro R.,
RA   Harari O., Norton J., Budde J., Bertelsen S., Jeng A.T., Cooper B.,
RA   Skorupa T., Carrell D., Levitch D., Hsu S., Choi J., Ryten M., Hardy J.,
RA   Ryten M., Trabzuni D., Weale M.E., Ramasamy A., Smith C., Sassi C.,
RA   Bras J., Gibbs J.R., Hernandez D.G., Lupton M.K., Powell J., Forabosco P.,
RA   Ridge P.G., Corcoran C.D., Tschanz J.T., Norton M.C., Munger R.G.,
RA   Schmutz C., Leary M., Demirci F.Y., Bamne M.N., Wang X., Lopez O.L.,
RA   Ganguli M., Medway C., Turton J., Lord J., Braae A., Barber I., Brown K.,
RA   Passmore P., Craig D., Johnston J., McGuinness B., Todd S., Heun R.,
RA   Kolsch H., Kehoe P.G., Hooper N.M., Vardy E.R., Mann D.M.,
RA   Pickering-Brown S., Brown K., Kalsheker N., Lowe J., Morgan K.,
RA   David Smith A., Wilcock G., Warden D., Holmes C., Pastor P.,
RA   Lorenzo-Betancor O., Brkanac Z., Scott E., Topol E., Morgan K., Rogaeva E.,
RA   Singleton A.B., Hardy J., Kamboh M.I., St George-Hyslop P., Cairns N.,
RA   Morris J.C., Kauwe J.S., Goate A.M.;
RT   "Rare coding variants in the phospholipase D3 gene confer risk for
RT   Alzheimer's disease.";
RL   Nature 505:550-554(2014).
RN   [109]
RP   INTERACTION WITH VDAC1.
RX   PubMed=25168729; DOI=10.1016/j.neuroscience.2014.07.079;
RA   Fernandez-Echevarria C., Diaz M., Ferrer I., Canerina-Amaro A., Marin R.;
RT   "Abeta promotes VDAC1 channel dephosphorylation in neuronal lipid rafts.
RT   Relevance to the mechanisms of neurotoxicity in Alzheimer's disease.";
RL   Neuroscience 278:354-366(2014).
RN   [110]
RP   INTERACTION WITH SORL1.
RX   PubMed=24523320; DOI=10.1126/scitranslmed.3007747;
RA   Caglayan S., Takagi-Niidome S., Liao F., Carlo A.S., Schmidt V.,
RA   Burgert T., Kitago Y., Fuechtbauer E.M., Fuechtbauer A., Holtzman D.M.,
RA   Takagi J., Willnow T.E.;
RT   "Lysosomal sorting of amyloid-beta by the SORLA receptor is impaired by a
RT   familial Alzheimer's disease mutation.";
RL   Sci. Transl. Med. 6:223RA20-223RA20(2014).
RN   [111]
RP   PHOSPHORYLATION AT SER-441 AND TYR-497.
RX   PubMed=26091039; DOI=10.1016/j.cell.2015.05.028;
RA   Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J.,
RA   Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N.,
RA   Pinna L.A., Pagliarini D.J., Dixon J.E.;
RT   "A single kinase generates the majority of the secreted phosphoproteome.";
RL   Cell 161:1619-1632(2015).
RN   [112]
RP   INTERACTION WITH LRRK2, PHOSPHORYLATION AT THR-743, AND MUTAGENESIS OF
RP   THR-743.
RX   PubMed=28720718; DOI=10.1126/scisignal.aam6790;
RA   Chen Z.C., Zhang W., Chua L.L., Chai C., Li R., Lin L., Cao Z.,
RA   Angeles D.C., Stanton L.W., Peng J.H., Zhou Z.D., Lim K.L., Zeng L.,
RA   Tan E.K.;
RT   "Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD
RT   activity and neurotoxicity in Parkinson's disease.";
RL   Sci. Signal. 10:0-0(2017).
RN   [113]
RP   X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 287-344.
RX   PubMed=2125487; DOI=10.1021/bi00495a002;
RA   Hynes T.R., Randal M., Kennedy L.A., Eigenbrot C., Kossiakof A.A.;
RT   "X-ray crystal structure of the protease inhibitor domain of Alzheimer's
RT   amyloid beta-protein precursor.";
RL   Biochemistry 29:10018-10022(1990).
RN   [114]
RP   STRUCTURE BY NMR OF 289-344.
RX   PubMed=1718421; DOI=10.1021/bi00107a015;
RA   Heald S.L., Tilton R.F. Jr., Hammond L.S., Lee A., Bayney R.M.,
RA   Kamarck M.E., Ramabhadran T.V., Dreyer R.N., Davis G., Unterbeck A.,
RA   Tamburini P.P.;
RT   "Sequential NMR resonance assignment and structure determination of the
RT   Kunitz-type inhibitor domain of the Alzheimer's beta-amyloid precursor
RT   protein.";
RL   Biochemistry 30:10467-10478(1991).
RN   [115]
RP   STRUCTURE BY NMR OF 672-699.
RX   PubMed=7516706; DOI=10.1021/bi00191a006;
RA   Talafous J., Marcinowski K.J., Klopman G., Zagorski M.G.;
RT   "Solution structure of residues 1-28 of the amyloid beta-peptide.";
RL   Biochemistry 33:7788-7796(1994).
RN   [116]
RP   STRUCTURE BY NMR OF 672-711.
RX   PubMed=7588758; DOI=10.1111/j.1432-1033.1995.293_1.x;
RA   Sticht H., Bayer P., Willbold D., Dames S., Hilbich C., Beyreuther K.,
RA   Frank R.W., Rosch P.;
RT   "Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease.";
RL   Eur. J. Biochem. 233:293-298(1995).
RN   [117]
RP   STRUCTURE BY NMR OF 696-706.
RX   PubMed=8973180; DOI=10.1021/bi961598j;
RA   Kohno T., Kobayashi K., Maeda T., Sato K., Takashima A.;
RT   "Three-dimensional structures of the amyloid beta peptide (25-35) in
RT   membrane-mimicking environment.";
RL   Biochemistry 35:16094-16104(1996).
RN   [118]
RP   X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF KUNITZ DOMAIN IN COMPLEX WITH
RP   CHYMOTRYPSIN; TRYPSIN AND BASIC PANCREATIC TRYPSIN INHIBITOR.
RX   PubMed=9300481; DOI=10.1002/pro.5560060902;
RA   Scheidig A.J., Hynes T.R., Pelletier L.A., Wells J.A., Kossiakoff A.A.;
RT   "Crystal structures of bovine chymotrypsin and trypsin complexed to the
RT   inhibitor domain of Alzheimer's amyloid beta-protein precursor (APPI) and
RT   basic pancreatic trypsin inhibitor (BPTI): engineering of inhibitors with
RT   altered specificities.";
RL   Protein Sci. 6:1806-1824(1997).
RN   [119]
RP   STRUCTURE BY NMR OF 672-711.
RX   PubMed=9693002; DOI=10.1021/bi972979f;
RA   Coles M., Bicknell W., Watson A.A., Fairlie D.P., Craik D.J.;
RT   "Solution structure of amyloid beta-peptide(1-40) in a water-micelle
RT   environment. Is the membrane-spanning domain where we think it is?";
RL   Biochemistry 37:11064-11077(1998).
RN   [120]
RP   X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 28-123.
RX   PubMed=10201399; DOI=10.1038/7562;
RA   Rossjohn J., Cappai R., Feil S.C., Henry A., McKinstry W.J., Galatis D.,
RA   Hesse L., Multhaup G., Beyreuther K., Masters C.L., Parker M.W.;
RT   "Crystal structure of the N-terminal, growth factor-like domain of
RT   Alzheimer amyloid precursor protein.";
RL   Nat. Struct. Biol. 6:327-331(1999).
RN   [121]
RP   STRUCTURE OF CAA-APP VARIANTS.
RX   PubMed=10821838; DOI=10.1074/jbc.m003154200;
RA   Miravalle L., Tokuda T., Chiarle R., Giaccone G., Bugiani O.,
RA   Tagliavini F., Frangione B., Ghiso J.;
RT   "Substitutions at codon 22 of Alzheimer's Abeta peptide induce diverse
RT   conformational changes and apoptotic effects in human cerebral endothelial
RT   cells.";
RL   J. Biol. Chem. 275:27110-27116(2000).
RN   [122]
RP   STRUCTURE BY NMR OF 681-706.
RX   PubMed=10940221; DOI=10.1006/jsbi.2000.4288;
RA   Zhang S., Iwata K., Lachenmann M.J., Peng J.W., Li S., Stimson E.R., Lu Y.,
RA   Felix A.M., Maggio J.E., Lee J.P.;
RT   "The Alzheimer's peptide a beta adopts a collapsed coil structure in
RT   water.";
RL   J. Struct. Biol. 130:130-141(2000).
RN   [123]
RP   STRUCTURE BY NMR OF 672-699.
RX   PubMed=10940222; DOI=10.1006/jsbi.2000.4267;
RA   Poulsen S.-A., Watson A.A., Craik D.J.;
RT   "Solution structures in aqueous SDS micelles of two amyloid beta peptides
RT   of Abeta(1-28) mutated at the alpha-secretase cleavage site.";
RL   J. Struct. Biol. 130:142-152(2000).
RN   [124] {ECO:0007744|PDB:1OWT}
RP   STRUCTURE BY NMR OF 124-189, DISULFIDE BONDS, AND COPPER-BINDING SITES.
RX   PubMed=12611883; DOI=10.1074/jbc.m300629200;
RA   Barnham K.J., McKinstry W.J., Multhaup G., Galatis D., Morton C.J.,
RA   Curtain C.C., Williamson N.A., White A.R., Hinds M.G., Norton R.S.,
RA   Beyreuther K., Masters C.L., Parker M.W., Cappai R.;
RT   "Structure of the Alzheimer's disease amyloid precursor protein copper
RT   binding domain. A regulator of neuronal copper homeostasis.";
RL   J. Biol. Chem. 278:17401-17407(2003).
RN   [125]
RP   X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 346-551, PARTIAL PROTEIN SEQUENCE,
RP   MUTAGENESIS OF ARG-499 AND LYS-503, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RX   PubMed=15304215; DOI=10.1016/j.molcel.2004.06.037;
RA   Wang Y., Ha Y.;
RT   "The X-ray structure of an antiparallel dimer of the human amyloid
RT   precursor protein E2 domain.";
RL   Mol. Cell 15:343-353(2004).
RN   [126]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 672-711 IN COMPLEX WITH IDE.
RX   PubMed=17051221; DOI=10.1038/nature05143;
RA   Shen Y., Joachimiak A., Rosner M.R., Tang W.-J.;
RT   "Structures of human insulin-degrading enzyme reveal a new substrate
RT   recognition mechanism.";
RL   Nature 443:870-874(2006).
RN   [127]
RP   X-RAY CRYSTALLOGRAPHY (0.85 ANGSTROMS) OF 133-189, AND DISULFIDE BONDS.
RX   PubMed=17909280; DOI=10.1107/s1744309107041139;
RA   Kong G.K., Adams J.J., Cappai R., Parker M.W.;
RT   "Structure of Alzheimer's disease amyloid precursor protein copper-binding
RT   domain at atomic resolution.";
RL   Acta Crystallogr. F 63:819-824(2007).
RN   [128] {ECO:0007744|PDB:2FJZ, ECO:0007744|PDB:2FK1, ECO:0007744|PDB:2FK2, ECO:0007744|PDB:2FK3, ECO:0007744|PDB:2FKL}
RP   X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 133-189 IN COMPLEXES WITH COPPER
RP   IONS, AND DISULFIDE BONDS.
RX   PubMed=17239395; DOI=10.1016/j.jmb.2006.12.041;
RA   Kong G.K., Adams J.J., Harris H.H., Boas J.F., Curtain C.C., Galatis D.,
RA   Masters C.L., Barnham K.J., McKinstry W.J., Cappai R., Parker M.W.;
RT   "Structural studies of the Alzheimer's amyloid precursor protein copper-
RT   binding domain reveal how it binds copper ions.";
RL   J. Mol. Biol. 367:148-161(2007).
RN   [129]
RP   X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 672-679 IN COMPLEX WITH IGG.
RX   PubMed=17895381; DOI=10.1073/pnas.0705888104;
RA   Gardberg A.S., Dice L.T., Ou S., Rich R.L., Helmbrecht E., Ko J.,
RA   Wetzel R., Myszka D.G., Patterson P.H., Dealwis C.;
RT   "Molecular basis for passive immunotherapy of Alzheimer's disease.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:15659-15664(2007).
RN   [130]
RP   X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 672-678 IN COMPLEXES WITH
RP   ANTIBODY FAB FRAGMENTS.
RX   PubMed=19923222; DOI=10.1074/jbc.m109.045187;
RA   Basi G.S., Feinberg H., Oshidari F., Anderson J., Barbour R., Baker J.,
RA   Comery T.A., Diep L., Gill D., Johnson-Wood K., Goel A., Grantcharova K.,
RA   Lee M., Li J., Partridge A., Griswold-Prenner I., Piot N., Walker D.,
RA   Widom A., Pangalos M.N., Seubert P., Jacobsen J.S., Schenk D., Weis W.I.;
RT   "Structural correlates of antibodies associated with acute reversal of
RT   amyloid beta-related behavioral deficits in a mouse model of Alzheimer
RT   disease.";
RL   J. Biol. Chem. 285:3417-3427(2010).
RN   [131]
RP   X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 18-190, PARTIAL PROTEIN SEQUENCE,
RP   SUBUNIT, DISULFIDE BONDS, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=20212142; DOI=10.1073/pnas.0911326107;
RA   Dahms S.O., Hoefgen S., Roeser D., Schlott B., Guhrs K.H., Than M.E.;
RT   "Structure and biochemical analysis of the heparin-induced E1 dimer of the
RT   amyloid precursor protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:5381-5386(2010).
RN   [132] {ECO:0007744|PDB:2LOH}
RP   STRUCTURE BY NMR OF 686-726, AND SUBCELLULAR LOCATION.
RX   PubMed=22584060; DOI=10.1016/j.febslet.2012.04.062;
RA   Nadezhdin K.D., Bocharova O.V., Bocharov E.V., Arseniev A.S.;
RT   "Dimeric structure of transmembrane domain of amyloid precursor protein in
RT   micellar environment.";
RL   FEBS Lett. 586:1687-1692(2012).
RN   [133] {ECO:0007744|PDB:2LP1}
RP   STRUCTURE BY NMR OF 671-770, AND SUBCELLULAR LOCATION.
RX   PubMed=22654059; DOI=10.1126/science.1219988;
RA   Barrett P.J., Song Y., Van Horn W.D., Hustedt E.J., Schafer J.M.,
RA   Hadziselimovic A., Beel A.J., Sanders C.R.;
RT   "The amyloid precursor protein has a flexible transmembrane domain and
RT   binds cholesterol.";
RL   Science 336:1168-1171(2012).
RN   [134] {ECO:0007744|PDB:4JFN}
RP   X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 23-185 IN COMPLEX WITH COPPER,
RP   FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, DOMAIN, DISULFIDE BONDS, AND
RP   MUTAGENESIS OF HIS-108; HIS-110; HIS-147 AND HIS-151.
RX   PubMed=25122912; DOI=10.1523/jneurosci.0180-14.2014;
RA   Baumkotter F., Schmidt N., Vargas C., Schilling S., Weber R., Wagner K.,
RA   Fiedler S., Klug W., Radzimanowski J., Nickolaus S., Keller S., Eggert S.,
RA   Wild K., Kins S.;
RT   "Amyloid precursor protein dimerization and synaptogenic function depend on
RT   copper binding to the growth factor-like domain.";
RL   J. Neurosci. 34:11159-11172(2014).
RN   [135] {ECO:0007744|PDB:2MGT}
RP   STRUCTURE BY NMR OF 672-687, ZINC-BINDING SITES, AND DOMAIN.
RX   PubMed=26898943; DOI=10.1038/srep21734;
RA   Istrate A.N., Kozin S.A., Zhokhov S.S., Mantsyzov A.B., Kechko O.I.,
RA   Pastore A., Makarov A.A., Polshakov V.I.;
RT   "Interplay of histidine residues of the Alzheimer's disease Abeta peptide
RT   governs its Zn-induced oligomerization.";
RL   Sci. Rep. 6:21734-21734(2016).
RN   [136] {ECO:0007744|PDB:5LFY}
RP   STRUCTURE BY NMR OF 672-681, AND DOMAIN.
RX   PubMed=28570778; DOI=10.1002/anie.201704615;
RA   Polshakov V.I., Mantsyzov A.B., Kozin S.A., Adzhubei A.A., Zhokhov S.S.,
RA   van Beek W., Kulikova A.A., Indeykina M.I., Mitkevich V.A., Makarov A.A.;
RT   "A Binuclear Zinc Interaction Fold Discovered in the Homodimer of
RT   Alzheimer's Amyloid-beta Fragment with Taiwanese Mutation D7H.";
RL   Angew. Chem. Int. Ed. Engl. 56:11734-11739(2017).
RN   [137] {ECO:0007744|PDB:5OQV}
RP   STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS) OF 672-713.
RX   PubMed=28882996; DOI=10.1126/science.aao2825;
RA   Gremer L., Scholzel D., Schenk C., Reinartz E., Labahn J., Ravelli R.B.G.,
RA   Tusche M., Lopez-Iglesias C., Hoyer W., Heise H., Willbold D.,
RA   Schroder G.F.;
RT   "Fibril structure of amyloid-beta(1-42) by cryo-electron microscopy.";
RL   Science 358:116-119(2017).
RN   [138] {ECO:0007744|PDB:5VOS}
RP   STRUCTURE BY ELECTRON MICROSCOPY (1.42 ANGSTROMS) OF 695-705.
RX   PubMed=29282295; DOI=10.1074/jbc.m117.806109;
RA   Krotee P., Griner S.L., Sawaya M.R., Cascio D., Rodriguez J.A., Shi D.,
RA   Philipp S., Murray K., Saelices L., Lee J., Seidler P., Glabe C.G.,
RA   Jiang L., Gonen T., Eisenberg D.S.;
RT   "Common fibrillar spines of amyloid-beta and human islet amyloid
RT   polypeptide revealed by microelectron diffraction and structure-based
RT   inhibitors.";
RL   J. Biol. Chem. 293:2888-2902(2018).
RN   [139]
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF 688-770 IN COMPLEX
RP   WITH GAMMA-SECRETASE, INTERACTION WITH PSEN1, SUBUNIT, PROTEOLYTIC CLEAVAGE
RP   BY PSEN1, TOPOLOGY, AND MUTAGENESIS OF VAL-695.
RX   PubMed=30630874; DOI=10.1126/science.aaw0930;
RA   Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.;
RT   "Recognition of the amyloid precursor protein by human gamma-secretase.";
RL   Science 0:0-0(2019).
RN   [140]
RP   REVIEW ON VARIANTS.
RX   PubMed=1363811; DOI=10.1038/ng0792-233;
RA   Hardy J.;
RT   "Framing beta-amyloid.";
RL   Nat. Genet. 1:233-234(1992).
RN   [141]
RP   VARIANT CAA-APP GLN-693.
RX   PubMed=2111584; DOI=10.1126/science.2111584;
RA   Levy E., Carman M.D., Fernandez-Madrid I.J., Power M.D., Lieberburg I.,
RA   van Duinen S.G., Bots G.T.A.M., Luyendijk W., Frangione B.;
RT   "Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral
RT   hemorrhage, Dutch type.";
RL   Science 248:1124-1126(1990).
RN   [142]
RP   VARIANT AD1 ILE-717.
RX   PubMed=1671712; DOI=10.1038/349704a0;
RA   Goate A., Chartier-Harlin M.-C., Mullan M., Brown J., Crawford F.,
RA   Fidani L., Giuffra L., Haynes A., Irving N., James L., Mant R., Newton P.,
RA   Rooke K., Roques P., Talbot C., Pericak-Vance M., Roses A.D.,
RA   Williamson R., Rossor M., Owen M., Hardy J.;
RT   "Segregation of a missense mutation in the amyloid precursor protein gene
RT   with familial Alzheimer's disease.";
RL   Nature 349:704-706(1991).
RN   [143]
RP   VARIANT AD1 ILE-717.
RX   PubMed=1908231; DOI=10.1016/0006-291x(91)91011-z;
RA   Yoshioka K., Miki T., Katsuya T., Ogihara T., Sakaki Y.;
RT   "The 717Val-->Ile substitution in amyloid precursor protein is associated
RT   with familial Alzheimer's disease regardless of ethnic groups.";
RL   Biochem. Biophys. Res. Commun. 178:1141-1146(1991).
RN   [144]
RP   VARIANT AD1 ILE-717.
RX   PubMed=1678058; DOI=10.1016/0140-6736(91)91612-x;
RA   Naruse S., Igarashi S., Kobayashi H., Aoki K., Inuzuka T., Kaneko K.,
RA   Shimizu T., Iihara K., Kojima T., Miyatake T., Tsuji S.;
RT   "Mis-sense mutation Val->Ile in exon 17 of amyloid precursor protein gene
RT   in Japanese familial Alzheimer's disease.";
RL   Lancet 337:978-979(1991).
RN   [145]
RP   VARIANT AD1 GLY-717.
RX   PubMed=1944558; DOI=10.1038/353844a0;
RA   Chartier-Harlin M.-C., Crawford F., Houlden H., Warren A., Hughes D.,
RA   Fidani L., Goate A., Rossor M., Roques P., Hardy J., Mullan M.;
RT   "Early-onset Alzheimer's disease caused by mutations at codon 717 of the
RT   beta-amyloid precursor protein gene.";
RL   Nature 353:844-846(1991).
RN   [146]
RP   VARIANT AD1 PHE-717.
RX   PubMed=1925564; DOI=10.1126/science.1925564;
RA   Murrell J.R., Farlow M., Ghetti B., Benson M.D.;
RT   "A mutation in the amyloid precursor protein associated with hereditary
RT   Alzheimer's disease.";
RL   Science 254:97-99(1991).
RN   [147]
RP   VARIANT AD1 GLY-693.
RX   PubMed=1415269;
RA   Kamino K., Orr H.T., Payami H., Wijsman E.M., Alonso M.E., Pulst S.M.,
RA   Anderson L., O'Dahl S., Nemens E., White J.A., Sadovnick A.D., Ball M.J.,
RA   Kaye J., Warren A., McInnis M.G., Antonarakis S.E., Korenberg J.R.,
RA   Sharma V., Kukull W., Larson E., Heston L.L., Martin G.M., Bird T.D.,
RA   Schellenberg G.D.;
RT   "Linkage and mutational analysis of familial Alzheimer disease kindreds for
RT   the APP gene region.";
RL   Am. J. Hum. Genet. 51:998-1014(1992).
RN   [148]
RP   VARIANT AD1 GLY-692.
RX   PubMed=1303239; DOI=10.1038/ng0692-218;
RA   Hendriks L., van Duijn C.M., Cras P., Cruts M., Van Hul W.,
RA   van Harskamp F., Warren A., McInnis M.G., Antonarakis S.E., Martin J.J.,
RA   Hofman A., Van Broeckhoven C.;
RT   "Presenile dementia and cerebral haemorrhage linked to a mutation at codon
RT   692 of the beta-amyloid precursor protein gene.";
RL   Nat. Genet. 1:218-221(1992).
RN   [149]
RP   VARIANT AD1 670-LYS-MET-671 DELINS ASN-LEU.
RX   PubMed=1302033; DOI=10.1038/ng0892-345;
RA   Mullan M., Crawford F., Axelman K., Houlden H., Lilius L., Winblad B.,
RA   Lannfelt L.;
RT   "A pathogenic mutation for probable Alzheimer's disease in the APP gene at
RT   the N-terminus of beta-amyloid.";
RL   Nat. Genet. 1:345-347(1992).
RN   [150]
RP   CHARACTERIZATION OF VARIANT AD1 670-LYS-MET-671 DELINS ASN-LEU.
RX   PubMed=1465129; DOI=10.1038/360672a0;
RA   Citron M., Oltersdorf T., Haass C., McConlogue L., Hung A.Y., Seubert P.,
RA   Vigo-Pelfrey C., Lieberburg I., Selkoe D.J.;
RT   "Mutation of the beta-amyloid precursor protein in familial Alzheimer's
RT   disease increases beta-protein production.";
RL   Nature 360:672-674(1992).
RN   [151]
RP   VARIANT VAL-713.
RX   PubMed=1307241; DOI=10.1038/ng0792-306;
RA   Jones C.T., Morris S., Yates C.M., Moffoot A., Sharpe C., Brock D.J.H.,
RA   St Clair D.;
RT   "Mutation in codon 713 of the beta amyloid precursor protein gene
RT   presenting with schizophrenia.";
RL   Nat. Genet. 1:306-309(1992).
RN   [152]
RP   VARIANT AD1 THR-713.
RX   PubMed=1303275; DOI=10.1038/ng1292-255;
RA   Carter D.A., Desmarais E., Bellis M., Campion D., Clerget-Darpoux F.,
RA   Brice A., Agid Y., Jaillard-Serradt A., Mallet J.;
RT   "More missense in amyloid gene.";
RL   Nat. Genet. 2:255-256(1992).
RN   [153]
RP   VARIANTS AD1 ILE-717 AND PHE-717.
RX   PubMed=8267572; DOI=10.1006/bbrc.1993.2491;
RA   Liepnieks J.J., Ghetti B., Farlow M., Roses A.D., Benson M.D.;
RT   "Characterization of amyloid fibril beta-peptide in familial Alzheimer's
RT   disease with APP717 mutations.";
RL   Biochem. Biophys. Res. Commun. 197:386-392(1993).
RN   [154]
RP   VARIANT ASP-665.
RX   PubMed=8154870; DOI=10.1002/ana.410350410;
RA   Peacock M.L., Murman D.L., Sima A.A.F., Warren J.T. Jr., Roses A.D.,
RA   Fink J.K.;
RT   "Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient
RT   with late-onset Alzheimer's disease.";
RL   Ann. Neurol. 35:432-438(1994).
RN   [155]
RP   VARIANT AD1 PHE-717.
RX   PubMed=8290042; DOI=10.1212/wnl.44.1.105;
RA   Farlow M., Murrell J., Ghetti B., Unverzagt F., Zeldenrust S., Benson M.D.;
RT   "Clinical characteristics in a kindred with early-onset Alzheimer's disease
RT   and their linkage to a G-->T change at position 2149 of the amyloid
RT   precursor protein gene.";
RL   Neurology 44:105-111(1994).
RN   [156]
RP   VARIANT AD1 ILE-717.
RX   PubMed=8577393; DOI=10.1016/0304-3940(95)12046-7;
RA   Brooks W.S., Martins R.N., De Voecht J., Nicholson G.A., Schofield P.R.,
RA   Kwok J.B.J., Fisher C., Yeung L.U., Van Broeckhoven C.;
RT   "A mutation in codon 717 of the amyloid precursor protein gene in an
RT   Australian family with Alzheimer's disease.";
RL   Neurosci. Lett. 199:183-186(1995).
RN   [157]
RP   CHARACTERIZATION OF VARIANTS AD1 GLY-717; ILE-717 AND PHE-717, AND
RP   MUTAGENESIS OF VAL-717.
RX   PubMed=8886002; DOI=10.1006/bbrc.1996.1577;
RA   Maruyama K., Tomita T., Shinozaki K., Kume H., Asada H., Saido T.C.,
RA   Ishiura S., Iwatsubo T., Obata K.;
RT   "Familial Alzheimer's disease-linked mutations at Val717 of amyloid
RT   precursor protein are specific for the increased secretion of A beta
RT   42(43).";
RL   Biochem. Biophys. Res. Commun. 227:730-735(1996).
RN   [158]
RP   VARIANT AD1 VAL-716.
RX   PubMed=9328472; DOI=10.1093/hmg/6.12.2087;
RA   Eckman C.B., Mehta N.D., Crook R., Perez-Tur J., Prihar G., Pfeiffer E.,
RA   Graff-Radford N., Hinder P., Yager D., Zenk B., Refolo L.M., Prada C.M.,
RA   Younkin S.G., Hutton M., Hardy J.;
RT   "A new pathogenic mutation in the APP gene (I716V) increases the relative
RT   proportion of A beta 42(43).";
RL   Hum. Mol. Genet. 6:2087-2089(1997).
RN   [159]
RP   VARIANT AD1 GLY-692, AND CHARACTERIZATION OF PHENOTYPE.
RX   PubMed=9754958; DOI=10.1007/s004010050892;
RA   Cras P., van Harskamp F., Hendriks L., Ceuterick C., van Duijn C.M.,
RA   Stefanko S.Z., Hofman A., Kros J.M., Van Broeckhoven C., Martin J.J.;
RT   "Presenile Alzheimer dementia characterized by amyloid angiopathy and large
RT   amyloid core type senile plaques in the APP 692Ala-->Gly mutation.";
RL   Acta Neuropathol. 96:253-260(1998).
RN   [160]
RP   VARIANT AD1 MET-715, AND CHARACTERIZATION OF VARIANT AD1 MET-715.
RX   PubMed=10097173; DOI=10.1073/pnas.96.7.4119;
RA   Ancolio K., Dumanchin C., Barelli H., Warter J.-M., Brice A., Campion D.,
RA   Frebourg T., Checler F.;
RT   "Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP)
RT   maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for
RT   probable early-onset Alzheimer's disease.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:4119-4124(1999).
RN   [161]
RP   VARIANT AD1 ILE-717.
RX   PubMed=10631141; DOI=10.1086/302702;
RA   Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J.,
RA   Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.;
RT   "High prevalence of pathogenic mutations in patients with early-onset
RT   dementia detected by sequence analyses of four different genes.";
RL   Am. J. Hum. Genet. 66:110-117(2000).
RN   [162]
RP   VARIANT AD1 PRO-723.
RX   PubMed=10665499;
RX   DOI=10.1002/1531-8249(200002)47:2<249::aid-ana18>3.0.co;2-8;
RA   Kwok J.B.J., Li Q.X., Hallupp M., Whyte S., Ames D., Beyreuther K.,
RA   Masters C.L., Schofield P.R.;
RT   "Novel Leu723Pro amyloid precursor protein mutation increases amyloid
RT   beta42(43) peptide levels and induces apoptosis.";
RL   Ann. Neurol. 47:249-253(2000).
RN   [163]
RP   VARIANT AD1 LEU-717.
RX   PubMed=10867787; DOI=10.1001/archneur.57.6.885;
RA   Murrell J.R., Hake A.M., Quaid K.A., Farlow M.R., Ghetti B.;
RT   "Early-onset Alzheimer disease caused by a new mutation (V717L) in the
RT   amyloid precursor protein gene.";
RL   Arch. Neurol. 57:885-887(2000).
RN   [164]
RP   VARIANT AD1 ILE-714, AND CHARACTERIZATION OF VARIANTS AD1 ILE-714 AND
RP   ILE-717.
RX   PubMed=11063718; DOI=10.1093/hmg/9.18.2589;
RA   Kumar-Singh S., De Jonghe C., Cruts M., Kleinert R., Wang R., Mercken M.,
RA   De Strooper B., Vanderstichele H., Loefgren A., Vanderhoeven I.,
RA   Backhovens H., Vanmechelen E., Kroisel P.M., Van Broeckhoven C.;
RT   "Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site
RT   mutation points to an essential role for N-truncated A beta(42) in
RT   Alzheimer's disease.";
RL   Hum. Mol. Genet. 9:2589-2598(2000).
RN   [165]
RP   CHARACTERIZATION OF VARIANT AD1 670-LYS-MET-671 DELINS ASN-LEU.
RX   PubMed=10677483; DOI=10.1073/pnas.97.4.1456;
RA   Lin X., Koelsch G., Wu S., Downs D., Dashti A., Tang J.;
RT   "Human aspartic protease memapsin 2 cleaves the beta-secretase site of
RT   beta-amyloid precursor protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 97:1456-1460(2000).
RN   [166]
RP   VARIANT CAA-APP ASN-694.
RX   PubMed=11409420; DOI=10.1002/ana.1009;
RA   Grabowski T.J., Cho H.S., Vonsattel J.P.G., Rebeck G.W., Greenberg S.M.;
RT   "Novel amyloid precursor protein mutation in an Iowa family with dementia
RT   and severe cerebral amyloid angiopathy.";
RL   Ann. Neurol. 49:697-705(2001).
RN   [167]
RP   CHARACTERIZATION OF VARIANT AD1 GLY-692.
RX   PubMed=11311152; DOI=10.1042/bj3550869;
RA   Walsh D.M., Hartley D.M., Condron M.M., Selkoe D.J., Teplow D.B.;
RT   "In vitro studies of amyloid beta-protein fibril assembly and toxicity
RT   provide clues to the aetiology of Flemish variant (Ala692-->Gly)
RT   Alzheimer's disease.";
RL   Biochem. J. 355:869-877(2001).
RN   [168]
RP   VARIANT AD1 GLY-693.
RX   PubMed=11528419; DOI=10.1038/nn0901-887;
RA   Nilsberth C., Westlind-Danielsson A., Eckman C.B., Condron M.M.,
RA   Axelman K., Forsell C., Stenh C., Luthman J., Teplow D.B., Younkin S.G.,
RA   Naeslund J., Lannfelt L.;
RT   "The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced
RT   Abeta protofibril formation.";
RL   Nat. Neurosci. 4:887-893(2001).
RN   [169]
RP   VARIANT AD1 ALA-714.
RX   PubMed=12034808; DOI=10.1212/wnl.58.10.1574;
RA   Pasalar P., Najmabadi H., Noorian A.R., Moghimi B., Jannati A.,
RA   Soltanzadeh A., Krefft T., Crook R., Hardy J.;
RT   "An Iranian family with Alzheimer's disease caused by a novel APP mutation
RT   (Thr714Ala).";
RL   Neurology 58:1574-1575(2002).
RN   [170]
RP   VARIANT CAA-APP ASN-694.
RX   PubMed=12654973; DOI=10.1212/01.wnl.0000050140.10044.a8;
RA   Greenberg S.M., Shin Y., Grabowski T.J., Cooper G.E., Rebeck G.W.,
RA   Iglesias S., Chapon F., Tournier-Lasserve E., Baron J.-C.;
RT   "Hemorrhagic stroke associated with the Iowa amyloid precursor protein
RT   mutation.";
RL   Neurology 60:1020-1022(2003).
RN   [171]
RP   VARIANT AD1 THR-713.
RX   PubMed=15365148; DOI=10.1212/01.wnl.0000137048.80666.86;
RA   Rossi G., Giaccone G., Maletta R., Morbin M., Capobianco R., Mangieri M.,
RA   Giovagnoli A.R., Bizzi A., Tomaino C., Perri M., Di Natale M.,
RA   Tagliavini F., Bugiani O., Bruni A.C.;
RT   "A family with Alzheimer disease and strokes associated with A713T mutation
RT   of the APP gene.";
RL   Neurology 63:910-912(2004).
RN   [172]
RP   VARIANT CAA-APP VAL-705.
RX   PubMed=16178030; DOI=10.1002/ana.20571;
RA   Obici L., Demarchi A., de Rosa G., Bellotti V., Marciano S., Donadei S.,
RA   Arbustini E., Palladini G., Diegoli M., Genovese E., Ferrari G.,
RA   Coverlizza S., Merlini G.;
RT   "A novel AbetaPP mutation exclusively associated with cerebral amyloid
RT   angiopathy.";
RL   Ann. Neurol. 58:639-644(2005).
RN   [173]
RP   VARIANT AD1 ILE-714.
RX   PubMed=15668448; DOI=10.1212/01.wnl.0000149761.70566.3e;
RA   Edwards-Lee T., Ringman J.M., Chung J., Werner J., Morgan A.,
RA   St George-Hyslop P.H., Thompson P., Dutton R., Mlikotic A., Rogaeva E.,
RA   Hardy J.;
RT   "An African American family with early-onset Alzheimer disease and an APP
RT   (T714I) mutation.";
RL   Neurology 64:377-379(2005).
RN   [174]
RP   VARIANT CAA-APP LYS-693.
RX   PubMed=20697050; DOI=10.1001/archneurol.2010.178;
RA   Bugiani O., Giaccone G., Rossi G., Mangieri M., Capobianco R., Morbin M.,
RA   Mazzoleni G., Cupidi C., Marcon G., Giovagnoli A., Bizzi A., Di Fede G.,
RA   Puoti G., Carella F., Salmaggi A., Romorini A., Patruno G.M., Magoni M.,
RA   Padovani A., Tagliavini F.;
RT   "Hereditary cerebral hemorrhage with amyloidosis associated with the E693K
RT   mutation of APP.";
RL   Arch. Neurol. 67:987-995(2010).
CC   -!- FUNCTION: Functions as a cell surface receptor and performs
CC       physiological functions on the surface of neurons relevant to neurite
CC       growth, neuronal adhesion and axonogenesis. Interaction between APP
CC       molecules on neighboring cells promotes synaptogenesis
CC       (PubMed:25122912). Involved in cell mobility and transcription
CC       regulation through protein-protein interactions. Can promote
CC       transcription activation through binding to APBB1-KAT5 and inhibits
CC       Notch signaling through interaction with Numb. Couples to apoptosis-
CC       inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o)
CC       alpha ATPase activity (By similarity). Acts as a kinesin I membrane
CC       receptor, mediating the axonal transport of beta-secretase and
CC       presenilin 1 (By similarity). By acting as a kinesin I membrane
CC       receptor, plays a role in axonal anterograde transport of cargo towards
CC       synapses in axons (PubMed:17062754, PubMed:23011729). Involved in
CC       copper homeostasis/oxidative stress through copper ion reduction. In
CC       vitro, copper-metallated APP induces neuronal death directly or is
CC       potentiated through Cu(2+)-mediated low-density lipoprotein oxidation.
CC       Can regulate neurite outgrowth through binding to components of the
CC       extracellular matrix such as heparin and collagen I and IV. The splice
CC       isoforms that contain the BPTI domain possess protease inhibitor
CC       activity. Induces a AGER-dependent pathway that involves activation of
CC       p38 MAPK, resulting in internalization of amyloid-beta peptide and
CC       leading to mitochondrial dysfunction in cultured cortical neurons.
CC       Provides Cu(2+) ions for GPC1 which are required for release of nitric
CC       oxide (NO) and subsequent degradation of the heparan sulfate chains on
CC       GPC1. {ECO:0000250, ECO:0000250|UniProtKB:P12023,
CC       ECO:0000269|PubMed:17062754, ECO:0000269|PubMed:23011729,
CC       ECO:0000269|PubMed:25122912}.
CC   -!- FUNCTION: Amyloid-beta peptides are lipophilic metal chelators with
CC       metal-reducing activity. Bind transient metals such as copper, zinc and
CC       iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+),
CC       respectively. Amyloid-beta peptides bind to lipoproteins and
CC       apolipoproteins E and J in the CSF and to HDL particles in plasma,
CC       inhibiting metal-catalyzed oxidation of lipoproteins. Promotes both tau
CC       aggregation and TPK II-mediated phosphorylation. Interaction with
CC       overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also
CC       binds GPC1 in lipid rafts.
CC   -!- FUNCTION: [Amyloid-beta protein 42]: More effective reductant than
CC       amyloid-beta protein 40. May activate mononuclear phagocytes in the
CC       brain and elicit inflammatory responses.
CC   -!- FUNCTION: Appicans elicit adhesion of neural cells to the extracellular
CC       matrix and may regulate neurite outgrowth in the brain. {ECO:0000250}.
CC   -!- FUNCTION: The gamma-CTF peptides as well as the caspase-cleaved
CC       peptides, including C31, are potent enhancers of neuronal apoptosis.
CC   -!- SUBUNIT: Binds, via its C-terminus, to the PID domain of several
CC       cytoplasmic proteins, including APBB family members, the APBA family,
CC       MAPK8IP1, SHC1 and, NUMB and DAB1 (By similarity). Binding to DAB1
CC       inhibits its serine phosphorylation (By similarity). Interacts (via
CC       NPXY motif) with DAB2 (via PID domain); the interaction is impaired by
CC       tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-
CC       like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via
CC       BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By
CC       similarity). Associates with microtubules in the presence of ATP and in
CC       a kinesin-dependent manner (By similarity). Interacts, through a C-
CC       terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in
CC       hippocampal neurons. Interacts with CPEB1 and AGER (By similarity).
CC       Interacts with ANKS1B. Interacts with ITM2B. Interacts with ITM2C.
CC       Interacts with IDE (PubMed:17051221). Homodimerizes; dimerization is
CC       enhanced in the presence of Cu(2+) ions and is promoted by heparin
CC       binding (PubMed:25122912, PubMed:20212142). Interacts with PLD3.
CC       Interacts with VDAC1 (PubMed:25168729). Interacts with NSG1; could
CC       regulate APP processing (By similarity). Interacts with SYT7 (By
CC       similarity). Interacts (via transmembrane region) with PSEN1; the
CC       interaction is direct (PubMed:30630874). Interacts with LRRK2
CC       (PubMed:28720718). Interacts (via cytoplasmic domain) with KIF5B
CC       (PubMed:23011729). Interacts (via C-terminus) with APBB2/FE65L1 (via C-
CC       terminus) (PubMed:14527950, PubMed:8855266). Interacts (via
CC       intracellular domain) with APBB3 (PubMed:10081969). Amyloid-beta
CC       associates with HADH2 (PubMed:9338779). Soluble APP binds, via its N-
CC       terminal head, to FBLN1. {ECO:0000250|UniProtKB:P08592,
CC       ECO:0000250|UniProtKB:P12023, ECO:0000269|PubMed:10081969,
CC       ECO:0000269|PubMed:10681545, ECO:0000269|PubMed:10816430,
CC       ECO:0000269|PubMed:11238726, ECO:0000269|PubMed:11278849,
CC       ECO:0000269|PubMed:11438549, ECO:0000269|PubMed:11517218,
CC       ECO:0000269|PubMed:11544248, ECO:0000269|PubMed:11689470,
CC       ECO:0000269|PubMed:11724784, ECO:0000269|PubMed:11877420,
CC       ECO:0000269|PubMed:11943163, ECO:0000269|PubMed:14527950,
CC       ECO:0000269|PubMed:15347684, ECO:0000269|PubMed:16174740,
CC       ECO:0000269|PubMed:16407538, ECO:0000269|PubMed:17051221,
CC       ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:17895381,
CC       ECO:0000269|PubMed:18468999, ECO:0000269|PubMed:19366692,
CC       ECO:0000269|PubMed:19901339, ECO:0000269|PubMed:20212142,
CC       ECO:0000269|PubMed:20811458, ECO:0000269|PubMed:22457725,
CC       ECO:0000269|PubMed:23011729, ECO:0000269|PubMed:24336208,
CC       ECO:0000269|PubMed:24523320, ECO:0000269|PubMed:25122912,
CC       ECO:0000269|PubMed:25168729, ECO:0000269|PubMed:28720718,
CC       ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:8446172,
CC       ECO:0000269|PubMed:8626687, ECO:0000269|PubMed:8855266,
CC       ECO:0000269|PubMed:8887653, ECO:0000269|PubMed:9300481,
CC       ECO:0000269|PubMed:9338779, ECO:0000269|PubMed:9843960,
CC       ECO:0000269|PubMed:9890987}.
CC   -!- SUBUNIT: [Amyloid-beta protein 40]: Interacts with S100A9.
CC   -!- SUBUNIT: [Amyloid-beta protein 42]: Interacts with FPR2.
CC       {ECO:0000269|PubMed:11689470}.
CC   -!- SUBUNIT: [C83]: Interacts with GSAP. {ECO:0000269|PubMed:20811458}.
CC   -!- SUBUNIT: [Isoform APP695]: Interacts with SORL1 (via N-terminal
CC       ectodomain); this interaction retains APP in the trans-Golgi network
CC       and reduces processing into soluble APP-alpha and amyloid-beta
CC       peptides. {ECO:0000269|PubMed:16174740, ECO:0000269|PubMed:16407538,
CC       ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:24523320}.
CC   -!- SUBUNIT: [C99]: Interacts with SORL1. {ECO:0000269|PubMed:16407538}.
CC   -!- SUBUNIT: [Isoform APP751]: Interacts with SORL1.
CC       {ECO:0000269|PubMed:16174740}.
CC   -!- SUBUNIT: [Isoform APP770]: Interacts with SORL1.
CC       {ECO:0000269|PubMed:16174740}.
CC   -!- INTERACTION:
CC       P05067; Q9NY61: AATF; NbExp=3; IntAct=EBI-77613, EBI-372428;
CC       P05067; P16112: ACAN; NbExp=3; IntAct=EBI-77613, EBI-9076211;
CC       P05067; P60709: ACTB; NbExp=8; IntAct=EBI-77613, EBI-353944;
CC       P05067; P61158: ACTR3; NbExp=3; IntAct=EBI-77613, EBI-351428;
CC       P05067; O14672: ADAM10; NbExp=7; IntAct=EBI-77613, EBI-1536151;
CC       P05067; A0AVL1: ADAM9; NbExp=3; IntAct=EBI-77613, EBI-25935864;
CC       P05067; P18509: ADCYAP1; NbExp=3; IntAct=EBI-77613, EBI-8588930;
CC       P05067; P41586-2: ADCYAP1R1; NbExp=3; IntAct=EBI-77613, EBI-17241711;
CC       P05067; Q15109: AGER; NbExp=3; IntAct=EBI-77613, EBI-1646426;
CC       P05067; Q13155: AIMP2; NbExp=3; IntAct=EBI-77613, EBI-745226;
CC       P05067; P63010-2: AP2B1; NbExp=3; IntAct=EBI-77613, EBI-11529439;
CC       P05067; Q02410: APBA1; NbExp=5; IntAct=EBI-77613, EBI-368690;
CC       P05067; Q99767: APBA2; NbExp=3; IntAct=EBI-77613, EBI-81711;
CC       P05067; O96018: APBA3; NbExp=7; IntAct=EBI-77613, EBI-6115839;
CC       P05067; O00213: APBB1; NbExp=10; IntAct=EBI-77613, EBI-81694;
CC       P05067; O00213-2: APBB1; NbExp=6; IntAct=EBI-77613, EBI-13307975;
CC       P05067; Q92870: APBB2; NbExp=7; IntAct=EBI-77613, EBI-79277;
CC       P05067; Q92870-2: APBB2; NbExp=3; IntAct=EBI-77613, EBI-21535880;
CC       P05067; O95704: APBB3; NbExp=8; IntAct=EBI-77613, EBI-286427;
CC       P05067; P02743: APCS; NbExp=3; IntAct=EBI-77613, EBI-2115799;
CC       P05067; Q96BI3: APH1A; NbExp=3; IntAct=EBI-77613, EBI-2606935;
CC       P05067; Q8WW43: APH1B; NbExp=3; IntAct=EBI-77613, EBI-2606497;
CC       P05067; Q06481-5: APLP2; NbExp=3; IntAct=EBI-77613, EBI-25646567;
CC       P05067; P02647: APOA1; NbExp=8; IntAct=EBI-77613, EBI-701692;
CC       P05067; P05067: APP; NbExp=107; IntAct=EBI-77613, EBI-77613;
CC       P05067; Q92624: APPBP2; NbExp=3; IntAct=EBI-77613, EBI-743771;
CC       P05067; Q6P4J0: ARD1A; NbExp=3; IntAct=EBI-77613, EBI-10252815;
CC       P05067; P61204: ARF3; NbExp=3; IntAct=EBI-77613, EBI-641535;
CC       P05067; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-77613, EBI-10186132;
CC       P05067; P56211: ARPP19; NbExp=3; IntAct=EBI-77613, EBI-5773880;
CC       P05067; P05026: ATP1B1; NbExp=3; IntAct=EBI-77613, EBI-714630;
CC       P05067; P54253: ATXN1; NbExp=8; IntAct=EBI-77613, EBI-930964;
CC       P05067; P56817: BACE1; NbExp=11; IntAct=EBI-77613, EBI-2433139;
CC       P05067; Q9Y5Z0: BACE2; NbExp=3; IntAct=EBI-77613, EBI-11282723;
CC       P05067; Q92934: BAD; NbExp=3; IntAct=EBI-77613, EBI-700771;
CC       P05067; P46379-2: BAG6; NbExp=5; IntAct=EBI-77613, EBI-10988864;
CC       P05067; Q96GW7: BCAN; NbExp=3; IntAct=EBI-77613, EBI-2690445;
CC       P05067; P51572: BCAP31; NbExp=3; IntAct=EBI-77613, EBI-77683;
CC       P05067; P10415: BCL2; NbExp=3; IntAct=EBI-77613, EBI-77694;
CC       P05067; P23560-2: BDNF; NbExp=3; IntAct=EBI-77613, EBI-12275524;
CC       P05067; O15392: BIRC5; NbExp=3; IntAct=EBI-77613, EBI-518823;
CC       P05067; Q13867: BLMH; NbExp=3; IntAct=EBI-77613, EBI-718504;
CC       P05067; P35613: BSG; NbExp=2; IntAct=EBI-77613, EBI-750709;
CC       P05067; Q8IU99: CALHM1; NbExp=3; IntAct=EBI-77613, EBI-1790341;
CC       P05067; P62158: CALM3; NbExp=3; IntAct=EBI-77613, EBI-397435;
CC       P05067; P27797: CALR; NbExp=5; IntAct=EBI-77613, EBI-1049597;
CC       P05067; O43852-3: CALU; NbExp=3; IntAct=EBI-77613, EBI-11536607;
CC       P05067; Q9UQM7: CAMK2A; NbExp=3; IntAct=EBI-77613, EBI-1383687;
CC       P05067; P27824-2: CANX; NbExp=3; IntAct=EBI-77613, EBI-25890990;
CC       P05067; P07384: CAPN1; NbExp=3; IntAct=EBI-77613, EBI-1542113;
CC       P05067; P29466-3: CASP1; NbExp=3; IntAct=EBI-77613, EBI-12248206;
CC       P05067; P42574: CASP3; NbExp=4; IntAct=EBI-77613, EBI-524064;
CC       P05067; Q14790: CASP8; NbExp=3; IntAct=EBI-77613, EBI-78060;
CC       P05067; Q03135: CAV1; NbExp=3; IntAct=EBI-77613, EBI-603614;
CC       P05067; P83916: CBX1; NbExp=6; IntAct=EBI-77613, EBI-78129;
CC       P05067; P40227: CCT6A; NbExp=3; IntAct=EBI-77613, EBI-356687;
CC       P05067; P16671: CD36; NbExp=3; IntAct=EBI-77613, EBI-2808214;
CC       P05067; Q08722-3: CD47; NbExp=3; IntAct=EBI-77613, EBI-17263290;
CC       P05067; P06493: CDK1; NbExp=3; IntAct=EBI-77613, EBI-444308;
CC       P05067; Q00535: CDK5; NbExp=3; IntAct=EBI-77613, EBI-1041567;
CC       P05067; P42773: CDKN2C; NbExp=3; IntAct=EBI-77613, EBI-711290;
CC       P05067; P43681: CHRNA4; NbExp=3; IntAct=EBI-77613, EBI-7132379;
CC       P05067; P36544: CHRNA7; NbExp=4; IntAct=EBI-77613, EBI-79333;
CC       P05067; Q16740: CLPP; NbExp=3; IntAct=EBI-77613, EBI-1056029;
CC       P05067; O94985-2: CLSTN1; NbExp=3; IntAct=EBI-77613, EBI-16041593;
CC       P05067; Q8IUW6: CLSTN3; NbExp=3; IntAct=EBI-77613, EBI-25832219;
CC       P05067; P10909: CLU; NbExp=3; IntAct=EBI-77613, EBI-1104674;
CC       P05067; P26441: CNTF; NbExp=3; IntAct=EBI-77613, EBI-1050897;
CC       P05067; Q02246: CNTN2; NbExp=3; IntAct=EBI-77613, EBI-4397248;
CC       P05067; Q8NE08: COL25A1; NbExp=3; IntAct=EBI-77613, EBI-25836642;
CC       P05067; Q96A83-2: COL26A1; NbExp=3; IntAct=EBI-77613, EBI-21553822;
CC       P05067; P29400-2: COL4A5; NbExp=3; IntAct=EBI-77613, EBI-12211159;
CC       P05067; Q14031: COL4A6; NbExp=3; IntAct=EBI-77613, EBI-2432407;
CC       P05067; P31146: CORO1A; NbExp=3; IntAct=EBI-77613, EBI-1046676;
CC       P05067; P20674: COX5A; NbExp=3; IntAct=EBI-77613, EBI-715032;
CC       P05067; P15086: CPB1; NbExp=3; IntAct=EBI-77613, EBI-25936844;
CC       P05067; P02511: CRYAB; NbExp=7; IntAct=EBI-77613, EBI-739060;
CC       P05067; P48730: CSNK1D; NbExp=3; IntAct=EBI-77613, EBI-751621;
CC       P05067; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-77613, EBI-9087876;
CC       P05067; P68400: CSNK2A1; NbExp=3; IntAct=EBI-77613, EBI-347804;
CC       P05067; P01034: CST3; NbExp=3; IntAct=EBI-77613, EBI-948622;
CC       P05067; P49711: CTCF; NbExp=3; IntAct=EBI-77613, EBI-932887;
CC       P05067; P07339: CTSD; NbExp=2; IntAct=EBI-77613, EBI-2115097;
CC       P05067; P99999: CYCS; NbExp=3; IntAct=EBI-77613, EBI-446479;
CC       P05067; O75553-4: DAB1; NbExp=3; IntAct=EBI-77613, EBI-21246842;
CC       P05067; P98082: DAB2; NbExp=3; IntAct=EBI-77613, EBI-1171238;
CC       P05067; Q14203-5: DCTN1; NbExp=5; IntAct=EBI-77613, EBI-25840379;
CC       P05067; Q13561: DCTN2; NbExp=3; IntAct=EBI-77613, EBI-715074;
CC       P05067; Q6I9W9: DKFZP586N0721; NbExp=3; IntAct=EBI-77613, EBI-25927172;
CC       P05067; O14645: DNALI1; NbExp=3; IntAct=EBI-77613, EBI-395638;
CC       P05067; Q01658: DR1; NbExp=3; IntAct=EBI-77613, EBI-750300;
CC       P05067; P21917: DRD4; NbExp=6; IntAct=EBI-77613, EBI-8592297;
CC       P05067; Q16828: DUSP6; NbExp=3; IntAct=EBI-77613, EBI-746870;
CC       P05067; Q92997: DVL3; NbExp=3; IntAct=EBI-77613, EBI-739789;
CC       P05067; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-77613, EBI-25840445;
CC       P05067; O14576-5: DYNC1I1; NbExp=3; IntAct=EBI-77613, EBI-25936079;
CC       P05067; Q01094: E2F1; NbExp=3; IntAct=EBI-77613, EBI-448924;
CC       P05067; Q3B7T1: EDRF1; NbExp=3; IntAct=EBI-77613, EBI-2870947;
CC       P05067; P20042: EIF2S2; NbExp=6; IntAct=EBI-77613, EBI-711977;
CC       P05067; P19419: ELK1; NbExp=3; IntAct=EBI-77613, EBI-726632;
CC       P05067; P11171-2: EPB41; NbExp=3; IntAct=EBI-77613, EBI-10197451;
CC       P05067; P11171-7: EPB41; NbExp=3; IntAct=EBI-77613, EBI-25852354;
CC       P05067; Q9BS26: ERP44; NbExp=3; IntAct=EBI-77613, EBI-541644;
CC       P05067; P00748: F12; NbExp=3; IntAct=EBI-77613, EBI-6378830;
CC       P05067; P00734: F2; NbExp=3; IntAct=EBI-77613, EBI-297094;
CC       P05067; P23142-4: FBLN1; NbExp=3; IntAct=EBI-77613, EBI-11956479;
CC       P05067; Q92915: FGF14; NbExp=3; IntAct=EBI-77613, EBI-10489272;
CC       P05067; P62942: FKBP1A; NbExp=3; IntAct=EBI-77613, EBI-1027571;
CC       P05067; P21333-2: FLNA; NbExp=3; IntAct=EBI-77613, EBI-9641086;
CC       P05067; O75955: FLOT1; NbExp=5; IntAct=EBI-77613, EBI-603643;
CC       P05067; Q9BTI6: FLOT2; NbExp=3; IntAct=EBI-77613, EBI-23703366;
CC       P05067; P01100: FOS; NbExp=3; IntAct=EBI-77613, EBI-852851;
CC       P05067; P25090: FPR2; NbExp=3; IntAct=EBI-77613, EBI-17291771;
CC       P05067; P09958: FURIN; NbExp=3; IntAct=EBI-77613, EBI-1056807;
CC       P05067; P06241: FYN; NbExp=3; IntAct=EBI-77613, EBI-515315;
CC       P05067; P04406: GAPDH; NbExp=3; IntAct=EBI-77613, EBI-354056;
CC       P05067; Q9UJY5-4: GGA1; NbExp=3; IntAct=EBI-77613, EBI-12108696;
CC       P05067; Q05586: GRIN1; NbExp=3; IntAct=EBI-77613, EBI-998542;
CC       P05067; P25098: GRK2; NbExp=3; IntAct=EBI-77613, EBI-3904795;
CC       P05067; P43250: GRK6; NbExp=3; IntAct=EBI-77613, EBI-722747;
CC       P05067; P43250-2: GRK6; NbExp=3; IntAct=EBI-77613, EBI-6428342;
CC       P05067; A4D1B5: GSAP; NbExp=3; IntAct=EBI-77613, EBI-15875313;
CC       P05067; P49841-2: GSK3B; NbExp=3; IntAct=EBI-77613, EBI-15870655;
CC       P05067; Q03013: GSTM4; NbExp=3; IntAct=EBI-77613, EBI-713363;
CC       P05067; Q00403: GTF2B; NbExp=3; IntAct=EBI-77613, EBI-389564;
CC       P05067; Q9Y5Q9: GTF3C3; NbExp=3; IntAct=EBI-77613, EBI-1054873;
CC       P05067; P09429: HMGB1; NbExp=3; IntAct=EBI-77613, EBI-389432;
CC       P05067; P30519: HMOX2; NbExp=3; IntAct=EBI-77613, EBI-712096;
CC       P05067; Q9UJC3: HOOK1; NbExp=3; IntAct=EBI-77613, EBI-746704;
CC       P05067; Q99714: HSD17B10; NbExp=7; IntAct=EBI-77613, EBI-79964;
CC       P05067; Q99714-2: HSD17B10; NbExp=3; IntAct=EBI-77613, EBI-25939412;
CC       P05067; P07900: HSP90AA1; NbExp=5; IntAct=EBI-77613, EBI-296047;
CC       P05067; P14625: HSP90B1; NbExp=3; IntAct=EBI-77613, EBI-359129;
CC       P05067; P11021: HSPA5; NbExp=6; IntAct=EBI-77613, EBI-354921;
CC       P05067; P11142: HSPA8; NbExp=8; IntAct=EBI-77613, EBI-351896;
CC       P05067; P04792: HSPB1; NbExp=3; IntAct=EBI-77613, EBI-352682;
CC       P05067; Q16082: HSPB2; NbExp=3; IntAct=EBI-77613, EBI-739395;
CC       P05067; P10809: HSPD1; NbExp=6; IntAct=EBI-77613, EBI-352528;
CC       P05067; P42858: HTT; NbExp=6; IntAct=EBI-77613, EBI-466029;
CC       P05067; Q9UMF0: ICAM5; NbExp=3; IntAct=EBI-77613, EBI-6398041;
CC       P05067; P14735: IDE; NbExp=3; IntAct=EBI-77613, EBI-2556886;
CC       P05067; Q16352: INA; NbExp=3; IntAct=EBI-77613, EBI-366258;
CC       P05067; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-77613, EBI-21911304;
CC       P05067; P05556: ITGB1; NbExp=3; IntAct=EBI-77613, EBI-703066;
CC       P05067; Q9Y287: ITM2B; NbExp=6; IntAct=EBI-77613, EBI-2866431;
CC       P05067; P05412: JUN; NbExp=5; IntAct=EBI-77613, EBI-852823;
CC       P05067; P17535: JUND; NbExp=3; IntAct=EBI-77613, EBI-2682803;
CC       P05067; Q92993: KAT5; NbExp=3; IntAct=EBI-77613, EBI-399080;
CC       P05067; Q92993-2: KAT5; NbExp=3; IntAct=EBI-77613, EBI-20795332;
CC       P05067; Q13303: KCNAB2; NbExp=3; IntAct=EBI-77613, EBI-948729;
CC       P05067; Q9Y2W7: KCNIP3; NbExp=3; IntAct=EBI-77613, EBI-751501;
CC       P05067; O60333-2: KIF1B; NbExp=3; IntAct=EBI-77613, EBI-10975473;
CC       P05067; Q07866-2: KLC1; NbExp=3; IntAct=EBI-77613, EBI-11979975;
CC       P05067; O14901: KLF11; NbExp=3; IntAct=EBI-77613, EBI-948266;
CC       P05067; Q92876: KLK6; NbExp=3; IntAct=EBI-77613, EBI-2432309;
CC       P05067; P01116-2: KRAS; NbExp=3; IntAct=EBI-77613, EBI-367427;
CC       P05067; Q16363-3: LAMA4; NbExp=3; IntAct=EBI-77613, EBI-17719490;
CC       P05067; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-77613, EBI-1108377;
CC       P05067; Q96FE5: LINGO1; NbExp=3; IntAct=EBI-77613, EBI-719955;
CC       P05067; Q07954-2: LRP1; NbExp=3; IntAct=EBI-77613, EBI-25833471;
CC       P05067; Q9NZR2: LRP1B; NbExp=3; IntAct=EBI-77613, EBI-1642131;
CC       P05067; P30533: LRPAP1; NbExp=3; IntAct=EBI-77613, EBI-715927;
CC       P05067; P42704: LRPPRC; NbExp=8; IntAct=EBI-77613, EBI-1050853;
CC       P05067; P07948: LYN; NbExp=3; IntAct=EBI-77613, EBI-79452;
CC       P05067; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-77613, EBI-373144;
CC       P05067; P36507: MAP2K2; NbExp=3; IntAct=EBI-77613, EBI-1056930;
CC       P05067; P28482: MAPK1; NbExp=3; IntAct=EBI-77613, EBI-959949;
CC       P05067; P53778: MAPK12; NbExp=3; IntAct=EBI-77613, EBI-602406;
CC       P05067; Q9UQF2: MAPK8IP1; NbExp=6; IntAct=EBI-77613, EBI-78404;
CC       P05067; P10636: MAPT; NbExp=8; IntAct=EBI-77613, EBI-366182;
CC       P05067; P10636-8: MAPT; NbExp=4; IntAct=EBI-77613, EBI-366233;
CC       P05067; Q9P0L2: MARK1; NbExp=3; IntAct=EBI-77613, EBI-968587;
CC       P05067; Q6IPE9: MARK4; NbExp=3; IntAct=EBI-77613, EBI-10250211;
CC       P05067; Q96L34: MARK4; NbExp=3; IntAct=EBI-77613, EBI-302319;
CC       P05067; Q00266: MAT1A; NbExp=3; IntAct=EBI-77613, EBI-967087;
CC       P05067; P02686-2: MBP; NbExp=3; IntAct=EBI-77613, EBI-12159027;
CC       P05067; Q93074: MED12; NbExp=2; IntAct=EBI-77613, EBI-394357;
CC       P05067; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-77613, EBI-4397720;
CC       P05067; O94851: MICAL2; NbExp=3; IntAct=EBI-77613, EBI-2804835;
CC       P05067; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-77613, EBI-21250407;
CC       P05067; P08473: MME; NbExp=3; IntAct=EBI-77613, EBI-353759;
CC       P05067; P08253: MMP2; NbExp=3; IntAct=EBI-77613, EBI-1033518;
CC       P05067; Q99547: MPHOSPH6; NbExp=3; IntAct=EBI-77613, EBI-373187;
CC       P05067; Q8N594: MPND; NbExp=3; IntAct=EBI-77613, EBI-2512452;
CC       P05067; P41227: NAA10; NbExp=3; IntAct=EBI-77613, EBI-747693;
CC       P05067; Q13765: NACA; NbExp=3; IntAct=EBI-77613, EBI-712216;
CC       P05067; Q13564: NAE1; NbExp=3; IntAct=EBI-77613, EBI-718631;
CC       P05067; P41271-2: NBL1; NbExp=3; IntAct=EBI-77613, EBI-12135485;
CC       P05067; P19404: NDUFV2; NbExp=3; IntAct=EBI-77613, EBI-713665;
CC       P05067; O76041: NEBL; NbExp=3; IntAct=EBI-77613, EBI-2880203;
CC       P05067; P12036: NEFH; NbExp=3; IntAct=EBI-77613, EBI-2880271;
CC       P05067; I6L9F6: NEFL; NbExp=6; IntAct=EBI-77613, EBI-10178578;
CC       P05067; P21359: NF1; NbExp=3; IntAct=EBI-77613, EBI-1172917;
CC       P05067; P01138: NGF; NbExp=9; IntAct=EBI-77613, EBI-1028250;
CC       P05067; P08138: NGFR; NbExp=2; IntAct=EBI-77613, EBI-1387782;
CC       P05067; Q6IAD4: NOTCH1; NbExp=3; IntAct=EBI-77613, EBI-25860267;
CC       P05067; Q99466: NOTCH4; NbExp=3; IntAct=EBI-77613, EBI-7970822;
CC       P05067; P43354: NR4A2; NbExp=3; IntAct=EBI-77613, EBI-2681738;
CC       P05067; Q6PK61: NRG1; NbExp=3; IntAct=EBI-77613, EBI-25938844;
CC       P05067; Q02818: NUCB1; NbExp=3; IntAct=EBI-77613, EBI-2622179;
CC       P05067; P49757-8: NUMB; NbExp=3; IntAct=EBI-77613, EBI-25937715;
CC       P05067; P04181: OAT; NbExp=3; IntAct=EBI-77613, EBI-721662;
CC       P05067; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-77613, EBI-1058491;
CC       P05067; P11940: PABPC1; NbExp=3; IntAct=EBI-77613, EBI-81531;
CC       P05067; O96013-2: PAK4; NbExp=3; IntAct=EBI-77613, EBI-21659863;
CC       P05067; Q99497: PARK7; NbExp=3; IntAct=EBI-77613, EBI-1164361;
CC       P05067; Q6ZW49: PAXIP1; NbExp=3; IntAct=EBI-77613, EBI-743225;
CC       P05067; P61457: PCBD1; NbExp=2; IntAct=EBI-77613, EBI-740475;
CC       P05067; P16234-2: PDGFRA; NbExp=3; IntAct=EBI-77613, EBI-13380852;
CC       P05067; P09619: PDGFRB; NbExp=3; IntAct=EBI-77613, EBI-641237;
CC       P05067; P30101: PDIA3; NbExp=6; IntAct=EBI-77613, EBI-979862;
CC       P05067; Q15084: PDIA6; NbExp=3; IntAct=EBI-77613, EBI-1043087;
CC       P05067; Q15118: PDK1; NbExp=3; IntAct=EBI-77613, EBI-7016221;
CC       P05067; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-77613, EBI-716063;
CC       P05067; P18669: PGAM1; NbExp=4; IntAct=EBI-77613, EBI-717905;
CC       P05067; Q8WUB8-2: PHF10; NbExp=3; IntAct=EBI-77613, EBI-10276329;
CC       P05067; Q8N2W9: PIAS4; NbExp=3; IntAct=EBI-77613, EBI-473160;
CC       P05067; P42338: PIK3CB; NbExp=3; IntAct=EBI-77613, EBI-2609540;
CC       P05067; P48736: PIK3CG; NbExp=3; IntAct=EBI-77613, EBI-1030384;
CC       P05067; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-77613, EBI-9090282;
CC       P05067; Q13526: PIN1; NbExp=4; IntAct=EBI-77613, EBI-714158;
CC       P05067; Q9BXM7: PINK1; NbExp=3; IntAct=EBI-77613, EBI-2846068;
CC       P05067; Q16512: PKN1; NbExp=3; IntAct=EBI-77613, EBI-602382;
CC       P05067; P00749: PLAU; NbExp=3; IntAct=EBI-77613, EBI-3905042;
CC       P05067; Q13393: PLD1; NbExp=3; IntAct=EBI-77613, EBI-2827556;
CC       P05067; O14939: PLD2; NbExp=3; IntAct=EBI-77613, EBI-1053996;
CC       P05067; P53350: PLK1; NbExp=3; IntAct=EBI-77613, EBI-476768;
CC       P05067; O14494: PLPP1; NbExp=3; IntAct=EBI-77613, EBI-2865290;
CC       P05067; O15162: PLSCR1; NbExp=3; IntAct=EBI-77613, EBI-740019;
CC       P05067; Q8WVK1: PLSCR1; NbExp=3; IntAct=EBI-77613, EBI-10238872;
CC       P05067; Q9HCM2: PLXNA4; NbExp=2; IntAct=EBI-77613, EBI-46257296;
CC       P05067; A0A6Q8PF08: PMP22; NbExp=3; IntAct=EBI-77613, EBI-50433196;
CC       P05067; P00491: PNP; NbExp=9; IntAct=EBI-77613, EBI-712238;
CC       P05067; P62937: PPIA; NbExp=4; IntAct=EBI-77613, EBI-437708;
CC       P05067; P62136: PPP1CA; NbExp=3; IntAct=EBI-77613, EBI-357253;
CC       P05067; P41236: PPP1R2; NbExp=3; IntAct=EBI-77613, EBI-1056517;
CC       P05067; P67775: PPP2CA; NbExp=3; IntAct=EBI-77613, EBI-712311;
CC       P05067; P63151: PPP2R2A; NbExp=3; IntAct=EBI-77613, EBI-1048931;
CC       P05067; Q00005: PPP2R2B; NbExp=3; IntAct=EBI-77613, EBI-1052159;
CC       P05067; Q15172: PPP2R5A; NbExp=3; IntAct=EBI-77613, EBI-641666;
CC       P05067; P48454: PPP3CC; NbExp=3; IntAct=EBI-77613, EBI-2827192;
CC       P05067; P17612: PRKACA; NbExp=3; IntAct=EBI-77613, EBI-476586;
CC       P05067; P22694: PRKACB; NbExp=3; IntAct=EBI-77613, EBI-2679622;
CC       P05067; P22694-8: PRKACB; NbExp=3; IntAct=EBI-77613, EBI-25937151;
CC       P05067; P22612: PRKACG; NbExp=3; IntAct=EBI-77613, EBI-3907086;
CC       P05067; Q9UGJ0-3: PRKAG2; NbExp=3; IntAct=EBI-77613, EBI-25939641;
CC       P05067; Q05655: PRKCD; NbExp=3; IntAct=EBI-77613, EBI-704279;
CC       P05067; Q02156: PRKCE; NbExp=3; IntAct=EBI-77613, EBI-706254;
CC       P05067; O60260-5: PRKN; NbExp=5; IntAct=EBI-77613, EBI-21251460;
CC       P05067; P04156: PRNP; NbExp=6; IntAct=EBI-77613, EBI-977302;
CC       P05067; P60891: PRPS1; NbExp=3; IntAct=EBI-77613, EBI-749195;
CC       P05067; P07602: PSAP; NbExp=3; IntAct=EBI-77613, EBI-716699;
CC       P05067; P49768: PSEN1; NbExp=6; IntAct=EBI-77613, EBI-297277;
CC       P05067; P49768-2: PSEN1; NbExp=6; IntAct=EBI-77613, EBI-11047108;
CC       P05067; P49810: PSEN2; NbExp=4; IntAct=EBI-77613, EBI-2010251;
CC       P05067; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-77613, EBI-998468;
CC       P05067; P28062-2: PSMB8; NbExp=3; IntAct=EBI-77613, EBI-372312;
CC       P05067; P17980: PSMC3; NbExp=6; IntAct=EBI-77613, EBI-359720;
CC       P05067; Q14289: PTK2B; NbExp=3; IntAct=EBI-77613, EBI-298640;
CC       P05067; P20340-2: RAB6A; NbExp=3; IntAct=EBI-77613, EBI-8840191;
CC       P05067; P63000: RAC1; NbExp=3; IntAct=EBI-77613, EBI-413628;
CC       P05067; P04049: RAF1; NbExp=3; IntAct=EBI-77613, EBI-365996;
CC       P05067; Q96S59: RANBP9; NbExp=3; IntAct=EBI-77613, EBI-636085;
CC       P05067; Q9Y272: RASD1; NbExp=3; IntAct=EBI-77613, EBI-740818;
CC       P05067; P61586: RHOA; NbExp=3; IntAct=EBI-77613, EBI-446668;
CC       P05067; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-77613, EBI-396669;
CC       P05067; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-77613, EBI-21535400;
CC       P05067; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-77613, EBI-25829984;
CC       P05067; O75116: ROCK2; NbExp=6; IntAct=EBI-77613, EBI-366288;
CC       P05067; P46779: RPL28; NbExp=3; IntAct=EBI-77613, EBI-366357;
CC       P05067; Q15349: RPS6KA2; NbExp=3; IntAct=EBI-77613, EBI-1384149;
CC       P05067; P23443-4: RPS6KB1; NbExp=3; IntAct=EBI-77613, EBI-25882353;
CC       P05067; P04271: S100B; NbExp=3; IntAct=EBI-77613, EBI-458391;
CC       P05067; P21673: SAT1; NbExp=3; IntAct=EBI-77613, EBI-711613;
CC       P05067; Q6AZY7-2: SCARA3; NbExp=3; IntAct=EBI-77613, EBI-21598366;
CC       P05067; Q8WTV0: SCARB1; NbExp=3; IntAct=EBI-77613, EBI-78657;
CC       P05067; P18827: SDC1; NbExp=3; IntAct=EBI-77613, EBI-2855248;
CC       P05067; Q15019-3: SEPTIN2; NbExp=3; IntAct=EBI-77613, EBI-11525407;
CC       P05067; O43236: SEPTIN4; NbExp=3; IntAct=EBI-77613, EBI-1047513;
CC       P05067; Q99719: SEPTIN5; NbExp=3; IntAct=EBI-77613, EBI-373345;
CC       P05067; Q92599-3: SEPTIN8; NbExp=3; IntAct=EBI-77613, EBI-25891137;
CC       P05067; P01011: SERPINA3; NbExp=3; IntAct=EBI-77613, EBI-296557;
CC       P05067; P29353: SHC1; NbExp=6; IntAct=EBI-77613, EBI-78835;
CC       P05067; Q92529: SHC3; NbExp=5; IntAct=EBI-77613, EBI-79084;
CC       P05067; Q8IUQ4-2: SIAH1; NbExp=3; IntAct=EBI-77613, EBI-11522811;
CC       P05067; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-77613, EBI-358545;
CC       P05067; Q7Z2H8: SLC36A1; NbExp=3; IntAct=EBI-77613, EBI-9978258;
CC       P05067; Q9NP59: SLC40A1; NbExp=5; IntAct=EBI-77613, EBI-725153;
CC       P05067; P84022: SMAD3; NbExp=3; IntAct=EBI-77613, EBI-347161;
CC       P05067; Q13485: SMAD4; NbExp=3; IntAct=EBI-77613, EBI-347263;
CC       P05067; P37840: SNCA; NbExp=6; IntAct=EBI-77613, EBI-985879;
CC       P05067; Q16143: SNCB; NbExp=3; IntAct=EBI-77613, EBI-727106;
CC       P05067; Q15036: SNX17; NbExp=3; IntAct=EBI-77613, EBI-1752620;
CC       P05067; O60749: SNX2; NbExp=3; IntAct=EBI-77613, EBI-1046690;
CC       P05067; Q8WV41: SNX33; NbExp=3; IntAct=EBI-77613, EBI-2481535;
CC       P05067; Q9UNH7: SNX6; NbExp=3; IntAct=EBI-77613, EBI-949294;
CC       P05067; Q92673: SORL1; NbExp=5; IntAct=EBI-77613, EBI-1171329;
CC       P05067; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-77613, EBI-11959123;
CC       P05067; P11277: SPTB; NbExp=6; IntAct=EBI-77613, EBI-514908;
CC       P05067; Q13501: SQSTM1; NbExp=6; IntAct=EBI-77613, EBI-307104;
CC       P05067; P61278: SST; NbExp=3; IntAct=EBI-77613, EBI-20823968;
CC       P05067; P32745: SSTR3; NbExp=3; IntAct=EBI-77613, EBI-6266935;
CC       P05067; P40763-2: STAT3; NbExp=3; IntAct=EBI-77613, EBI-10692009;
CC       P05067; Q8IWL8: STH; NbExp=3; IntAct=EBI-77613, EBI-12843506;
CC       P05067; O14662-5: STX16; NbExp=3; IntAct=EBI-77613, EBI-9089968;
CC       P05067; Q13190-4: STX5; NbExp=3; IntAct=EBI-77613, EBI-25938350;
CC       P05067; O43752: STX6; NbExp=3; IntAct=EBI-77613, EBI-2695795;
CC       P05067; P61764: STXBP1; NbExp=7; IntAct=EBI-77613, EBI-960169;
CC       P05067; Q9Y5B9: SUPT16H; NbExp=3; IntAct=EBI-77613, EBI-1046849;
CC       P05067; P43405: SYK; NbExp=3; IntAct=EBI-77613, EBI-78302;
CC       P05067; P43405-2: SYK; NbExp=3; IntAct=EBI-77613, EBI-25892332;
CC       P05067; P08247: SYP; NbExp=3; IntAct=EBI-77613, EBI-9071725;
CC       P05067; Q13148: TARDBP; NbExp=6; IntAct=EBI-77613, EBI-372899;
CC       P05067; P20226: TBP; NbExp=3; IntAct=EBI-77613, EBI-355371;
CC       P05067; Q16650: TBR1; NbExp=3; IntAct=EBI-77613, EBI-1047158;
CC       P05067; O43680: TCF21; NbExp=3; IntAct=EBI-77613, EBI-723267;
CC       P05067; P01137: TGFB1; NbExp=3; IntAct=EBI-77613, EBI-779636;
CC       P05067; P61812: TGFB2; NbExp=7; IntAct=EBI-77613, EBI-779581;
CC       P05067; Q15583: TGIF1; NbExp=3; IntAct=EBI-77613, EBI-714215;
CC       P05067; Q15583-2: TGIF1; NbExp=3; IntAct=EBI-77613, EBI-12691451;
CC       P05067; P04216: THY1; NbExp=3; IntAct=EBI-77613, EBI-9071715;
CC       P05067; P04183: TK1; NbExp=3; IntAct=EBI-77613, EBI-712550;
CC       P05067; Q9BX74: TM2D1; NbExp=3; IntAct=EBI-77613, EBI-25832057;
CC       P05067; P49755: TMED10; NbExp=3; IntAct=EBI-77613, EBI-998422;
CC       P05067; Q9BTD3: TMEM121; NbExp=3; IntAct=EBI-77613, EBI-12155101;
CC       P05067; Q9NV96: TMEM30A; NbExp=3; IntAct=EBI-77613, EBI-2836942;
CC       P05067; P62328: TMSB4X; NbExp=3; IntAct=EBI-77613, EBI-712598;
CC       P05067; P01375: TNF; NbExp=3; IntAct=EBI-77613, EBI-359977;
CC       P05067; O75509: TNFRSF21; NbExp=2; IntAct=EBI-77613, EBI-2313231;
CC       P05067; O43508: TNFSF12; NbExp=3; IntAct=EBI-77613, EBI-6932080;
CC       P05067; O75888-3: TNFSF13; NbExp=3; IntAct=EBI-77613, EBI-12856452;
CC       P05067; Q96GM8: TOE1; NbExp=3; IntAct=EBI-77613, EBI-717460;
CC       P05067; O14656: TOR1A; NbExp=3; IntAct=EBI-77613, EBI-524257;
CC       P05067; O14656-2: TOR1A; NbExp=3; IntAct=EBI-77613, EBI-25847109;
CC       P05067; Q05BL1: TP53BP2; NbExp=3; IntAct=EBI-77613, EBI-11952721;
CC       P05067; Q13625: TP53BP2; NbExp=3; IntAct=EBI-77613, EBI-77642;
CC       P05067; Q9C026: TRIM9; NbExp=3; IntAct=EBI-77613, EBI-720828;
CC       P05067; Q15714-2: TSC22D1; NbExp=3; IntAct=EBI-77613, EBI-12034704;
CC       P05067; P02766: TTR; NbExp=3; IntAct=EBI-77613, EBI-711909;
CC       P05067; Q71U36: TUBA1A; NbExp=3; IntAct=EBI-77613, EBI-302552;
CC       P05067; P68363: TUBA1B; NbExp=3; IntAct=EBI-77613, EBI-487083;
CC       P05067; P68366: TUBA4A; NbExp=3; IntAct=EBI-77613, EBI-351772;
CC       P05067; P07437: TUBB; NbExp=5; IntAct=EBI-77613, EBI-350864;
CC       P05067; Q8TBC4: UBA3; NbExp=3; IntAct=EBI-77613, EBI-717567;
CC       P05067; P0CG47: UBB; NbExp=3; IntAct=EBI-77613, EBI-413034;
CC       P05067; P62837: UBE2D2; NbExp=3; IntAct=EBI-77613, EBI-347677;
CC       P05067; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-77613, EBI-741480;
CC       P05067; P09936: UCHL1; NbExp=5; IntAct=EBI-77613, EBI-714860;
CC       P05067; P13051-2: UNG; NbExp=3; IntAct=EBI-77613, EBI-25834258;
CC       P05067; O75604-3: USP2; NbExp=3; IntAct=EBI-77613, EBI-10696113;
CC       P05067; Q9BVJ6: UTP14A; NbExp=3; IntAct=EBI-77613, EBI-473284;
CC       P05067; Q9H270: VPS11; NbExp=3; IntAct=EBI-77613, EBI-373380;
CC       P05067; Q8N0S8: VPS29; NbExp=3; IntAct=EBI-77613, EBI-25892084;
CC       P05067; Q96AX1: VPS33A; NbExp=3; IntAct=EBI-77613, EBI-2527283;
CC       P05067; Q96QK1: VPS35; NbExp=3; IntAct=EBI-77613, EBI-1054634;
CC       P05067; O76024: WFS1; NbExp=3; IntAct=EBI-77613, EBI-720609;
CC       P05067; O00744: WNT10B; NbExp=3; IntAct=EBI-77613, EBI-21797207;
CC       P05067; P19544-6: WT1; NbExp=3; IntAct=EBI-77613, EBI-11745701;
CC       P05067; P31946: YWHAB; NbExp=3; IntAct=EBI-77613, EBI-359815;
CC       P05067; O60293: ZFC3H1; NbExp=3; IntAct=EBI-77613, EBI-746701;
CC       P05067; P17028: ZNF24; NbExp=3; IntAct=EBI-77613, EBI-707773;
CC       P05067; Q8N895: ZNF366; NbExp=3; IntAct=EBI-77613, EBI-2813661;
CC       P05067; Q03936: ZNF92; NbExp=4; IntAct=EBI-77613, EBI-12176441;
CC       P05067; Q8NHT4; NbExp=3; IntAct=EBI-77613, EBI-25939025;
CC       P05067; O35431: Apba2; Xeno; NbExp=5; IntAct=EBI-77613, EBI-2028211;
CC       P05067; P15253: CALR; Xeno; NbExp=3; IntAct=EBI-77613, EBI-9005200;
CC       P05067; Q9WVI9-1: Mapk8ip1; Xeno; NbExp=2; IntAct=EBI-77613, EBI-288461;
CC       P05067; Q8BGY9: Slc5a7; Xeno; NbExp=2; IntAct=EBI-77613, EBI-2010752;
CC       P05067; Q306T3; Xeno; NbExp=3; IntAct=EBI-77613, EBI-8294101;
CC       P05067-2; Q9H7C9: AAMDC; NbExp=3; IntAct=EBI-17264467, EBI-10308705;
CC       P05067-2; P63010-2: AP2B1; NbExp=3; IntAct=EBI-17264467, EBI-11529439;
CC       P05067-2; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-17264467, EBI-10186132;
CC       P05067-2; O15392: BIRC5; NbExp=3; IntAct=EBI-17264467, EBI-518823;
CC       P05067-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-17264467, EBI-396453;
CC       P05067-2; P06241-3: FYN; NbExp=3; IntAct=EBI-17264467, EBI-10691738;
CC       P05067-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-17264467, EBI-2806068;
CC       P05067-2; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-17264467, EBI-21911304;
CC       P05067-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-17264467, EBI-1044640;
CC       P05067-2; O95447: LCA5L; NbExp=3; IntAct=EBI-17264467, EBI-8473670;
CC       P05067-2; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-17264467, EBI-1108377;
CC       P05067-2; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-17264467, EBI-4397720;
CC       P05067-2; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-17264467, EBI-21250407;
CC       P05067-2; P15941-11: MUC1; NbExp=3; IntAct=EBI-17264467, EBI-17263240;
CC       P05067-2; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-17264467, EBI-716063;
CC       P05067-2; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-17264467, EBI-21535400;
CC       P05067-2; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-17264467, EBI-25829984;
CC       P05067-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-17264467, EBI-10182463;
CC       P05067-2; Q8IUQ4-2: SIAH1; NbExp=3; IntAct=EBI-17264467, EBI-11522811;
CC       P05067-2; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-17264467, EBI-358545;
CC       P05067-2; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-17264467, EBI-11959123;
CC       P05067-2; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-17264467, EBI-2510414;
CC       P05067-2; Q13148: TARDBP; NbExp=3; IntAct=EBI-17264467, EBI-372899;
CC       P05067-2; Q16650: TBR1; NbExp=3; IntAct=EBI-17264467, EBI-1047158;
CC       P05067-2; Q5HYA8: TMEM67; NbExp=3; IntAct=EBI-17264467, EBI-11334880;
CC       P05067-2; P09936: UCHL1; NbExp=3; IntAct=EBI-17264467, EBI-714860;
CC       P05067-4; O00213: APBB1; NbExp=5; IntAct=EBI-302641, EBI-81694;
CC       P05067-4; P51693: APLP1; NbExp=2; IntAct=EBI-302641, EBI-74648;
CC       P05067-4; Q06481: APLP2; NbExp=2; IntAct=EBI-302641, EBI-79306;
CC       P05067-4; P05067-4: APP; NbExp=8; IntAct=EBI-302641, EBI-302641;
CC       P05067-4; Q13867: BLMH; NbExp=2; IntAct=EBI-302641, EBI-718504;
CC       P05067-4; Q9NZU0: FLRT3; NbExp=3; IntAct=EBI-302641, EBI-1057092;
CC       P05067-4; P46089: GPR3; NbExp=2; IntAct=EBI-302641, EBI-3909653;
CC       P05067-4; O43736: ITM2A; NbExp=3; IntAct=EBI-302641, EBI-2431769;
CC       P05067-4; Q68DU8: KCTD16; NbExp=3; IntAct=EBI-302641, EBI-20768174;
CC       P05067-4; Q96FE5: LINGO1; NbExp=2; IntAct=EBI-302641, EBI-719955;
CC       P05067-4; P04629: NTRK1; NbExp=7; IntAct=EBI-302641, EBI-1028226;
CC       P05067-4; Q13526: PIN1; NbExp=2; IntAct=EBI-302641, EBI-714158;
CC       P05067-4; P60201: PLP1; NbExp=5; IntAct=EBI-302641, EBI-8653150;
CC       P05067-4; P04156: PRNP; NbExp=2; IntAct=EBI-302641, EBI-977302;
CC       P05067-4; P49768: PSEN1; NbExp=4; IntAct=EBI-302641, EBI-297277;
CC       P05067-4; Q92673: SORL1; NbExp=8; IntAct=EBI-302641, EBI-1171329;
CC       P05067-4; PRO_0000033163 [Q99523]: SORT1; NbExp=4; IntAct=EBI-302641, EBI-21467118;
CC       P05067-4; Q9HCB6: SPON1; NbExp=3; IntAct=EBI-302641, EBI-2431846;
CC       P05067-4; O95793: STAU1; NbExp=2; IntAct=EBI-302641, EBI-358174;
CC       P05067-4; O35430: Apba1; Xeno; NbExp=2; IntAct=EBI-302641, EBI-704760;
CC       P05067-4; O35431: Apba2; Xeno; NbExp=2; IntAct=EBI-302641, EBI-2028211;
CC       P05067-4; O70248: Apba3; Xeno; NbExp=2; IntAct=EBI-302641, EBI-8513381;
CC       P05067-4; Q8VEK0: Tmem30a; Xeno; NbExp=6; IntAct=EBI-302641, EBI-8381028;
CC       P05067-8; P17677: GAP43; NbExp=3; IntAct=EBI-302661, EBI-1267511;
CC       P05067-8; Q9NSC5: HOMER3; NbExp=3; IntAct=EBI-302661, EBI-748420;
CC       P05067-8; Q9Y287: ITM2B; NbExp=4; IntAct=EBI-302661, EBI-2866431;
CC       PRO_0000000089; O95631: NTN1; NbExp=3; IntAct=EBI-20829246, EBI-2678626;
CC       PRO_0000000090; Q9UIK5: TMEFF2; NbExp=3; IntAct=EBI-21194918, EBI-11423693;
CC       PRO_0000000091; Q92673: SORL1; NbExp=4; IntAct=EBI-3894543, EBI-1171329;
CC       PRO_0000000091; Q8K3H7: CALR; Xeno; NbExp=2; IntAct=EBI-3894543, EBI-9005068;
CC       PRO_0000000091; Q8VEK0: Tmem30a; Xeno; NbExp=3; IntAct=EBI-3894543, EBI-8381028;
CC       PRO_0000000092; Q9BYF1: ACE2; NbExp=3; IntAct=EBI-821758, EBI-7730807;
CC       PRO_0000000092; PRO_0000000092 [P05067]: APP; NbExp=77; IntAct=EBI-821758, EBI-821758;
CC       PRO_0000000092; P48047: ATP5PO; NbExp=2; IntAct=EBI-821758, EBI-355815;
CC       PRO_0000000092; P36544: CHRNA7; NbExp=7; IntAct=EBI-821758, EBI-79333;
CC       PRO_0000000092; P10909-5: CLU; NbExp=2; IntAct=EBI-821758, EBI-10961636;
CC       PRO_0000000092; PRO_0000005794 [P39060]: COL18A1; NbExp=2; IntAct=EBI-821758, EBI-2566375;
CC       PRO_0000000092; PRO_0000033156 [O00230]: CORT; NbExp=4; IntAct=EBI-821758, EBI-20824092;
CC       PRO_0000000092; Q99714: HSD17B10; NbExp=2; IntAct=EBI-821758, EBI-79964;
CC       PRO_0000000092; Q8N423: LILRB2; NbExp=7; IntAct=EBI-821758, EBI-2816428;
CC       PRO_0000000092; P10636: MAPT; NbExp=5; IntAct=EBI-821758, EBI-366182;
CC       PRO_0000000092; P08253: MMP2; NbExp=4; IntAct=EBI-821758, EBI-1033518;
CC       PRO_0000000092; Q9NZV6: MSRB1; NbExp=4; IntAct=EBI-821758, EBI-12330065;
CC       PRO_0000000092; P03897: MT-ND3; NbExp=2; IntAct=EBI-821758, EBI-1246249;
CC       PRO_0000000092; Q8IVG9: MT-RNR2; NbExp=4; IntAct=EBI-821758, EBI-8643752;
CC       PRO_0000000092; O95411: MYO18A; NbExp=3; IntAct=EBI-821758, EBI-302378;
CC       PRO_0000000092; O95631: NTN1; NbExp=6; IntAct=EBI-821758, EBI-2678626;
CC       PRO_0000000092; Q15113: PCOLCE; NbExp=4; IntAct=EBI-821758, EBI-8869614;
CC       PRO_0000000092; Q08752: PPID; NbExp=4; IntAct=EBI-821758, EBI-716596;
CC       PRO_0000000092; P30405: PPIF; NbExp=2; IntAct=EBI-821758, EBI-5544229;
CC       PRO_0000000092; P04156: PRNP; NbExp=3; IntAct=EBI-821758, EBI-977302;
CC       PRO_0000000092; P11686-1: SFTPC; NbExp=5; IntAct=EBI-821758, EBI-16143688;
CC       PRO_0000000092; PRO_0000033088 [P61278]: SST; NbExp=8; IntAct=EBI-821758, EBI-20824010;
CC       PRO_0000000092; P21980: TGM2; NbExp=2; IntAct=EBI-821758, EBI-727668;
CC       PRO_0000000092; O60602: TLR5; NbExp=3; IntAct=EBI-821758, EBI-3505951;
CC       PRO_0000000092; Q9NZC2: TREM2; NbExp=4; IntAct=EBI-821758, EBI-14036387;
CC       PRO_0000000092; P02766: TTR; NbExp=2; IntAct=EBI-821758, EBI-711909;
CC       PRO_0000000092; P15253: CALR; Xeno; NbExp=2; IntAct=EBI-821758, EBI-9005200;
CC       PRO_0000000092; Q05941: Chrna7; Xeno; NbExp=3; IntAct=EBI-821758, EBI-79422;
CC       PRO_0000000092; P03452: HA; Xeno; NbExp=2; IntAct=EBI-821758, EBI-2548105;
CC       PRO_0000000092; P97484: Pirb; Xeno; NbExp=8; IntAct=EBI-821758, EBI-15728641;
CC       PRO_0000000092; K9N5Q8: S; Xeno; NbExp=2; IntAct=EBI-821758, EBI-25474996;
CC       PRO_0000000092; PRO_0000449647 [P0DTC2]: S; Xeno; NbExp=3; IntAct=EBI-821758, EBI-25490323;
CC       PRO_0000000092; Q99NH8: Trem2; Xeno; NbExp=2; IntAct=EBI-821758, EBI-15982016;
CC       PRO_0000000093; P02649: APOE; NbExp=4; IntAct=EBI-2431589, EBI-1222467;
CC       PRO_0000000093; PRO_0000000093 [P05067]: APP; NbExp=29; IntAct=EBI-2431589, EBI-2431589;
CC       PRO_0000000093; P10909: CLU; NbExp=4; IntAct=EBI-2431589, EBI-1104674;
CC       PRO_0000000093; P49840: GSK3A; NbExp=3; IntAct=EBI-2431589, EBI-1044067;
CC       PRO_0000000093; P49841: GSK3B; NbExp=2; IntAct=EBI-2431589, EBI-373586;
CC       PRO_0000000093; P14735-1: IDE; NbExp=3; IntAct=EBI-2431589, EBI-15607031;
CC       PRO_0000000093; P08253: MMP2; NbExp=2; IntAct=EBI-2431589, EBI-1033518;
CC       PRO_0000000093; P08138: NGFR; NbExp=2; IntAct=EBI-2431589, EBI-1387782;
CC       PRO_0000000093; Q5JRX3-1: PITRM1; NbExp=3; IntAct=EBI-2431589, EBI-16109799;
CC       PRO_0000000093; Q08752: PPID; NbExp=2; IntAct=EBI-2431589, EBI-716596;
CC       PRO_0000000093; Q92673: SORL1; NbExp=3; IntAct=EBI-2431589, EBI-1171329;
CC       PRO_0000000093; O60602: TLR5; NbExp=3; IntAct=EBI-2431589, EBI-3505951;
CC       PRO_0000000093; P31696: AGRN; Xeno; NbExp=3; IntAct=EBI-2431589, EBI-457650;
CC       PRO_0000000093; P15253: CALR; Xeno; NbExp=2; IntAct=EBI-2431589, EBI-9005200;
CC       PRO_0000000093; P07174: Ngfr; Xeno; NbExp=2; IntAct=EBI-2431589, EBI-1038810;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10383380,
CC       ECO:0000269|PubMed:20580937, ECO:0000269|PubMed:2649245,
CC       ECO:0000305|PubMed:25122912}; Single-pass type I membrane protein
CC       {ECO:0000269|PubMed:30630874, ECO:0000305|PubMed:10383380,
CC       ECO:0000305|PubMed:25122912}. Membrane {ECO:0000269|PubMed:2900137,
CC       ECO:0000305|PubMed:22584060}; Single-pass type I membrane protein
CC       {ECO:0000269|PubMed:2900137, ECO:0000269|PubMed:30630874,
CC       ECO:0000305|PubMed:22584060}. Perikaryon {ECO:0000269|PubMed:10341243}.
CC       Cell projection, growth cone {ECO:0000269|PubMed:10341243}. Membrane,
CC       clathrin-coated pit {ECO:0000269|PubMed:20580937}. Early endosome
CC       {ECO:0000269|PubMed:20580937}. Cytoplasmic vesicle
CC       {ECO:0000269|PubMed:20580937, ECO:0000269|PubMed:25122912}. Note=Cell
CC       surface protein that rapidly becomes internalized via clathrin-coated
CC       pits. Only a minor proportion is present at the cell membrane; most of
CC       the protein is present in intracellular vesicles (PubMed:20580937).
CC       During maturation, the immature APP (N-glycosylated in the endoplasmic
CC       reticulum) moves to the Golgi complex where complete maturation occurs
CC       (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble
CC       APP is released into the extracellular space and the C-terminal is
CC       internalized to endosomes and lysosomes. Some APP accumulates in
CC       secretory transport vesicles leaving the late Golgi compartment and
CC       returns to the cell surface. APP sorts to the basolateral surface in
CC       epithelial cells. During neuronal differentiation, the Thr-743
CC       phosphorylated form is located mainly in growth cones, moderately in
CC       neurites and sparingly in the cell body (PubMed:10341243). Casein
CC       kinase phosphorylation can occur either at the cell surface or within a
CC       post-Golgi compartment. Associates with GPC1 in perinuclear
CC       compartments. Colocalizes with SORL1 in a vesicular pattern in
CC       cytoplasm and perinuclear regions. {ECO:0000269|PubMed:10341243,
CC       ECO:0000269|PubMed:20580937}.
CC   -!- SUBCELLULAR LOCATION: [C83]: Endoplasmic reticulum
CC       {ECO:0000269|PubMed:14527950}. Golgi apparatus
CC       {ECO:0000269|PubMed:14527950}. Early endosome
CC       {ECO:0000269|PubMed:14527950}.
CC   -!- SUBCELLULAR LOCATION: [C99]: Early endosome
CC       {ECO:0000269|PubMed:14527950}.
CC   -!- SUBCELLULAR LOCATION: [Soluble APP-beta]: Secreted
CC       {ECO:0000269|PubMed:10656250, ECO:0000269|PubMed:2649245}.
CC   -!- SUBCELLULAR LOCATION: [Amyloid-beta protein 40]: Cell surface
CC       {ECO:0000269|PubMed:16154999}.
CC   -!- SUBCELLULAR LOCATION: [Amyloid-beta protein 42]: Cell surface
CC       {ECO:0000269|PubMed:11689470, ECO:0000269|PubMed:16154999}.
CC       Note=Associates with FPR2 at the cell surface and the complex is then
CC       rapidly internalized. {ECO:0000269|PubMed:11689470}.
CC   -!- SUBCELLULAR LOCATION: [Gamma-secretase C-terminal fragment 59]: Nucleus
CC       {ECO:0000269|PubMed:11544248}. Cytoplasm {ECO:0000269|PubMed:11544248}.
CC       Note=Located to both the cytoplasm and nuclei of neurons. It can be
CC       translocated to the nucleus through association with APBB1 (Fe65)
CC       (PubMed:11544248). In dopaminergic neurons, the phosphorylated Thr-743
CC       form is localized to the nucleus (By similarity).
CC       {ECO:0000250|UniProtKB:P12023, ECO:0000269|PubMed:11544248}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=11;
CC         Comment=Additional isoforms seem to exist. Experimental confirmation
CC         may be lacking for some isoforms.;
CC       Name=APP770; Synonyms=PreA4 770;
CC         IsoId=P05067-1; Sequence=Displayed;
CC       Name=APP305;
CC         IsoId=P05067-2; Sequence=VSP_000005, VSP_000006;
CC       Name=L-APP677;
CC         IsoId=P05067-3; Sequence=VSP_000002, VSP_000004, VSP_000009;
CC       Name=APP695; Synonyms=PreA4 695;
CC         IsoId=P05067-4; Sequence=VSP_000002, VSP_000004;
CC       Name=L-APP696;
CC         IsoId=P05067-5; Sequence=VSP_000002, VSP_000003, VSP_000009;
CC       Name=APP714;
CC         IsoId=P05067-6; Sequence=VSP_000002, VSP_000003;
CC       Name=L-APP733;
CC         IsoId=P05067-7; Sequence=VSP_000007, VSP_000008, VSP_000009;
CC       Name=APP751; Synonyms=PreA4 751;
CC         IsoId=P05067-8; Sequence=VSP_000007, VSP_000008;
CC       Name=L-APP752;
CC         IsoId=P05067-9; Sequence=VSP_000009;
CC       Name=APP639;
CC         IsoId=P05067-10; Sequence=VSP_009116, VSP_009117, VSP_009118;
CC       Name=11;
CC         IsoId=P05067-11; Sequence=VSP_045446, VSP_045447;
CC   -!- TISSUE SPECIFICITY: Expressed in the brain and in cerebrospinal fluid
CC       (at protein level) (PubMed:2649245). Expressed in all fetal tissues
CC       examined with highest levels in brain, kidney, heart and spleen. Weak
CC       expression in liver. In adult brain, highest expression found in the
CC       frontal lobe of the cortex and in the anterior perisylvian cortex-
CC       opercular gyri. Moderate expression in the cerebellar cortex, the
CC       posterior perisylvian cortex-opercular gyri and the temporal associated
CC       cortex. Weak expression found in the striate, extra-striate and motor
CC       cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695
CC       is the predominant form in neuronal tissue, isoform APP751 and isoform
CC       APP770 are widely expressed in non-neuronal cells. Isoform APP751 is
CC       the most abundant form in T-lymphocytes. Appican is expressed in
CC       astrocytes. {ECO:0000269|PubMed:12859342, ECO:0000269|PubMed:1406936,
CC       ECO:0000269|PubMed:2649245}.
CC   -!- INDUCTION: Increased levels during neuronal differentiation.
CC   -!- DOMAIN: The transmembrane helix undergoes a conformation change and
CC       unravels partially when bound to PSEN1, facilitating cleavage by PSEN1.
CC       {ECO:0000269|PubMed:30630874}.
CC   -!- DOMAIN: The basolateral sorting signal (BaSS) is required for sorting
CC       of membrane proteins to the basolateral surface of epithelial cells.
CC       {ECO:0000269|PubMed:9843960}.
CC   -!- DOMAIN: The GFLD subdomain binds Cu(2+) ions; this promotes
CC       homodimerization. {ECO:0000269|PubMed:25122912}.
CC   -!- DOMAIN: The NPXY sequence motif found in many tyrosine-phosphorylated
CC       proteins is required for the specific binding of the PID domain.
CC       However, additional amino acids either N- or C-terminal to the NPXY
CC       motif are often required for complete interaction. The PID domain-
CC       containing proteins which bind APP require the YENPTY motif for full
CC       interaction. These interactions are independent of phosphorylation on
CC       the terminal tyrosine residue. The YENPXY site is also involved in
CC       clathrin-mediated endocytosis. {ECO:0000269|PubMed:10383380}.
CC   -!- DOMAIN: The C-terminal region can bind zinc ions; this favors
CC       dimerization and formation of higher oligomers.
CC       {ECO:0000269|PubMed:26898943, ECO:0000269|PubMed:28570778}.
CC   -!- DOMAIN: The OX-2 motif shows some similarity to a region in the N-
CC       terminus of CD200/MOX2. {ECO:0000269|PubMed:2649245}.
CC   -!- PTM: Proteolytically processed under normal cellular conditions.
CC       Cleavage either by alpha-secretase, beta-secretase or theta-secretase
CC       leads to generation and extracellular release of soluble APP peptides,
CC       S-APP-alpha and S-APP-beta, and the retention of corresponding
CC       membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent
CC       processing of C80 and C83 by gamma-secretase yields P3 peptides. This
CC       is the major secretory pathway and is non-amyloidogenic. Alternatively,
CC       presenilin/nicastrin-mediated gamma-secretase processing of C99
CC       releases the amyloid-beta proteins, amyloid-beta protein 40 and
CC       amyloid-beta protein 42, major components of amyloid plaques, and the
CC       cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-
CC       CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as
CC       substrate (in vitro) (PubMed:30630874). Amyloid-beta protein 40 and
CC       Amyloid-beta protein 42 are cleaved by ACE (PubMed:11604391,
CC       PubMed:16154999). Many other minor amyloid-beta peptides, amyloid-beta
CC       1-X peptides, are found in cerebral spinal fluid (CSF) including the
CC       amyloid-beta X-15 peptides, produced from the cleavage by alpha-
CC       secretase and all terminating at Gln-686. {ECO:0000269|PubMed:10656250,
CC       ECO:0000269|PubMed:11604391, ECO:0000269|PubMed:16154999,
CC       ECO:0000269|PubMed:30630874}.
CC   -!- PTM: Proteolytically cleaved by caspases during neuronal apoptosis.
CC       Cleavage at Asp-739 by either CASP6, CASP8 or CASP9 results in the
CC       production of the neurotoxic C31 peptide and the increased production
CC       of amyloid-beta peptides. {ECO:0000269|PubMed:10319819}.
CC   -!- PTM: N-glycosylated (PubMed:2900137). N- and O-glycosylated
CC       (PubMed:2649245). O-glycosylation on Ser and Thr residues with core 1
CC       or possibly core 8 glycans. Partial tyrosine glycosylation (Tyr-681) is
CC       found on some minor, short amyloid-beta peptides (amyloid-beta 1-15, 1-
CC       16, 1-17, 1-18, 1-19 and 1-20) but not found on amyloid-beta protein
CC       38, amyloid-beta protein 40 nor on amyloid-beta protein 42.
CC       Modification on a tyrosine is unusual and is more prevelant in AD
CC       patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr,
CC       Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O-
CC       AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is O-
CC       acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac 2,8Neu5Ac
CC       linked. O-glycosylations in the vicinity of the cleavage sites may
CC       influence the proteolytic processing. Appicans are L-APP isoforms with
CC       O-linked chondroitin sulfate. {ECO:0000269|PubMed:16335952,
CC       ECO:0000269|PubMed:21712440, ECO:0000269|PubMed:22576872,
CC       ECO:0000269|PubMed:2649245, ECO:0000269|PubMed:2900137}.
CC   -!- PTM: Phosphorylation in the C-terminal on tyrosine, threonine and
CC       serine residues is neuron-specific (PubMed:10341243). Phosphorylation
CC       can affect APP processing, neuronal differentiation and interaction
CC       with other proteins (PubMed:10341243). Phosphorylated on Thr-743 in
CC       neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2
CC       kinase in a cell-cycle dependent manner with maximal levels at the G2/M
CC       phase and, in vitro, by GSK-3-beta (PubMed:11146006, PubMed:8131745).
CC       The Thr-743 phosphorylated form causes a conformational change which
CC       reduces binding of Fe65 family members (PubMed:11517218). In
CC       dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes
CC       the production and the nuclear translocation of the APP intracellular
CC       domain (AICD) which induces DA neuron apoptosis (PubMed:28720718).
CC       Phosphorylation on Tyr-757 is required for SHC binding
CC       (PubMed:11877420). Phosphorylated in the extracellular domain by casein
CC       kinases on both soluble and membrane-bound APP. This phosphorylation is
CC       inhibited by heparin (PubMed:8999878). {ECO:0000269|PubMed:10341243,
CC       ECO:0000269|PubMed:11146006, ECO:0000269|PubMed:11517218,
CC       ECO:0000269|PubMed:11877420, ECO:0000269|PubMed:28720718,
CC       ECO:0000269|PubMed:8131745, ECO:0000269|PubMed:8999878}.
CC   -!- PTM: Extracellular binding and reduction of copper, results in a
CC       corresponding oxidation of Cys-144 and Cys-158, and the formation of a
CC       disulfide bond. In vitro, the APP-Cu(+) complex in the presence of
CC       hydrogen peroxide results in an increased production of amyloid-beta-
CC       containing peptides.
CC   -!- PTM: Trophic-factor deprivation triggers the cleavage of surface APP by
CC       beta-secretase to release sAPP-beta which is further cleaved to release
CC       an N-terminal fragment of APP (N-APP).
CC   -!- PTM: Amyloid-beta peptides are degraded by IDE.
CC       {ECO:0000250|UniProtKB:P12023}.
CC   -!- PTM: Sulfated on tyrosine residues. {ECO:0000269|PubMed:2649245}.
CC   -!- MASS SPECTROMETRY: [Gamma-secretase C-terminal fragment 59]:
CC       Mass=6461.6; Method=MALDI; Evidence={ECO:0000269|PubMed:12214090};
CC   -!- MASS SPECTROMETRY: [Gamma-secretase C-terminal fragment 57]:
CC       Mass=6451.6; Method=MALDI; Evidence={ECO:0000269|PubMed:12214090};
CC   -!- DISEASE: Alzheimer disease 1 (AD1) [MIM:104300]: A form of Alzheimer
CC       disease, a neurodegenerative disorder characterized by progressive
CC       dementia, loss of cognitive abilities, and deposition of fibrillar
CC       amyloid proteins as intraneuronal neurofibrillary tangles,
CC       extracellular amyloid plaques and vascular amyloid deposits. The major
CC       constituents of these plaques are neurotoxic amyloid-beta protein 40
CC       and amyloid-beta protein 42, that are produced by the proteolysis of
CC       the transmembrane APP protein. The cytotoxic C-terminal fragments
CC       (CTFs) and the caspase-cleaved products, such as C31, are also
CC       implicated in neuronal death. It can be associated with cerebral
CC       amyloid angiopathy. Alzheimer disease can be associated with cerebral
CC       amyloid angiopathy. {ECO:0000269|PubMed:10097173,
CC       ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10656250,
CC       ECO:0000269|PubMed:10665499, ECO:0000269|PubMed:10677483,
CC       ECO:0000269|PubMed:10867787, ECO:0000269|PubMed:11063718,
CC       ECO:0000269|PubMed:11311152, ECO:0000269|PubMed:11528419,
CC       ECO:0000269|PubMed:12034808, ECO:0000269|PubMed:1302033,
CC       ECO:0000269|PubMed:1303239, ECO:0000269|PubMed:1303275,
CC       ECO:0000269|PubMed:1415269, ECO:0000269|PubMed:1465129,
CC       ECO:0000269|PubMed:15201367, ECO:0000269|PubMed:15365148,
CC       ECO:0000269|PubMed:15668448, ECO:0000269|PubMed:1671712,
CC       ECO:0000269|PubMed:1678058, ECO:0000269|PubMed:1908231,
CC       ECO:0000269|PubMed:1925564, ECO:0000269|PubMed:1944558,
CC       ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8290042,
CC       ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8577393,
CC       ECO:0000269|PubMed:8886002, ECO:0000269|PubMed:9328472,
CC       ECO:0000269|PubMed:9754958}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Cerebral amyloid angiopathy, APP-related (CAA-APP)
CC       [MIM:605714]: A hereditary localized amyloidosis due to amyloid-beta A4
CC       peptide(s) deposition in the cerebral vessels. The principal clinical
CC       characteristics are recurrent cerebral and cerebellar hemorrhages,
CC       recurrent strokes, cerebral ischemia, cerebral infarction, and
CC       progressive mental deterioration. Patients develop cerebral hemorrhage
CC       because of the severe cerebral amyloid angiopathy. Parenchymal amyloid
CC       deposits are rare and largely in the form of pre-amyloid lesions or
CC       diffuse plaque-like structures. They are Congo red negative and lack
CC       the dense amyloid cores commonly present in Alzheimer disease. Some
CC       affected individuals manifest progressive aphasic dementia,
CC       leukoencephalopathy, and occipital calcifications.
CC       {ECO:0000269|PubMed:11409420, ECO:0000269|PubMed:12654973,
CC       ECO:0000269|PubMed:16178030, ECO:0000269|PubMed:20697050,
CC       ECO:0000269|PubMed:2111584}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: Chelation of metal ions, notably copper, iron and zinc,
CC       can induce histidine-bridging between amyloid-beta molecules resulting
CC       in amyloid-beta-metal aggregates. The affinity for copper is much
CC       higher than for other transient metals and is increased under acidic
CC       conditions. Extracellular zinc-binding increases binding of heparin to
CC       APP and inhibits collagen-binding. {ECO:0000269|PubMed:26898943,
CC       ECO:0000269|PubMed:28570778}.
CC   -!- MISCELLANEOUS: [Isoform APP770]: A major isoform.
CC   -!- MISCELLANEOUS: [Isoform L-APP677]: The L-isoforms are referred to as
CC       appicans. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform APP695]: A major isoform. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform L-APP696]: The L-isoforms are referred to as
CC       appicans. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform L-APP733]: The L-isoforms are referred to as
CC       appicans. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform APP751]: A major isoform. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the APP family. {ECO:0000255|PROSITE-
CC       ProRule:PRU01217}.
CC   -!- CAUTION: Was reported to bind TNFRSF21 triggering caspase activation
CC       and degeneration of both neuronal cell bodies (via caspase-3) and axons
CC       (via caspase-6) (PubMed:19225519). This work was later retracted
CC       (PubMed:38110576). {ECO:0000305|PubMed:19225519,
CC       ECO:0000305|PubMed:38110576}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAA58727.1; Type=Miscellaneous discrepancy; Note=Contamination by an Alu repeat.; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Alzforum; Note=APP mutations;
CC       URL="https://www.alzforum.org/mutations/app";
CC   -!- WEB RESOURCE: Name=AD mutations;
CC       URL="https://uantwerpen.vib.be/CMTMutations";
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Amyloid beta entry;
CC       URL="https://en.wikipedia.org/wiki/Amyloid_beta";
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DR   EMBL; Y00264; CAA68374.1; -; mRNA.
DR   EMBL; X13466; CAA31830.1; -; Genomic_DNA.
DR   EMBL; X13467; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13468; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13469; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13470; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13471; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13472; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13473; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13474; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13475; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13476; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13477; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13478; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13479; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13487; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X13488; CAA31830.1; JOINED; Genomic_DNA.
DR   EMBL; X06989; CAA30050.1; -; mRNA.
DR   EMBL; M33112; AAB59502.1; -; Genomic_DNA.
DR   EMBL; M34862; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34863; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34864; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34865; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34866; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34867; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34868; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34869; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34870; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34871; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34872; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34873; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34874; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34876; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34877; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34878; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34879; AAB59502.1; JOINED; Genomic_DNA.
DR   EMBL; M34875; AAB59501.1; ALT_TERM; Genomic_DNA.
DR   EMBL; M34862; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34863; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34864; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34865; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34866; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34867; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34868; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34869; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34870; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34871; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34872; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; M34873; AAB59501.1; JOINED; Genomic_DNA.
DR   EMBL; D87675; BAA22264.1; -; Genomic_DNA.
DR   EMBL; AK312326; BAG35248.1; -; mRNA.
DR   EMBL; AK295621; BAG58500.1; -; mRNA.
DR   EMBL; AY919674; AAW82435.1; -; Genomic_DNA.
DR   EMBL; AP001439; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AP001440; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AP001441; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AP001442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AP001443; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471079; EAX09958.1; -; Genomic_DNA.
DR   EMBL; CH471079; EAX09959.1; -; Genomic_DNA.
DR   EMBL; CH471079; EAX09960.1; -; Genomic_DNA.
DR   EMBL; CH471079; EAX09961.1; -; Genomic_DNA.
DR   EMBL; CH471079; EAX09963.1; -; Genomic_DNA.
DR   EMBL; CH471079; EAX09965.1; -; Genomic_DNA.
DR   EMBL; BC004369; AAH04369.1; -; mRNA.
DR   EMBL; BC065529; AAH65529.1; -; mRNA.
DR   EMBL; M35675; AAA60163.1; ALT_SEQ; mRNA.
DR   EMBL; M24547; AAC13654.1; -; Genomic_DNA.
DR   EMBL; M24546; AAC13654.1; JOINED; Genomic_DNA.
DR   EMBL; M28373; AAA58727.1; ALT_SEQ; mRNA.
DR   EMBL; X06982; CAA30042.1; -; mRNA.
DR   EMBL; X06981; CAA30041.1; -; mRNA.
DR   EMBL; M18734; AAA51726.1; -; mRNA.
DR   EMBL; M29270; AAA51768.1; -; Genomic_DNA.
DR   EMBL; M29269; AAA51768.1; JOINED; Genomic_DNA.
DR   EMBL; AB066441; BAB71958.2; -; mRNA.
DR   EMBL; M15533; AAA35540.1; -; mRNA.
DR   EMBL; M15532; AAA51564.1; -; mRNA.
DR   EMBL; M37896; AAA51727.1; -; Genomic_DNA.
DR   EMBL; M37895; AAA51727.1; JOINED; Genomic_DNA.
DR   EMBL; S45136; AAB23646.1; -; Genomic_DNA.
DR   EMBL; S60317; AAC60601.2; -; Genomic_DNA.
DR   EMBL; AF282245; AAQ14327.1; -; mRNA.
DR   EMBL; S60721; AAB26263.2; -; mRNA.
DR   EMBL; S61380; AAB26264.2; -; mRNA.
DR   EMBL; S61383; AAB26265.2; -; mRNA.
DR   EMBL; M16765; AAA51722.1; -; mRNA.
DR   CCDS; CCDS13576.1; -. [P05067-1]
DR   CCDS; CCDS13577.1; -. [P05067-4]
DR   CCDS; CCDS33523.1; -. [P05067-8]
DR   CCDS; CCDS46638.1; -. [P05067-10]
DR   CCDS; CCDS56212.1; -. [P05067-11]
DR   CCDS; CCDS56213.1; -. [P05067-9]
DR   PIR; S01442; S01442.
DR   PIR; S02260; QRHUA4.
DR   RefSeq; NP_000475.1; NM_000484.4. [P05067-1]
DR   RefSeq; NP_001129488.1; NM_001136016.3. [P05067-11]
DR   RefSeq; NP_001129601.1; NM_001136129.3. [P05067-10]
DR   RefSeq; NP_001129602.1; NM_001136130.2.
DR   RefSeq; NP_001129603.1; NM_001136131.2.
DR   RefSeq; NP_001191230.1; NM_001204301.2. [P05067-9]
DR   RefSeq; NP_001191231.1; NM_001204302.2. [P05067-7]
DR   RefSeq; NP_001191232.1; NM_001204303.2. [P05067-3]
DR   RefSeq; NP_001372182.1; NM_001385253.1. [P05067-6]
DR   RefSeq; NP_958816.1; NM_201413.3. [P05067-8]
DR   RefSeq; NP_958817.1; NM_201414.3. [P05067-4]
DR   PDB; 1AAP; X-ray; 1.50 A; A/B=287-344.
DR   PDB; 1AMB; NMR; -; A=672-699.
DR   PDB; 1AMC; NMR; -; A=672-699.
DR   PDB; 1AML; NMR; -; A=672-711.
DR   PDB; 1BA4; NMR; -; A=672-711.
DR   PDB; 1BA6; NMR; -; A=672-711.
DR   PDB; 1BJB; NMR; -; A=672-699.
DR   PDB; 1BJC; NMR; -; A=672-699.
DR   PDB; 1BRC; X-ray; 2.50 A; I=287-342.
DR   PDB; 1CA0; X-ray; 2.10 A; D/I=289-342.
DR   PDB; 1HZ3; NMR; -; A=681-706.
DR   PDB; 1IYT; NMR; -; A=672-713.
DR   PDB; 1MWP; X-ray; 1.80 A; A=28-123.
DR   PDB; 1OWT; NMR; -; A=124-189.
DR   PDB; 1QCM; NMR; -; A=696-706.
DR   PDB; 1QWP; NMR; -; A=696-706.
DR   PDB; 1QXC; NMR; -; A=696-706.
DR   PDB; 1QYT; NMR; -; A=696-706.
DR   PDB; 1TAW; X-ray; 1.80 A; B=287-344.
DR   PDB; 1TKN; NMR; -; A=460-569.
DR   PDB; 1X11; X-ray; 2.50 A; C/D=754-766.
DR   PDB; 1Z0Q; NMR; -; A=672-713.
DR   PDB; 1ZE7; NMR; -; A=672-687.
DR   PDB; 1ZE9; NMR; -; A=672-687.
DR   PDB; 1ZJD; X-ray; 2.60 A; B=289-344.
DR   PDB; 2BEG; NMR; -; A/B/C/D/E=672-713.
DR   PDB; 2BP4; NMR; -; A=672-687.
DR   PDB; 2FJZ; X-ray; 1.61 A; A=133-189.
DR   PDB; 2FK1; X-ray; 1.60 A; A=133-189.
DR   PDB; 2FK2; X-ray; 1.65 A; A=133-189.
DR   PDB; 2FK3; X-ray; 2.40 A; A/B/C/D/E/F/G/H=133-189.
DR   PDB; 2FKL; X-ray; 2.50 A; A/B=124-189.
DR   PDB; 2FMA; X-ray; 0.85 A; A=133-189.
DR   PDB; 2G47; X-ray; 2.10 A; C/D=672-711.
DR   PDB; 2IPU; X-ray; 1.65 A; P/Q=672-679.
DR   PDB; 2LFM; NMR; -; A=672-711.
DR   PDB; 2LLM; NMR; -; A=686-726.
DR   PDB; 2LMN; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR   PDB; 2LMO; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR   PDB; 2LMP; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=672-711.
DR   PDB; 2LMQ; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=672-711.
DR   PDB; 2LNQ; NMR; -; A/B/C/D/E/F/G/H=672-711.
DR   PDB; 2LOH; NMR; -; A/B=686-726.
DR   PDB; 2LP1; NMR; -; A=671-770.
DR   PDB; 2LZ3; NMR; -; A/B=699-726.
DR   PDB; 2LZ4; NMR; -; A/B=699-726.
DR   PDB; 2M4J; NMR; -; A/B/C/D/E/F/G/H/I=672-711.
DR   PDB; 2M9R; NMR; -; A=672-711.
DR   PDB; 2M9S; NMR; -; A=672-711.
DR   PDB; 2MGT; NMR; -; A/B=672-687.
DR   PDB; 2MJ1; NMR; -; A=688-705.
DR   PDB; 2MPZ; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a=686-711.
DR   PDB; 2MVX; NMR; -; A/B/C/D/E/F/G/H/I/J=672-711.
DR   PDB; 2MXU; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L=672-713.
DR   PDB; 2NAO; NMR; -; A/B/C/D/E/F=672-713.
DR   PDB; 2OTK; NMR; -; C=672-711.
DR   PDB; 2R0W; X-ray; 2.50 A; Q=672-679.
DR   PDB; 2WK3; X-ray; 2.59 A; C/D=672-713.
DR   PDB; 2Y29; X-ray; 2.30 A; A=687-692.
DR   PDB; 2Y2A; X-ray; 1.91 A; A=687-692.
DR   PDB; 2Y3J; X-ray; 1.99 A; A/B/C/D/E/F/G/H=701-706.
DR   PDB; 2Y3K; X-ray; 1.90 A; A/B/C/D/E/F/G/H=706-713.
DR   PDB; 2Y3L; X-ray; 2.10 A; A/B/C/G=706-713.
DR   PDB; 3AYU; X-ray; 2.00 A; B=586-595.
DR   PDB; 3BAE; X-ray; 1.59 A; A=672-699.
DR   PDB; 3BKJ; X-ray; 1.59 A; A=672-687.
DR   PDB; 3DXC; X-ray; 2.10 A; B/D=739-770.
DR   PDB; 3DXD; X-ray; 2.20 A; B/D=739-770.
DR   PDB; 3DXE; X-ray; 2.00 A; B/D=739-770.
DR   PDB; 3GCI; X-ray; 2.04 A; P=707-713.
DR   PDB; 3IFL; X-ray; 1.50 A; P=672-678.
DR   PDB; 3IFN; X-ray; 1.50 A; P=672-711.
DR   PDB; 3IFO; X-ray; 2.15 A; P/Q=672-678.
DR   PDB; 3IFP; X-ray; 2.95 A; P/Q/R/S=672-678.
DR   PDB; 3JQ5; X-ray; 2.03 A; B=672-679.
DR   PDB; 3JQL; X-ray; 1.20 A; B=687-692.
DR   PDB; 3JTI; X-ray; 1.80 A; B=699-706.
DR   PDB; 3KTM; X-ray; 2.70 A; A/B/C/D/E/F/G/H=18-190.
DR   PDB; 3L33; X-ray; 2.48 A; E/F/G/H=290-341.
DR   PDB; 3L81; X-ray; 1.60 A; B=761-767.
DR   PDB; 3MOQ; X-ray; 2.05 A; A/B/C/D=689-712.
DR   PDB; 3MXC; X-ray; 2.00 A; L=754-762.
DR   PDB; 3MXY; X-ray; 2.30 A; L=754-762.
DR   PDB; 3NYJ; X-ray; 3.20 A; A=365-567.
DR   PDB; 3NYL; X-ray; 2.80 A; A=365-570.
DR   PDB; 3OVJ; X-ray; 1.80 A; A/B/C/D=687-692.
DR   PDB; 3OW9; X-ray; 1.80 A; A/B=687-692.
DR   PDB; 3PZZ; X-ray; 1.29 A; A/B=700-705.
DR   PDB; 3Q2X; X-ray; 1.45 A; A=698-703.
DR   PDB; 3SV1; X-ray; 3.30 A; D/E/F=754-767.
DR   PDB; 3U0T; X-ray; 2.50 A; E/F=701-711.
DR   PDB; 3UMH; X-ray; 2.00 A; A=370-575.
DR   PDB; 3UMI; X-ray; 2.40 A; A=370-575.
DR   PDB; 3UMK; X-ray; 2.60 A; A=370-575.
DR   PDB; 4HIX; X-ray; 2.20 A; A=672-699.
DR   PDB; 4JFN; X-ray; 1.75 A; A=23-185.
DR   PDB; 4M1C; X-ray; 3.50 A; G/H=672-711.
DR   PDB; 4MDR; X-ray; 1.85 A; B=758-767.
DR   PDB; 4MVI; X-ray; 1.70 A; B=672-711.
DR   PDB; 4MVK; X-ray; 1.50 A; B=689-694.
DR   PDB; 4MVL; X-ray; 2.30 A; E/F/G/H=672-711.
DR   PDB; 4NGE; X-ray; 2.70 A; B/E=672-711.
DR   PDB; 4OJF; X-ray; 2.00 A; A=672-679.
DR   PDB; 4ONF; X-ray; 2.00 A; P=672-678.
DR   PDB; 4ONG; X-ray; 2.20 A; P=672-711.
DR   PDB; 4PQD; X-ray; 1.33 A; A=22-126.
DR   PDB; 4PWQ; X-ray; 1.40 A; A/B=18-190.
DR   PDB; 4XXD; X-ray; 2.41 A; C/F=683-699.
DR   PDB; 5AEF; EM; 5.00 A; A/B=686-713.
DR   PDB; 5AM8; X-ray; 1.90 A; P/Q/R/S=675-681.
DR   PDB; 5AMB; X-ray; 1.55 A; P/Q=706-713.
DR   PDB; 5BUO; X-ray; 2.31 A; A/B=370-710.
DR   PDB; 5C67; X-ray; 1.83 A; C/E=294-344.
DR   PDB; 5CSZ; X-ray; 1.80 A; D/E=672-682.
DR   PDB; 5HOW; X-ray; 2.29 A; A/B/C/D/E/F=688-705.
DR   PDB; 5HOX; X-ray; 1.90 A; A/B/C/D/E/F=688-707.
DR   PDB; 5HOY; X-ray; 2.29 A; A/B/C/D/E/F=688-707.
DR   PDB; 5KK3; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=672-713.
DR   PDB; 5LFY; NMR; -; A/B=672-681.
DR   PDB; 5LV0; X-ray; 2.70 A; C/D=706-711.
DR   PDB; 5MY4; X-ray; 2.21 A; C=674-683.
DR   PDB; 5MYO; X-ray; 1.59 A; E=674-683.
DR   PDB; 5MYX; X-ray; 1.49 A; E/F=674-689.
DR   PDB; 5ONP; X-ray; 1.34 A; B=700-704.
DR   PDB; 5ONQ; X-ray; 1.17 A; B=700-704.
DR   PDB; 5OQV; EM; 4.00 A; A/B/C/D/E/F/G/H/I=672-713.
DR   PDB; 5TXD; X-ray; 1.45 A; Z=698-703.
DR   PDB; 5VOS; EM; 1.42 A; A=695-705.
DR   PDB; 5VZY; X-ray; 2.32 A; A=682-696.
DR   PDB; 5W3P; X-ray; 1.92 A; P=672-687.
DR   PDB; 6CO3; X-ray; 2.38 A; Q=672-682.
DR   PDB; 6GFI; X-ray; 2.30 A; C/E=294-346.
DR   PDB; 6ITU; X-ray; 2.17 A; B=755-766.
DR   PDB; 6IYC; EM; 2.60 A; E=688-770.
DR   PDB; 6NB9; EM; 1.05 A; A=691-705.
DR   PDB; 6O4J; EM; 1.40 A; A/B=687-697.
DR   PDB; 6OC9; NMR; -; A/B/C/D/E/F/G/H/I/J=672-711.
DR   PDB; 6OIZ; EM; 1.10 A; A=691-705.
DR   PDB; 6RHY; NMR; -; A/B/C/D=672-713.
DR   PDB; 6SHS; EM; 4.40 A; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR   PDB; 6SZF; NMR; -; A=672-713.
DR   PDB; 6TI5; NMR; -; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=672-711.
DR   PDB; 6TI6; NMR; -; A/C/E/G/I/K/M/O=672-711, B/D/F/H/J/L/N/P=672-713.
DR   PDB; 6TI7; NMR; -; A/C/E/G/J/L/N/P=672-711, B/D/F/H/I/K/M/O=672-713.
DR   PDB; 6W0O; Other; 2.77 A; 1/2/3/4/5/6=672-711.
DR   PDB; 6WXM; X-ray; 2.30 A; A/B/C/D/E/F/G/H/I/J/K=685-706.
DR   PDB; 6XOV; EM; 3.30 A; B=672-711.
DR   PDB; 6YHF; NMR; -; A=697-726.
DR   PDB; 6YHI; NMR; -; A=697-726.
DR   PDB; 6YHO; NMR; -; A=697-726.
DR   PDB; 6YHP; NMR; -; A=697-726.
DR   PDB; 6YHX; NMR; -; A=697-726.
DR   PDB; 7B3J; NMR; -; A=672-726.
DR   PDB; 7B3K; NMR; -; A=672-726.
DR   PDB; 7E6P; X-ray; 2.50 A; A=686-701.
DR   PDB; 7F29; EM; 3.10 A; A/B/C/D/E/F=677-713.
DR   PDB; 7JXN; X-ray; 2.00 A; A/B/C/D=686-706.
DR   PDB; 7JXO; X-ray; 2.81 A; A/B/C=686-706.
DR   PDB; 7O1Q; EM; 3.40 A; A/B/C/D/E/F/G=672-713.
DR   PDB; 7OW1; X-ray; 1.40 A; A=674-685.
DR   PDB; 7OXN; X-ray; 2.50 A; A=672-685.
DR   PDB; 7Q4B; EM; 2.50 A; A/B/C/D/E/F/G/H/I/R=672-713.
DR   PDB; 7Q4M; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 7RTZ; X-ray; 2.10 A; A/B=682-711.
DR   PDB; 7U4P; X-ray; 1.80 A; A/B/C=687-707.
DR   PDB; 7WFY; X-ray; 2.45 A; A=754-761.
DR   PDB; 7WVY; EM; 3.00 A; L=672-713.
DR   PDB; 7Y3J; X-ray; 2.60 A; A=687-697.
DR   PDB; 7Y8Q; NMR; -; A/B/C/D/E/F/G/H=672-711.
DR   PDB; 8AZS; EM; 2.90 A; H=672-713.
DR   PDB; 8AZT; EM; 3.70 A; B=672-713.
DR   PDB; 8B9Q; NMR; -; A=672-711.
DR   PDB; 8B9R; NMR; -; A=672-711.
DR   PDB; 8BFA; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8BFB; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8BFZ; EM; 2.79 A; A/B=672-713.
DR   PDB; 8BG0; EM; 1.90 A; A/B/C/D=672-711.
DR   PDB; 8C3H; X-ray; 1.71 A; D/E=763-770.
DR   PDB; 8EZD; EM; 2.83 A; A/B/C/D/E/F/G/H=672-713.
DR   PDB; 8EZE; EM; 2.76 A; A/B/C/D/E/F/G/H=672-713.
DR   PDB; 8FF2; EM; 2.87 A; A/B/C/D/E/F/G/I/J/K=672-711.
DR   PDB; 8FF3; EM; 3.09 A; A/B/C/a/b/c=672-711.
DR   PDB; 8H8Q; X-ray; 2.50 A; A=686-700.
DR   PDB; 8I4O; X-ray; 3.10 A; B/D/F/H/J/L=681-700.
DR   PDB; 8KEW; EM; 3.30 A; A/B/C/D/F/G=1-770.
DR   PDB; 8KF1; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J/K/L=1-770.
DR   PDB; 8KF3; EM; 3.50 A; A/B/C/D/E/F/G/H/I=1-770.
DR   PDB; 8KF4; EM; 3.00 A; A/B/C/D/E/F=1-770.
DR   PDB; 8KF5; EM; 3.40 A; A/B/C/D/E/F=1-770.
DR   PDB; 8KF6; EM; 3.70 A; A/B/C/D/E/F/G/H/I=1-770.
DR   PDB; 8OL2; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8OL3; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8OL5; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8OL6; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8OL7; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8OLG; EM; 4.20 A; A/B/C/D/E=672-713.
DR   PDB; 8OLN; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8OLO; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=672-713.
DR   PDB; 8OLQ; EM; 4.00 A; A/B/C/D/E=672-713.
DR   PDB; 8OT1; EM; 2.59 A; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR   PDB; 8OT3; EM; 2.73 A; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR   PDB; 8OT4; EM; 2.97 A; A/B/C/D/E/F/G/H/I/J/K/L=672-711.
DR   PDB; 8OTF; EM; 3.30 A; A/B/C/D/E/F=1-770.
DR   PDB; 8OVK; EM; 2.88 A; A/B/C/D/E/F/G/H/I/J=672-711.
DR   PDB; 8OVM; EM; 3.24 A; A/B/C/D/E=672-711.
DR   PDB; 8OWD; EM; 3.28 A; A/B/C/D/E=672-711.
DR   PDB; 8OWE; EM; 3.75 A; A/B/C/D/E/F/G/H/I/J=672-711.
DR   PDB; 8OWJ; EM; 3.75 A; A/B/C/D/E/F/G/H/I/J=672-711.
DR   PDB; 8OWK; EM; 3.86 A; A/B/C/D/E/F/G/H/I/J=672-711.
DR   PDB; 8QN6; EM; 2.40 A; A/F=672-711.
DR   PDB; 8QN7; EM; 2.70 A; A=672-711.
DR   PDB; 8SEJ; EM; 3.17 A; A/B/C/D/E/F/G/H/I/J=680-713.
DR   PDB; 8SEK; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=672-711.
DR   PDB; 8SEL; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=672-711.
DR   PDB; 8T82; X-ray; 1.10 A; A=706-711.
DR   PDB; 8T89; X-ray; 1.50 A; A=687-692.
DR   PDB; 8X52; EM; 2.90 A; E=671-770.
DR   PDB; 8X53; EM; 3.00 A; E=672-717.
DR   PDB; 8X54; EM; 2.90 A; E=671-770.
DR   PDB; 8Z9V; EM; 7.84 A; e=678-713.
DR   PDB; 9CZN; EM; 2.60 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=680-713.
DR   PDB; 9CZP; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=680-713.
DR   PDB; 9IIO; EM; 3.30 A; 2/3/4/5/6/A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y=672-711.
DR   PDB; 9JAZ; EM; 3.00 A; A/AA/B/BB/C/CC/D/DD/E/EE/F/FF=672-713.
DR   PDB; 9JB0; EM; 2.90 A; A/AA/B/BB/C/CC/D/DD/E/EE/F/FF=672-713.
DR   PDB; 9JB1; EM; 2.50 A; FF/FG/FH/FI/FJ/FK/FL/FM/FN/FO/FP/FQ=672-713.
DR   PDB; 9JB2; EM; 2.90 A; A/B/BA/BB/BC/BD/BE/C/CA/CB/CC/CD/CE/D/E=672-713.
DR   PDBsum; 1AAP; -.
DR   PDBsum; 1AMB; -.
DR   PDBsum; 1AMC; -.
DR   PDBsum; 1AML; -.
DR   PDBsum; 1BA4; -.
DR   PDBsum; 1BA6; -.
DR   PDBsum; 1BJB; -.
DR   PDBsum; 1BJC; -.
DR   PDBsum; 1BRC; -.
DR   PDBsum; 1CA0; -.
DR   PDBsum; 1HZ3; -.
DR   PDBsum; 1IYT; -.
DR   PDBsum; 1MWP; -.
DR   PDBsum; 1OWT; -.
DR   PDBsum; 1QCM; -.
DR   PDBsum; 1QWP; -.
DR   PDBsum; 1QXC; -.
DR   PDBsum; 1QYT; -.
DR   PDBsum; 1TAW; -.
DR   PDBsum; 1TKN; -.
DR   PDBsum; 1X11; -.
DR   PDBsum; 1Z0Q; -.
DR   PDBsum; 1ZE7; -.
DR   PDBsum; 1ZE9; -.
DR   PDBsum; 1ZJD; -.
DR   PDBsum; 2BEG; -.
DR   PDBsum; 2BP4; -.
DR   PDBsum; 2FJZ; -.
DR   PDBsum; 2FK1; -.
DR   PDBsum; 2FK2; -.
DR   PDBsum; 2FK3; -.
DR   PDBsum; 2FKL; -.
DR   PDBsum; 2FMA; -.
DR   PDBsum; 2G47; -.
DR   PDBsum; 2IPU; -.
DR   PDBsum; 2LFM; -.
DR   PDBsum; 2LLM; -.
DR   PDBsum; 2LMN; -.
DR   PDBsum; 2LMO; -.
DR   PDBsum; 2LMP; -.
DR   PDBsum; 2LMQ; -.
DR   PDBsum; 2LNQ; -.
DR   PDBsum; 2LOH; -.
DR   PDBsum; 2LP1; -.
DR   PDBsum; 2LZ3; -.
DR   PDBsum; 2LZ4; -.
DR   PDBsum; 2M4J; -.
DR   PDBsum; 2M9R; -.
DR   PDBsum; 2M9S; -.
DR   PDBsum; 2MGT; -.
DR   PDBsum; 2MJ1; -.
DR   PDBsum; 2MPZ; -.
DR   PDBsum; 2MVX; -.
DR   PDBsum; 2MXU; -.
DR   PDBsum; 2NAO; -.
DR   PDBsum; 2OTK; -.
DR   PDBsum; 2R0W; -.
DR   PDBsum; 2WK3; -.
DR   PDBsum; 2Y29; -.
DR   PDBsum; 2Y2A; -.
DR   PDBsum; 2Y3J; -.
DR   PDBsum; 2Y3K; -.
DR   PDBsum; 2Y3L; -.
DR   PDBsum; 3AYU; -.
DR   PDBsum; 3BAE; -.
DR   PDBsum; 3BKJ; -.
DR   PDBsum; 3DXC; -.
DR   PDBsum; 3DXD; -.
DR   PDBsum; 3DXE; -.
DR   PDBsum; 3GCI; -.
DR   PDBsum; 3IFL; -.
DR   PDBsum; 3IFN; -.
DR   PDBsum; 3IFO; -.
DR   PDBsum; 3IFP; -.
DR   PDBsum; 3JQ5; -.
DR   PDBsum; 3JQL; -.
DR   PDBsum; 3JTI; -.
DR   PDBsum; 3KTM; -.
DR   PDBsum; 3L33; -.
DR   PDBsum; 3L81; -.
DR   PDBsum; 3MOQ; -.
DR   PDBsum; 3MXC; -.
DR   PDBsum; 3MXY; -.
DR   PDBsum; 3NYJ; -.
DR   PDBsum; 3NYL; -.
DR   PDBsum; 3OVJ; -.
DR   PDBsum; 3OW9; -.
DR   PDBsum; 3PZZ; -.
DR   PDBsum; 3Q2X; -.
DR   PDBsum; 3SV1; -.
DR   PDBsum; 3U0T; -.
DR   PDBsum; 3UMH; -.
DR   PDBsum; 3UMI; -.
DR   PDBsum; 3UMK; -.
DR   PDBsum; 4HIX; -.
DR   PDBsum; 4JFN; -.
DR   PDBsum; 4M1C; -.
DR   PDBsum; 4MDR; -.
DR   PDBsum; 4MVI; -.
DR   PDBsum; 4MVK; -.
DR   PDBsum; 4MVL; -.
DR   PDBsum; 4NGE; -.
DR   PDBsum; 4OJF; -.
DR   PDBsum; 4ONF; -.
DR   PDBsum; 4ONG; -.
DR   PDBsum; 4PQD; -.
DR   PDBsum; 4PWQ; -.
DR   PDBsum; 4XXD; -.
DR   PDBsum; 5AEF; -.
DR   PDBsum; 5AM8; -.
DR   PDBsum; 5AMB; -.
DR   PDBsum; 5BUO; -.
DR   PDBsum; 5C67; -.
DR   PDBsum; 5CSZ; -.
DR   PDBsum; 5HOW; -.
DR   PDBsum; 5HOX; -.
DR   PDBsum; 5HOY; -.
DR   PDBsum; 5KK3; -.
DR   PDBsum; 5LFY; -.
DR   PDBsum; 5LV0; -.
DR   PDBsum; 5MY4; -.
DR   PDBsum; 5MYO; -.
DR   PDBsum; 5MYX; -.
DR   PDBsum; 5ONP; -.
DR   PDBsum; 5ONQ; -.
DR   PDBsum; 5OQV; -.
DR   PDBsum; 5TXD; -.
DR   PDBsum; 5VOS; -.
DR   PDBsum; 5VZY; -.
DR   PDBsum; 5W3P; -.
DR   PDBsum; 6CO3; -.
DR   PDBsum; 6GFI; -.
DR   PDBsum; 6ITU; -.
DR   PDBsum; 6IYC; -.
DR   PDBsum; 6NB9; -.
DR   PDBsum; 6O4J; -.
DR   PDBsum; 6OC9; -.
DR   PDBsum; 6OIZ; -.
DR   PDBsum; 6RHY; -.
DR   PDBsum; 6SHS; -.
DR   PDBsum; 6SZF; -.
DR   PDBsum; 6TI5; -.
DR   PDBsum; 6TI6; -.
DR   PDBsum; 6TI7; -.
DR   PDBsum; 6W0O; -.
DR   PDBsum; 6WXM; -.
DR   PDBsum; 6XOV; -.
DR   PDBsum; 6YHF; -.
DR   PDBsum; 6YHI; -.
DR   PDBsum; 6YHO; -.
DR   PDBsum; 6YHP; -.
DR   PDBsum; 6YHX; -.
DR   PDBsum; 7B3J; -.
DR   PDBsum; 7B3K; -.
DR   PDBsum; 7E6P; -.
DR   PDBsum; 7F29; -.
DR   PDBsum; 7JXN; -.
DR   PDBsum; 7JXO; -.
DR   PDBsum; 7O1Q; -.
DR   PDBsum; 7OW1; -.
DR   PDBsum; 7OXN; -.
DR   PDBsum; 7Q4B; -.
DR   PDBsum; 7Q4M; -.
DR   PDBsum; 7RTZ; -.
DR   PDBsum; 7U4P; -.
DR   PDBsum; 7WFY; -.
DR   PDBsum; 7WVY; -.
DR   PDBsum; 7Y3J; -.
DR   PDBsum; 7Y8Q; -.
DR   PDBsum; 8AZS; -.
DR   PDBsum; 8AZT; -.
DR   PDBsum; 8B9Q; -.
DR   PDBsum; 8B9R; -.
DR   PDBsum; 8BFA; -.
DR   PDBsum; 8BFB; -.
DR   PDBsum; 8BFZ; -.
DR   PDBsum; 8BG0; -.
DR   PDBsum; 8C3H; -.
DR   PDBsum; 8EZD; -.
DR   PDBsum; 8EZE; -.
DR   PDBsum; 8FF2; -.
DR   PDBsum; 8FF3; -.
DR   PDBsum; 8H8Q; -.
DR   PDBsum; 8I4O; -.
DR   PDBsum; 8KEW; -.
DR   PDBsum; 8KF1; -.
DR   PDBsum; 8KF3; -.
DR   PDBsum; 8KF4; -.
DR   PDBsum; 8KF5; -.
DR   PDBsum; 8KF6; -.
DR   PDBsum; 8OL2; -.
DR   PDBsum; 8OL3; -.
DR   PDBsum; 8OL5; -.
DR   PDBsum; 8OL6; -.
DR   PDBsum; 8OL7; -.
DR   PDBsum; 8OLG; -.
DR   PDBsum; 8OLN; -.
DR   PDBsum; 8OLO; -.
DR   PDBsum; 8OLQ; -.
DR   PDBsum; 8OT1; -.
DR   PDBsum; 8OT3; -.
DR   PDBsum; 8OT4; -.
DR   PDBsum; 8OTF; -.
DR   PDBsum; 8OVK; -.
DR   PDBsum; 8OVM; -.
DR   PDBsum; 8OWD; -.
DR   PDBsum; 8OWE; -.
DR   PDBsum; 8OWJ; -.
DR   PDBsum; 8OWK; -.
DR   PDBsum; 8QN6; -.
DR   PDBsum; 8QN7; -.
DR   PDBsum; 8SEJ; -.
DR   PDBsum; 8SEK; -.
DR   PDBsum; 8SEL; -.
DR   PDBsum; 8T82; -.
DR   PDBsum; 8T89; -.
DR   PDBsum; 8X52; -.
DR   PDBsum; 8X53; -.
DR   PDBsum; 8X54; -.
DR   PDBsum; 8Z9V; -.
DR   PDBsum; 9CZN; -.
DR   PDBsum; 9CZP; -.
DR   PDBsum; 9IIO; -.
DR   PDBsum; 9JAZ; -.
DR   PDBsum; 9JB0; -.
DR   PDBsum; 9JB1; -.
DR   PDBsum; 9JB2; -.
DR   AlphaFoldDB; P05067; -.
DR   BMRB; P05067; -.
DR   EMDB; EMD-0405; -.
DR   EMDB; EMD-0619; -.
DR   EMDB; EMD-10204; -.
DR   EMDB; EMD-13800; -.
DR   EMDB; EMD-13809; -.
DR   EMDB; EMD-15770; -.
DR   EMDB; EMD-15771; -.
DR   EMDB; EMD-16018; -.
DR   EMDB; EMD-16019; -.
DR   EMDB; EMD-16022; -.
DR   EMDB; EMD-16023; -.
DR   EMDB; EMD-16942; -.
DR   EMDB; EMD-16944; -.
DR   EMDB; EMD-16949; -.
DR   EMDB; EMD-16952; -.
DR   EMDB; EMD-16953; -.
DR   EMDB; EMD-16957; -.
DR   EMDB; EMD-16959; -.
DR   EMDB; EMD-16960; -.
DR   EMDB; EMD-16961; -.
DR   EMDB; EMD-17177; -.
DR   EMDB; EMD-18226; -.
DR   EMDB; EMD-21501; -.
DR   EMDB; EMD-22281; -.
DR   EMDB; EMD-28740; -.
DR   EMDB; EMD-28741; -.
DR   EMDB; EMD-29036; -.
DR   EMDB; EMD-29037; -.
DR   EMDB; EMD-29038; -.
DR   EMDB; EMD-37170; -.
DR   EMDB; EMD-37195; -.
DR   EMDB; EMD-37197; -.
DR   EMDB; EMD-37198; -.
DR   EMDB; EMD-37199; -.
DR   EMDB; EMD-37200; -.
DR   EMDB; EMD-38059; -.
DR   EMDB; EMD-38060; -.
DR   EMDB; EMD-38061; -.
DR   EMDB; EMD-3851; -.
DR   EMDB; EMD-39869; -.
DR   EMDB; EMD-40416; -.
DR   EMDB; EMD-40419; -.
DR   EMDB; EMD-40421; -.
DR   EMDB; EMD-46422; -.
DR   EMDB; EMD-46424; -.
DR   EMDB; EMD-50437; -.
DR   EMDB; EMD-50438; -.
DR   EMDB; EMD-50439; -.
DR   EMDB; EMD-50440; -.
DR   EMDB; EMD-60603; -.
DR   EMDB; EMD-61302; -.
DR   EMDB; EMD-61303; -.
DR   EMDB; EMD-61304; -.
DR   EMDB; EMD-61305; -.
DR   EMDB; EMD-61944; -.
DR   EMDB; EMD-61945; -.
DR   EMDB; EMD-61946; -.
DR   EMDB; EMD-63646; -.
DR   EMDB; EMD-63647; -.
DR   EMDB; EMD-63648; -.
DR   EMDB; EMD-64274; -.
DR   EMDB; EMD-9751; -.
DR   PCDDB; P05067; -.
DR   SASBDB; P05067; -.
DR   SMR; P05067; -.
DR   BioGRID; 106848; 2408.
DR   ComplexPortal; CPX-1062; Amyloid-beta protein 40/42 complex.
DR   ComplexPortal; CPX-1069; Amyloid-beta protein 40 complex.
DR   ComplexPortal; CPX-1070; Amyloid-beta protein 42 complex.
DR   ComplexPortal; CPX-1120; Amyloid-beta protein 40/42 oligomeric complex.
DR   ComplexPortal; CPX-1134; Amyloid-beta protein 42 oligomeric complex.
DR   ComplexPortal; CPX-1180; Amyloid-beta protein 40 oligomeric complex.
DR   CORUM; P05067; -.
DR   DIP; DIP-574N; -.
DR   ELM; P05067; -.
DR   FunCoup; P05067; 1765.
DR   IntAct; P05067; 926.
DR   MINT; P05067; -.
DR   STRING; 9606.ENSP00000284981; -.
DR   BindingDB; P05067; -.
DR   ChEMBL; CHEMBL2487; -.
DR   DrugBank; DB12274; Aducanumab.
DR   DrugBank; DB06086; Affitope AD01.
DR   DrugBank; DB01370; Aluminium.
DR   DrugBank; DB14517; Aluminium phosphate.
DR   DrugBank; DB14518; Aluminum acetate.
DR   DrugBank; DB05150; CAD106.
DR   DrugBank; DB09130; Copper.
DR   DrugBank; DB11672; Curcumin.
DR   DrugBank; DB00746; Deferoxamine.
DR   DrugBank; DB06782; Dimercaprol.
DR   DrugBank; DB05938; Edonerpic.
DR   DrugBank; DB09148; Florbetaben F-18.
DR   DrugBank; DB09149; Florbetapir F-18.
DR   DrugBank; DB09151; Flutemetamol (18F).
DR   DrugBank; DB12034; Gantenerumab.
DR   DrugBank; DB02235; L-methionine (R)-S-oxide.
DR   DrugBank; DB14580; Lecanemab.
DR   DrugBank; DB05846; Mito-4509.
DR   DrugBank; DB04892; Phenserine.
DR   DrugBank; DB18298; PTI-110.
DR   DrugBank; DB02709; Resveratrol.
DR   DrugBank; DB05088; Tetrathiomolybdate.
DR   DrugBank; DB06527; Tramiprosate.
DR   DrugBank; DB03754; Tromethamine.
DR   DrugBank; DB19191; Valiltramiprosate.
DR   DrugBank; DB01593; Zinc.
DR   DrugBank; DB14487; Zinc acetate.
DR   DrugBank; DB14533; Zinc chloride.
DR   DrugBank; DB14548; Zinc sulfate, unspecified form.
DR   DrugCentral; P05067; -.
DR   MEROPS; I02.015; -.
DR   TCDB; 1.C.50.1.2; the amyloid Beta-protein peptide (aBetapp) family.
DR   GlyConnect; 49; 2 N-Linked glycans.
DR   GlyCosmos; P05067; 15 sites, 9 glycans.
DR   GlyGen; P05067; 27 sites, 13 N-linked glycans (3 sites), 6 O-linked glycans (23 sites).
DR   iPTMnet; P05067; -.
DR   MetOSite; P05067; -.
DR   PhosphoSitePlus; P05067; -.
DR   SwissPalm; P05067; -.
DR   BioMuta; APP; -.
DR   DMDM; 112927; -.
DR   jPOST; P05067; -.
DR   MassIVE; P05067; -.
DR   PaxDb; 9606-ENSP00000284981; -.
DR   PeptideAtlas; P05067; -.
DR   ProteomicsDB; 4307; -.
DR   ProteomicsDB; 51774; -. [P05067-1]
DR   ProteomicsDB; 51775; -. [P05067-10]
DR   ProteomicsDB; 51776; -. [P05067-2]
DR   ProteomicsDB; 51777; -. [P05067-3]
DR   ProteomicsDB; 51778; -. [P05067-4]
DR   ProteomicsDB; 51779; -. [P05067-5]
DR   ProteomicsDB; 51780; -. [P05067-6]
DR   ProteomicsDB; 51781; -. [P05067-7]
DR   ProteomicsDB; 51782; -. [P05067-8]
DR   ProteomicsDB; 51783; -. [P05067-9]
DR   Pumba; P05067; -.
DR   ABCD; P05067; 142 sequenced antibodies.
DR   Antibodypedia; 668; 4422 antibodies from 55 providers.
DR   DNASU; 351; -.
DR   YCharOS; P05067; Tested 11 antibodies from 5 manufacturers.
DR   Ensembl; ENST00000346798.8; ENSP00000284981.4; ENSG00000142192.23. [P05067-1]
DR   Ensembl; ENST00000348990.9; ENSP00000345463.5; ENSG00000142192.23. [P05067-4]
DR   Ensembl; ENST00000354192.7; ENSP00000346129.3; ENSG00000142192.23. [P05067-10]
DR   Ensembl; ENST00000357903.7; ENSP00000350578.3; ENSG00000142192.23. [P05067-8]
DR   Ensembl; ENST00000358918.7; ENSP00000351796.3; ENSG00000142192.23. [P05067-9]
DR   Ensembl; ENST00000440126.7; ENSP00000387483.2; ENSG00000142192.23. [P05067-11]
DR   GeneID; 351; -.
DR   KEGG; hsa:351; -.
DR   MANE-Select; ENST00000346798.8; ENSP00000284981.4; NM_000484.4; NP_000475.1.
DR   UCSC; uc002ylz.4; human. [P05067-1]
DR   AGR; HGNC:620; -.
DR   ClinPGx; PA24910; -.
DR   CTD; 351; -.
DR   DisGeNET; 351; -.
DR   GeneCards; APP; -.
DR   HGNC; HGNC:620; APP.
DR   HPA; ENSG00000142192; Low tissue specificity.
DR   MalaCards; APP; -.
DR   MIM; 104300; phenotype.
DR   MIM; 104760; gene.
DR   MIM; 605714; phenotype.
DR   NIAGADS; ENSG00000142192; -.
DR   OpenTargets; ENSG00000142192; -.
DR   Orphanet; 324723; ABeta amyloidosis, Arctic type.
DR   Orphanet; 100006; ABeta amyloidosis, Dutch type.
DR   Orphanet; 324708; ABeta amyloidosis, Iowa type.
DR   Orphanet; 324713; ABeta amyloidosis, Italian type.
DR   Orphanet; 324718; ABetaA21G amyloidosis.
DR   Orphanet; 324703; ABetaL34V amyloidosis.
DR   Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR   VEuPathDB; HostDB:ENSG00000142192; -.
DR   eggNOG; KOG3540; Eukaryota.
DR   GeneTree; ENSGT00530000063252; -.
DR   InParanoid; P05067; -.
DR   OMA; THRVQKC; -.
DR   OrthoDB; 6147836at2759; -.
DR   PAN-GO; P05067; 9 GO annotations based on evolutionary models.
DR   PhylomeDB; P05067; -.
DR   BioCyc; MetaCyc:ENSG00000142192-MONOMER; -.
DR   PathwayCommons; P05067; -.
DR   Reactome; R-HSA-114608; Platelet degranulation.
DR   Reactome; R-HSA-3000178; ECM proteoglycans.
DR   Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR   Reactome; R-HSA-416476; G alpha (q) signalling events.
DR   Reactome; R-HSA-418594; G alpha (i) signalling events.
DR   Reactome; R-HSA-432720; Lysosome Vesicle Biogenesis.
DR   Reactome; R-HSA-444473; Formyl peptide receptors bind formyl peptides and many other ligands.
DR   Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR   Reactome; R-HSA-844456; The NLRP3 inflammasome.
DR   Reactome; R-HSA-879415; Advanced glycosylation endproduct receptor signaling.
DR   Reactome; R-HSA-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
DR   Reactome; R-HSA-8957275; Post-translational protein phosphorylation.
DR   Reactome; R-HSA-933542; TRAF6 mediated NF-kB activation.
DR   Reactome; R-HSA-9609523; Insertion of tail-anchored proteins into the endoplasmic reticulum membrane.
DR   Reactome; R-HSA-9660826; Purinergic signaling in leishmaniasis infection.
DR   Reactome; R-HSA-977225; Amyloid fiber formation.
DR   Reactome; R-HSA-9837999; Mitochondrial protein degradation. [P05067-4]
DR   SABIO-RK; P05067; -.
DR   SignaLink; P05067; -.
DR   SIGNOR; P05067; -.
DR   Agora; ENSG00000142192; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 351; 12 hits in 1170 CRISPR screens.
DR   CD-CODE; 2C639066; Synthetic Condensate 000143.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   CD-CODE; 9F779CC8; Nuclear body.
DR   ChiTaRS; APP; human.
DR   EvolutionaryTrace; P05067; -.
DR   GeneWiki; Amyloid_precursor_protein; -.
DR   GenomeRNAi; 351; -.
DR   Pharos; P05067; Tclin.
DR   PRO; PR:P05067; -.
DR   Proteomes; UP000005640; Chromosome 21.
DR   RNAct; P05067; protein.
DR   Bgee; ENSG00000142192; Expressed in prefrontal cortex and 208 other cell types or tissues.
DR   ExpressionAtlas; P05067; baseline and differential.
DR   GO; GO:0106003; C:amyloid-beta complex; IDA:UniProt.
DR   GO; GO:0097449; C:astrocyte projection; IEA:Ensembl.
DR   GO; GO:0030424; C:axon; ISS:UniProtKB.
DR   GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR   GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0030425; C:dendrite; IDA:ARUK-UCL.
DR   GO; GO:0043198; C:dendritic shaft; IDA:MGI.
DR   GO; GO:0043197; C:dendritic spine; IDA:MGI.
DR   GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR   GO; GO:0031901; C:early endosome membrane; IDA:UniProt.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR   GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR   GO; GO:0031904; C:endosome lumen; TAS:Reactome.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005615; C:extracellular space; IDA:ARUK-UCL.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR   GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR   GO; GO:0005798; C:Golgi-associated vesicle; ISS:UniProtKB.
DR   GO; GO:1990812; C:growth cone filopodium; IEA:Ensembl.
DR   GO; GO:1990761; C:growth cone lamellipodium; IEA:Ensembl.
DR   GO; GO:0044304; C:main axon; IEA:Ensembl.
DR   GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR   GO; GO:0045121; C:membrane raft; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR   GO; GO:0098992; C:neuronal dense core vesicle; IEA:Ensembl.
DR   GO; GO:0005641; C:nuclear envelope lumen; IDA:Alzheimers_University_of_Toronto.
DR   GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR   GO; GO:0043235; C:receptor complex; IDA:MGI.
DR   GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR   GO; GO:0045202; C:synapse; IDA:MGI.
DR   GO; GO:0032588; C:trans-Golgi network membrane; TAS:Reactome.
DR   GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR   GO; GO:0019899; F:enzyme binding; IPI:ARUK-UCL.
DR   GO; GO:0070851; F:growth factor receptor binding; IEA:Ensembl.
DR   GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0016504; F:peptidase activator activity; IEA:Ensembl.
DR   GO; GO:0120283; F:protein serine/threonine kinase binding; IPI:ARUK-UCL.
DR   GO; GO:0051425; F:PTB domain binding; IPI:BHF-UCL.
DR   GO; GO:0048018; F:receptor ligand activity; IDA:UniProt.
DR   GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR   GO; GO:0030546; F:signaling receptor activator activity; IBA:GO_Central.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:BHF-UCL.
DR   GO; GO:0046914; F:transition metal ion binding; IEA:InterPro.
DR   GO; GO:0008344; P:adult locomotory behavior; ISS:UniProtKB.
DR   GO; GO:1990000; P:amyloid fibril formation; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL.
DR   GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL.
DR   GO; GO:0008088; P:axo-dendritic transport; ISS:UniProtKB.
DR   GO; GO:0016199; P:axon midline choice point recognition; ISS:UniProtKB.
DR   GO; GO:0007409; P:axonogenesis; ISS:UniProtKB.
DR   GO; GO:0006816; P:calcium ion transport; IEA:Ensembl.
DR   GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProt.
DR   GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
DR   GO; GO:0071280; P:cellular response to copper ion; IEA:Ensembl.
DR   GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl.
DR   GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
DR   GO; GO:0071874; P:cellular response to norepinephrine stimulus; IEA:Ensembl.
DR   GO; GO:0007417; P:central nervous system development; IBA:GO_Central.
DR   GO; GO:0050890; P:cognition; ISS:UniProtKB.
DR   GO; GO:0048669; P:collateral sprouting in absence of injury; ISS:UniProtKB.
DR   GO; GO:0016358; P:dendrite development; ISS:UniProtKB.
DR   GO; GO:0006897; P:endocytosis; ISS:UniProtKB.
DR   GO; GO:0030198; P:extracellular matrix organization; ISS:UniProtKB.
DR   GO; GO:0110088; P:hippocampal neuron apoptotic process; IEA:Ensembl.
DR   GO; GO:0006878; P:intracellular copper ion homeostasis; ISS:UniProtKB.
DR   GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0007612; P:learning; IMP:ARUK-UCL.
DR   GO; GO:0007611; P:learning or memory; IMP:ARUK-UCL.
DR   GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB.
DR   GO; GO:0007617; P:mating behavior; ISS:UniProtKB.
DR   GO; GO:0014005; P:microglia development; IGI:ARUK-UCL.
DR   GO; GO:0001774; P:microglial cell activation; IGI:ARUK-UCL.
DR   GO; GO:0098815; P:modulation of excitatory postsynaptic potential; IGI:ARUK-UCL.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB.
DR   GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL.
DR   GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IGI:ARUK-UCL.
DR   GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR   GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL.
DR   GO; GO:0016322; P:neuron remodeling; ISS:UniProtKB.
DR   GO; GO:0098989; P:NMDA selective glutamate receptor signaling pathway; TAS:ARUK-UCL.
DR   GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR   GO; GO:1905908; P:positive regulation of amyloid fibril formation; IMP:ARUK-UCL.
DR   GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IGI:ARUK-UCL.
DR   GO; GO:0032722; P:positive regulation of chemokine production; IGI:ARUK-UCL.
DR   GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IGI:ARUK-UCL.
DR   GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL.
DR   GO; GO:0050729; P:positive regulation of inflammatory response; IMP:ARUK-UCL.
DR   GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IGI:ARUK-UCL.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; IGI:ARUK-UCL.
DR   GO; GO:0046330; P:positive regulation of JNK cascade; IGI:ARUK-UCL.
DR   GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IGI:ARUK-UCL.
DR   GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISS:UniProtKB.
DR   GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IMP:ARUK-UCL.
DR   GO; GO:0051247; P:positive regulation of protein metabolic process; IMP:ARUK-UCL.
DR   GO; GO:2000406; P:positive regulation of T cell migration; IMP:ARUK-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IGI:ARUK-UCL.
DR   GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL.
DR   GO; GO:0010468; P:regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IGI:ARUK-UCL.
DR   GO; GO:0040014; P:regulation of multicellular organism growth; ISS:UniProtKB.
DR   GO; GO:0043523; P:regulation of neuron apoptotic process; IEA:Ensembl.
DR   GO; GO:1905606; P:regulation of presynapse assembly; IDA:SynGO.
DR   GO; GO:0150003; P:regulation of spontaneous synaptic transmission; IGI:ARUK-UCL.
DR   GO; GO:0050803; P:regulation of synapse structure or activity; ISS:UniProtKB.
DR   GO; GO:0006417; P:regulation of translation; ISS:UniProtKB.
DR   GO; GO:0030111; P:regulation of Wnt signaling pathway; IC:ARUK-UCL.
DR   GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR   GO; GO:1990418; P:response to insulin-like growth factor stimulus; IEA:Ensembl.
DR   GO; GO:0070555; P:response to interleukin-1; ISS:ARUK-UCL.
DR   GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR   GO; GO:0036269; P:swimming behavior; IEA:Ensembl.
DR   GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL.
DR   GO; GO:0008542; P:visual learning; ISS:UniProtKB.
DR   CDD; cd22607; Kunitz_ABPP-like; 1.
DR   DisProt; DP01280; -.
DR   FunFam; 3.30.1490.140:FF:000001; Amyloid beta (A4) protein b; 1.
DR   FunFam; 3.90.570.10:FF:000001; Amyloid beta A4 protein; 1.
DR   FunFam; 4.10.230.10:FF:000001; Amyloid beta A4 protein; 1.
DR   FunFam; 4.10.410.10:FF:000001; Amyloid beta A4 protein; 1.
DR   FunFam; 1.20.120.770:FF:000001; Amyloid beta A4 protein-like isoform 1; 1.
DR   Gene3D; 1.20.120.770; Amyloid precursor protein, E2 domain; 1.
DR   Gene3D; 4.10.230.10; Amyloidogenic glycoprotein, amyloid-beta peptide; 1.
DR   Gene3D; 3.30.1490.140; Amyloidogenic glycoprotein, copper-binding domain; 1.
DR   Gene3D; 3.90.570.10; Amyloidogenic glycoprotein, heparin-binding domain; 1.
DR   Gene3D; 4.10.410.10; Pancreatic trypsin inhibitor Kunitz domain; 1.
DR   Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1.
DR   IDEAL; IID00294; -.
DR   InterPro; IPR036669; Amyloid_Cu-bd_sf.
DR   InterPro; IPR008155; Amyloid_glyco.
DR   InterPro; IPR013803; Amyloid_glyco_Abeta.
DR   InterPro; IPR037071; Amyloid_glyco_Abeta_sf.
DR   InterPro; IPR011178; Amyloid_glyco_Cu-bd.
DR   InterPro; IPR024329; Amyloid_glyco_E2_domain.
DR   InterPro; IPR008154; Amyloid_glyco_extra.
DR   InterPro; IPR015849; Amyloid_glyco_heparin-bd.
DR   InterPro; IPR036454; Amyloid_glyco_heparin-bd_sf.
DR   InterPro; IPR019745; Amyloid_glyco_intracell_CS.
DR   InterPro; IPR019543; APP_amyloid_C.
DR   InterPro; IPR019744; APP_CUBD_CS.
DR   InterPro; IPR036176; E2_sf.
DR   InterPro; IPR002223; Kunitz_BPTI.
DR   InterPro; IPR036880; Kunitz_BPTI_sf.
DR   InterPro; IPR011993; PH-like_dom_sf.
DR   InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR   PANTHER; PTHR23103; ALZHEIMER'S DISEASE BETA-AMYLOID RELATED; 1.
DR   PANTHER; PTHR23103:SF7; AMYLOID-BETA PRECURSOR PROTEIN; 1.
DR   Pfam; PF10515; APP_amyloid; 1.
DR   Pfam; PF12924; APP_Cu_bd; 1.
DR   Pfam; PF12925; APP_E2; 1.
DR   Pfam; PF02177; APP_N; 1.
DR   Pfam; PF03494; Beta-APP; 1.
DR   Pfam; PF00014; Kunitz_BPTI; 1.
DR   PRINTS; PR00203; AMYLOIDA4.
DR   PRINTS; PR00759; BASICPTASE.
DR   PRINTS; PR00204; BETAAMYLOID.
DR   SMART; SM00006; A4_EXTRA; 1.
DR   SMART; SM00131; KU; 1.
DR   SUPFAM; SSF56491; A heparin-binding domain; 1.
DR   SUPFAM; SSF89811; Amyloid beta a4 protein copper binding domain (domain 2); 1.
DR   SUPFAM; SSF57362; BPTI-like; 1.
DR   SUPFAM; SSF109843; CAPPD, an extracellular domain of amyloid beta A4 protein; 1.
DR   PROSITE; PS00319; APP_CUBD; 1.
DR   PROSITE; PS51869; APP_E1; 1.
DR   PROSITE; PS51870; APP_E2; 1.
DR   PROSITE; PS00320; APP_INTRA; 1.
DR   PROSITE; PS00280; BPTI_KUNITZ_1; 1.
DR   PROSITE; PS50279; BPTI_KUNITZ_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Alzheimer disease; Amyloid;
KW   Amyloidosis; Apoptosis; Cell adhesion; Cell membrane; Cell projection;
KW   Coated pit; Copper; Cytoplasm; Cytoplasmic vesicle;
KW   Direct protein sequencing; Disease variant; Disulfide bond; Endocytosis;
KW   Endoplasmic reticulum; Endosome; Glycoprotein; Golgi apparatus;
KW   Heparin-binding; Iron; Isopeptide bond; Membrane; Metal-binding;
KW   Neurodegeneration; Notch signaling pathway; Nucleus; Oxidation;
KW   Phosphoprotein; Protease inhibitor; Proteoglycan;
KW   Proteomics identification; Reference proteome; Secreted;
KW   Serine protease inhibitor; Signal; Sulfation; Transmembrane;
KW   Transmembrane helix; Ubl conjugation; Zinc.
FT   SIGNAL          1..17
FT                   /evidence="ECO:0000269|PubMed:12665801,
FT                   ECO:0000269|PubMed:2900137, ECO:0000269|PubMed:3597385"
FT   CHAIN           18..770
FT                   /note="Amyloid-beta precursor protein"
FT                   /id="PRO_0000000088"
FT   CHAIN           18..687
FT                   /note="Soluble APP-alpha"
FT                   /id="PRO_0000000089"
FT   CHAIN           18..671
FT                   /note="Soluble APP-beta"
FT                   /id="PRO_0000000090"
FT   CHAIN           18..286
FT                   /note="N-APP"
FT                   /id="PRO_0000381966"
FT   CHAIN           672..770
FT                   /note="C99"
FT                   /id="PRO_0000000091"
FT   CHAIN           672..713
FT                   /note="Amyloid-beta protein 42"
FT                   /evidence="ECO:0000305|PubMed:16154999"
FT                   /id="PRO_0000000092"
FT   CHAIN           672..711
FT                   /note="Amyloid-beta protein 40"
FT                   /evidence="ECO:0000305|PubMed:11604391,
FT                   ECO:0000305|PubMed:16154999"
FT                   /id="PRO_0000000093"
FT   CHAIN           688..770
FT                   /note="C83"
FT                   /id="PRO_0000000094"
FT   PEPTIDE         688..713
FT                   /note="P3(42)"
FT                   /id="PRO_0000000095"
FT   PEPTIDE         688..711
FT                   /note="P3(40)"
FT                   /id="PRO_0000000096"
FT   CHAIN           691..770
FT                   /note="C80"
FT                   /id="PRO_0000384574"
FT   CHAIN           712..770
FT                   /note="Gamma-secretase C-terminal fragment 59"
FT                   /id="PRO_0000000097"
FT   CHAIN           714..770
FT                   /note="Gamma-secretase C-terminal fragment 57"
FT                   /id="PRO_0000000098"
FT   CHAIN           721..770
FT                   /note="Gamma-secretase C-terminal fragment 50"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000099"
FT   CHAIN           740..770
FT                   /note="C31"
FT                   /id="PRO_0000000100"
FT   TOPO_DOM        18..701
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        702..722
FT                   /note="Helical"
FT                   /evidence="ECO:0000305|PubMed:22584060,
FT                   ECO:0000305|PubMed:22654059, ECO:0000305|PubMed:30630874"
FT   TOPO_DOM        723..770
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305"
FT   DOMAIN          28..189
FT                   /note="E1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT   DOMAIN          291..341
FT                   /note="BPTI/Kunitz inhibitor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT   DOMAIN          374..565
FT                   /note="E2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01218"
FT   REGION          28..123
FT                   /note="GFLD subdomain"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT   REGION          131..189
FT                   /note="CuBD subdomain"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT   REGION          194..284
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          391..423
FT                   /note="Heparin-binding"
FT   REGION          491..522
FT                   /note="Heparin-binding"
FT   REGION          523..540
FT                   /note="Collagen-binding"
FT                   /evidence="ECO:0000269|PubMed:8576160"
FT   REGION          695..722
FT                   /note="Interaction with PSEN1"
FT                   /evidence="ECO:0000269|PubMed:30630874"
FT   REGION          732..751
FT                   /note="Interaction with G(o)-alpha"
FT   REGION          756..770
FT                   /note="Required for the interaction with KIF5B and for
FT                   anterograde transport in axons"
FT                   /evidence="ECO:0000269|PubMed:17062754"
FT   MOTIF           344..365
FT                   /note="OX-2"
FT                   /evidence="ECO:0000269|PubMed:2649245"
FT   MOTIF           724..734
FT                   /note="Basolateral sorting signal"
FT   MOTIF           757..762
FT                   /note="YENPXY motif; contains endocytosis signal"
FT                   /evidence="ECO:0000269|PubMed:10383380"
FT   COMPBIAS        194..207
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        228..264
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        268..281
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         96..110
FT                   /ligand="heparin"
FT                   /ligand_id="ChEBI:CHEBI:28304"
FT                   /evidence="ECO:0000269|PubMed:8158260"
FT   BINDING         147
FT                   /ligand="Cu(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29036"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0000269|PubMed:17239395, ECO:0000269|PubMed:25122912,
FT                   ECO:0007744|PDB:2FK1"
FT   BINDING         151
FT                   /ligand="Cu(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29036"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0000269|PubMed:17239395, ECO:0000269|PubMed:25122912,
FT                   ECO:0007744|PDB:2FK1"
FT   BINDING         168
FT                   /ligand="Cu(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29036"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0000269|PubMed:17239395, ECO:0007744|PDB:2FK1"
FT   BINDING         183
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000305|PubMed:8344894"
FT   BINDING         186
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000305|PubMed:8344894"
FT   BINDING         187
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000305|PubMed:8344894"
FT   BINDING         677
FT                   /ligand="Cu(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29036"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:11274207"
FT   BINDING         677
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:11274207,
FT                   ECO:0000269|PubMed:26898943"
FT   BINDING         681
FT                   /ligand="Cu(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29036"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000305|PubMed:11274207"
FT   BINDING         681
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000305|PubMed:10413512,
FT                   ECO:0000305|PubMed:11274207"
FT   BINDING         684
FT                   /ligand="Cu(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29036"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:11274207"
FT   BINDING         684
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:10413512,
FT                   ECO:0000269|PubMed:11274207, ECO:0000269|PubMed:26898943"
FT   BINDING         685
FT                   /ligand="Cu(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29036"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:11274207"
FT   BINDING         685
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:11274207,
FT                   ECO:0000269|PubMed:26898943"
FT   SITE            170
FT                   /note="Required for Cu(2+) reduction"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT   SITE            197..198
FT                   /note="Cleavage; by caspases"
FT                   /evidence="ECO:0000269|PubMed:10319819"
FT   SITE            219..220
FT                   /note="Cleavage; by caspases"
FT                   /evidence="ECO:0000269|PubMed:10319819"
FT   SITE            301..302
FT                   /note="Reactive bond"
FT   SITE            671..672
FT                   /note="Cleavage; by beta-secretase"
FT                   /evidence="ECO:0000305|PubMed:11851430"
FT   SITE            672..673
FT                   /note="Cleavage; by caspase-6; when associated with variant
FT                   670-N-L-671"
FT   SITE            678..679
FT                   /note="Cleavage; by ACE"
FT                   /evidence="ECO:0000269|PubMed:11604391,
FT                   ECO:0000269|PubMed:16154999"
FT   SITE            687..688
FT                   /note="Cleavage; by alpha-secretase"
FT                   /evidence="ECO:0000305|PubMed:11851430"
FT   SITE            690..691
FT                   /note="Cleavage; by theta-secretase"
FT                   /evidence="ECO:0000269|PubMed:16816112"
FT   SITE            704
FT                   /note="Implicated in free radical propagation"
FT                   /evidence="ECO:0000250"
FT   SITE            706
FT                   /note="Susceptible to oxidation"
FT                   /evidence="ECO:0000269|PubMed:10535332"
FT   SITE            711..712
FT                   /note="Cleavage; by gamma-secretase; site 1"
FT                   /evidence="ECO:0000305|PubMed:11851430"
FT   SITE            713..714
FT                   /note="Cleavage; by gamma-secretase; site 2"
FT                   /evidence="ECO:0000305|PubMed:11851430"
FT   SITE            720..721
FT                   /note="Cleavage; by gamma-secretase; site 3"
FT                   /evidence="ECO:0000269|PubMed:11851430,
FT                   ECO:0000305|PubMed:30630874"
FT   SITE            739..740
FT                   /note="Cleavage; by caspase-6, caspase-8 or caspase-9"
FT                   /evidence="ECO:0000269|PubMed:10319819"
FT   MOD_RES         198
FT                   /note="Phosphoserine; by CK2"
FT                   /evidence="ECO:0000269|PubMed:8999878"
FT   MOD_RES         206
FT                   /note="Phosphoserine; by CK1"
FT                   /evidence="ECO:0000269|PubMed:8999878"
FT   MOD_RES         217
FT                   /note="Sulfotyrosine"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         262
FT                   /note="Sulfotyrosine"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         336
FT                   /note="Sulfotyrosine"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         441
FT                   /note="Phosphoserine; by FAM20C"
FT                   /evidence="ECO:0000269|PubMed:26091039"
FT   MOD_RES         497
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:26091039"
FT   MOD_RES         729
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P08592"
FT   MOD_RES         730
FT                   /note="Phosphoserine; by APP-kinase I"
FT                   /evidence="ECO:0000250|UniProtKB:P08592"
FT   MOD_RES         743
FT                   /note="Phosphothreonine; by CDK5 and MAPK10"
FT                   /evidence="ECO:0000269|PubMed:28720718,
FT                   ECO:0000269|PubMed:8131745, ECO:0007744|PubMed:24275569"
FT   MOD_RES         757
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:11877420"
FT   CARBOHYD        542
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:16335952"
FT   CARBOHYD        571
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000305"
FT   CARBOHYD        633
FT                   /note="O-linked (GalNAc...) threonine; partial"
FT                   /evidence="ECO:0000269|PubMed:21712440,
FT                   ECO:0000269|PubMed:22576872"
FT   CARBOHYD        651
FT                   /note="O-linked (GalNAc...) threonine; partial"
FT                   /evidence="ECO:0000269|PubMed:21712440,
FT                   ECO:0000269|PubMed:22576872"
FT   CARBOHYD        652
FT                   /note="O-linked (GalNAc...) threonine; partial"
FT                   /evidence="ECO:0000269|PubMed:21712440,
FT                   ECO:0000269|PubMed:22576872"
FT   CARBOHYD        656
FT                   /note="O-linked (Xyl...) (chondroitin sulfate) serine; in
FT                   L-APP isoforms"
FT                   /evidence="ECO:0000269|PubMed:21712440"
FT   CARBOHYD        659
FT                   /note="O-linked (HexNAc...) threonine; partial"
FT                   /evidence="ECO:0000269|PubMed:22576872"
FT   CARBOHYD        663
FT                   /note="O-linked (GalNAc...) threonine; partial"
FT                   /evidence="ECO:0000269|PubMed:22576872,
FT                   ECO:0000305|PubMed:21712440"
FT   CARBOHYD        667
FT                   /note="O-linked (GalNAc...) serine; partial"
FT                   /evidence="ECO:0000269|PubMed:22576872,
FT                   ECO:0000305|PubMed:21712440"
FT   CARBOHYD        681
FT                   /note="O-linked (HexNAc...) tyrosine; partial"
FT                   /evidence="ECO:0000269|PubMed:22576872"
FT   DISULFID        38..62
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0007744|PDB:1MWP, ECO:0007744|PDB:3KTM,
FT                   ECO:0007744|PDB:4JFN, ECO:0007744|PDB:4PQD,
FT                   ECO:0007744|PDB:4PWQ"
FT   DISULFID        73..117
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0007744|PDB:1MWP, ECO:0007744|PDB:3KTM,
FT                   ECO:0007744|PDB:4JFN, ECO:0007744|PDB:4PQD,
FT                   ECO:0007744|PDB:4PWQ"
FT   DISULFID        98..105
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0007744|PDB:1MWP, ECO:0007744|PDB:3KTM,
FT                   ECO:0007744|PDB:4PQD, ECO:0007744|PDB:4PWQ"
FT   DISULFID        133..187
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0000269|PubMed:12611883, ECO:0000269|PubMed:17239395,
FT                   ECO:0000269|PubMed:17909280, ECO:0007744|PDB:1OWT,
FT                   ECO:0007744|PDB:2FJZ, ECO:0007744|PDB:2FK1,
FT                   ECO:0007744|PDB:2FK2, ECO:0007744|PDB:2FK3,
FT                   ECO:0007744|PDB:2FKL, ECO:0007744|PDB:2FMA,
FT                   ECO:0007744|PDB:3KTM, ECO:0007744|PDB:4PWQ"
FT   DISULFID        144..174
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0000269|PubMed:12611883, ECO:0000269|PubMed:17239395,
FT                   ECO:0000269|PubMed:17909280, ECO:0007744|PDB:1OWT,
FT                   ECO:0007744|PDB:2FJZ, ECO:0007744|PDB:2FK1,
FT                   ECO:0007744|PDB:2FK2, ECO:0007744|PDB:2FK3,
FT                   ECO:0007744|PDB:2FKL, ECO:0007744|PDB:2FMA,
FT                   ECO:0007744|PDB:3KTM, ECO:0007744|PDB:4PWQ"
FT   DISULFID        158..186
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217,
FT                   ECO:0000269|PubMed:12611883, ECO:0000269|PubMed:17239395,
FT                   ECO:0000269|PubMed:17909280, ECO:0007744|PDB:1OWT,
FT                   ECO:0007744|PDB:2FJZ, ECO:0007744|PDB:2FK1,
FT                   ECO:0007744|PDB:2FK2, ECO:0007744|PDB:2FK3,
FT                   ECO:0007744|PDB:2FKL, ECO:0007744|PDB:2FMA,
FT                   ECO:0007744|PDB:3KTM, ECO:0007744|PDB:4PWQ"
FT   DISULFID        291..341
FT                   /evidence="ECO:0007744|PDB:1AAP, ECO:0007744|PDB:1BRC,
FT                   ECO:0007744|PDB:1CA0, ECO:0007744|PDB:1TAW,
FT                   ECO:0007744|PDB:1ZJD, ECO:0007744|PDB:3L33"
FT   DISULFID        300..324
FT                   /evidence="ECO:0007744|PDB:1AAP, ECO:0007744|PDB:1BRC,
FT                   ECO:0007744|PDB:1CA0, ECO:0007744|PDB:1TAW,
FT                   ECO:0007744|PDB:1ZJD, ECO:0007744|PDB:3L33,
FT                   ECO:0007744|PDB:5C67"
FT   DISULFID        316..337
FT                   /evidence="ECO:0007744|PDB:1AAP, ECO:0007744|PDB:1BRC,
FT                   ECO:0007744|PDB:1CA0, ECO:0007744|PDB:1TAW,
FT                   ECO:0007744|PDB:1ZJD, ECO:0007744|PDB:3L33,
FT                   ECO:0007744|PDB:5C67"
FT   CROSSLNK        763
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P08592"
FT   VAR_SEQ         1..19
FT                   /note="MLPGLALLLLAAWTARALE -> MDQLEDLLVLFINY (in isoform
FT                   11)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_045446"
FT   VAR_SEQ         19..74
FT                   /note="Missing (in isoform APP639)"
FT                   /evidence="ECO:0000303|PubMed:12859342"
FT                   /id="VSP_009116"
FT   VAR_SEQ         289..363
FT                   /note="Missing (in isoform APP639)"
FT                   /evidence="ECO:0000303|PubMed:12859342"
FT                   /id="VSP_009117"
FT   VAR_SEQ         289
FT                   /note="E -> V (in isoform APP695, isoform L-APP696, isoform
FT                   L-APP677 and isoform APP714)"
FT                   /evidence="ECO:0000303|PubMed:2881207"
FT                   /id="VSP_000002"
FT   VAR_SEQ         290..364
FT                   /note="Missing (in isoform APP695 and isoform L-APP677)"
FT                   /evidence="ECO:0000303|PubMed:2881207"
FT                   /id="VSP_000004"
FT   VAR_SEQ         290..345
FT                   /note="Missing (in isoform L-APP696 and isoform APP714)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_000003"
FT   VAR_SEQ         290..305
FT                   /note="VCSEQAETGPCRAMIS -> KWYKEVHSGQARWLML (in isoform
FT                   APP305)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_000005"
FT   VAR_SEQ         306..770
FT                   /note="Missing (in isoform APP305)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_000006"
FT   VAR_SEQ         345..364
FT                   /note="MSQSLLKTTQEPLARDPVKL -> I (in isoform 11)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_045447"
FT   VAR_SEQ         345
FT                   /note="M -> I (in isoform L-APP733 and isoform APP751)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:1587857, ECO:0000303|PubMed:2893289"
FT                   /id="VSP_000007"
FT   VAR_SEQ         346..364
FT                   /note="Missing (in isoform L-APP733 and isoform APP751)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:1587857, ECO:0000303|PubMed:2893289"
FT                   /id="VSP_000008"
FT   VAR_SEQ         364
FT                   /note="L -> V (in isoform APP639)"
FT                   /evidence="ECO:0000303|PubMed:12859342"
FT                   /id="VSP_009118"
FT   VAR_SEQ         637..654
FT                   /note="Missing (in isoform L-APP677, isoform L-APP696,
FT                   isoform L-APP733 and isoform L-APP752)"
FT                   /evidence="ECO:0000303|PubMed:1587857"
FT                   /id="VSP_000009"
FT   VARIANT         501
FT                   /note="E -> K (in dbSNP:rs45588932)"
FT                   /evidence="ECO:0000269|Ref.10"
FT                   /id="VAR_022315"
FT   VARIANT         665
FT                   /note="E -> D (in a patient with late onset Alzheimer
FT                   disease; dbSNP:rs63750363)"
FT                   /evidence="ECO:0000269|PubMed:8154870"
FT                   /id="VAR_010107"
FT   VARIANT         670..671
FT                   /note="KM -> NL (in AD1; Swedish mutation; highly increases
FT                   hydrolysis by BACE1 and amyloid-beta proteins production;
FT                   dbSNP:rs281865161)"
FT                   /evidence="ECO:0000269|PubMed:10656250,
FT                   ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:1302033,
FT                   ECO:0000269|PubMed:1465129"
FT                   /id="VAR_000015"
FT   VARIANT         678
FT                   /note="D -> N (in AD1; dbSNP:rs63750064)"
FT                   /evidence="ECO:0000269|PubMed:15201367"
FT                   /id="VAR_044424"
FT   VARIANT         692
FT                   /note="A -> G (in AD1; Flemish mutation; increases the
FT                   solubility of processed amyloid-beta peptides and increases
FT                   the stability of peptide oligomers; dbSNP:rs63750671)"
FT                   /evidence="ECO:0000269|PubMed:11311152,
FT                   ECO:0000269|PubMed:1303239, ECO:0000269|PubMed:9754958"
FT                   /id="VAR_000016"
FT   VARIANT         693
FT                   /note="E -> G (in AD1; dbSNP:rs63751039)"
FT                   /evidence="ECO:0000269|PubMed:11528419,
FT                   ECO:0000269|PubMed:1415269"
FT                   /id="VAR_014215"
FT   VARIANT         693
FT                   /note="E -> K (in CAA-APP; Italian type; dbSNP:rs63750579)"
FT                   /evidence="ECO:0000269|PubMed:20697050"
FT                   /id="VAR_014216"
FT   VARIANT         693
FT                   /note="E -> Q (in CAA-APP; Dutch type; dbSNP:rs63750579)"
FT                   /evidence="ECO:0000269|PubMed:2111584"
FT                   /id="VAR_000017"
FT   VARIANT         694
FT                   /note="D -> N (in CAA-APP; Iowa type; dbSNP:rs63749810)"
FT                   /evidence="ECO:0000269|PubMed:11409420,
FT                   ECO:0000269|PubMed:12654973"
FT                   /id="VAR_014217"
FT   VARIANT         705
FT                   /note="L -> V (in CAA-APP; Italian type; dbSNP:rs63750921)"
FT                   /evidence="ECO:0000269|PubMed:16178030"
FT                   /id="VAR_032276"
FT   VARIANT         713
FT                   /note="A -> T (in AD1; dbSNP:rs63750066)"
FT                   /evidence="ECO:0000269|PubMed:1303275,
FT                   ECO:0000269|PubMed:15365148"
FT                   /id="VAR_000019"
FT   VARIANT         713
FT                   /note="A -> V (in one chronic schizophrenia patient;
FT                   uncertain significance; dbSNP:rs1800557)"
FT                   /evidence="ECO:0000269|PubMed:1307241"
FT                   /id="VAR_000018"
FT   VARIANT         714
FT                   /note="T -> A (in AD1; dbSNP:rs63750643)"
FT                   /evidence="ECO:0000269|PubMed:12034808"
FT                   /id="VAR_032277"
FT   VARIANT         714
FT                   /note="T -> I (in AD1; increased amyloid-beta protein 42/40
FT                   ratio; dbSNP:rs63750973)"
FT                   /evidence="ECO:0000269|PubMed:11063718,
FT                   ECO:0000269|PubMed:15668448"
FT                   /id="VAR_014218"
FT   VARIANT         715
FT                   /note="V -> M (in AD1; decreased amyloid-beta protein 40/
FT                   total amyloid-beta; dbSNP:rs63750734)"
FT                   /evidence="ECO:0000269|PubMed:10097173"
FT                   /id="VAR_010108"
FT   VARIANT         716
FT                   /note="I -> V (in AD1; dbSNP:rs63750399)"
FT                   /evidence="ECO:0000269|PubMed:9328472"
FT                   /id="VAR_000020"
FT   VARIANT         717
FT                   /note="V -> F (in AD1; increased amyloid-beta protein 42/40
FT                   ratio; dbSNP:rs63750264)"
FT                   /evidence="ECO:0000269|PubMed:1925564,
FT                   ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8290042,
FT                   ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8886002"
FT                   /id="VAR_000023"
FT   VARIANT         717
FT                   /note="V -> G (in AD1; increased amyloid-beta protein 42/40
FT                   ratio; dbSNP:rs63749964)"
FT                   /evidence="ECO:0000269|PubMed:1944558,
FT                   ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8886002"
FT                   /id="VAR_000022"
FT   VARIANT         717
FT                   /note="V -> I (in AD1; increased amyloid-beta protein 42/40
FT                   ratio; dbSNP:rs63750264)"
FT                   /evidence="ECO:0000269|PubMed:10631141,
FT                   ECO:0000269|PubMed:11063718, ECO:0000269|PubMed:1671712,
FT                   ECO:0000269|PubMed:1678058, ECO:0000269|PubMed:1908231,
FT                   ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8476439,
FT                   ECO:0000269|PubMed:8577393, ECO:0000269|PubMed:8886002"
FT                   /id="VAR_000021"
FT   VARIANT         717
FT                   /note="V -> L (in AD1; dbSNP:rs63750264)"
FT                   /evidence="ECO:0000269|PubMed:10867787"
FT                   /id="VAR_014219"
FT   VARIANT         723
FT                   /note="L -> P (in AD1; dbSNP:rs63751122)"
FT                   /evidence="ECO:0000269|PubMed:10665499"
FT                   /id="VAR_010109"
FT   MUTAGEN         99..102
FT                   /note="KRGR->NQGG: Reduced heparin-binding."
FT                   /evidence="ECO:0000269|PubMed:8158260"
FT   MUTAGEN         108
FT                   /note="H->A: Loss of the copper binding site in the GFLD
FT                   subdomain; when associated with A-110."
FT                   /evidence="ECO:0000269|PubMed:25122912"
FT   MUTAGEN         110
FT                   /note="H->A: Loss of the copper binding site in the GFLD
FT                   subdomain; when associated with A-108."
FT                   /evidence="ECO:0000269|PubMed:25122912"
FT   MUTAGEN         137
FT                   /note="H->N: Binds copper. Forms dimer."
FT                   /evidence="ECO:0000269|PubMed:7913895"
FT   MUTAGEN         141
FT                   /note="M->T: Binds copper. Forms dimer."
FT                   /evidence="ECO:0000269|PubMed:7913895"
FT   MUTAGEN         144
FT                   /note="C->S: Binds copper. No dimer formation. No copper
FT                   reducing activity."
FT                   /evidence="ECO:0000269|PubMed:10461923,
FT                   ECO:0000269|PubMed:7913895"
FT   MUTAGEN         147..149
FT                   /note="HLH->ALA: 50% decrease in copper reducing activity."
FT                   /evidence="ECO:0000269|PubMed:10461923"
FT   MUTAGEN         147
FT                   /note="H->A: Loss of a copper binding site; when associated
FT                   with A-151."
FT                   /evidence="ECO:0000269|PubMed:25122912"
FT   MUTAGEN         147
FT                   /note="H->A: Some decrease in copper reducing activity."
FT                   /evidence="ECO:0000269|PubMed:11784781,
FT                   ECO:0000269|PubMed:7913895"
FT   MUTAGEN         147
FT                   /note="H->N: Binds copper. Forms dimer."
FT                   /evidence="ECO:0000269|PubMed:11784781,
FT                   ECO:0000269|PubMed:7913895"
FT   MUTAGEN         147
FT                   /note="H->Y: Greatly reduced copper-mediated low-density
FT                   lipoprotein oxidation."
FT                   /evidence="ECO:0000269|PubMed:11784781,
FT                   ECO:0000269|PubMed:7913895"
FT   MUTAGEN         151
FT                   /note="H->A: Loss of a copper binding site; when associated
FT                   with A-147."
FT                   /evidence="ECO:0000269|PubMed:25122912"
FT   MUTAGEN         151
FT                   /note="H->K: Greatly reduced copper-mediated low-density
FT                   lipoprotein oxidation."
FT                   /evidence="ECO:0000269|PubMed:11784781,
FT                   ECO:0000269|PubMed:7913895"
FT   MUTAGEN         151
FT                   /note="H->N: Binds copper. Forms dimer."
FT                   /evidence="ECO:0000269|PubMed:11784781,
FT                   ECO:0000269|PubMed:7913895"
FT   MUTAGEN         198
FT                   /note="S->A: Greatly reduced casein kinase
FT                   phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:10806211,
FT                   ECO:0000269|PubMed:8999878"
FT   MUTAGEN         206
FT                   /note="S->A: Reduced casein kinase phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:10806211,
FT                   ECO:0000269|PubMed:8999878"
FT   MUTAGEN         499
FT                   /note="R->A: Reduced affinity for heparin; when associated
FT                   with A-503."
FT                   /evidence="ECO:0000269|PubMed:15304215"
FT   MUTAGEN         503
FT                   /note="K->A: Reduced affinity for heparin; when associated
FT                   with A-499."
FT                   /evidence="ECO:0000269|PubMed:15304215"
FT   MUTAGEN         656
FT                   /note="S->A: Abolishes chondroitin sulfate binding in L-
FT                   APP733 isoform."
FT                   /evidence="ECO:0000269|PubMed:7737970"
FT   MUTAGEN         676
FT                   /note="R->G: 60-70% zinc-induced amyloid-beta protein 28
FT                   aggregation."
FT                   /evidence="ECO:0000269|PubMed:10413512"
FT   MUTAGEN         681
FT                   /note="Y->F: 60-70% zinc-induced amyloid-beta protein 28
FT                   aggregation."
FT                   /evidence="ECO:0000269|PubMed:10413512"
FT   MUTAGEN         684
FT                   /note="H->R: Only 23% zinc-induced amyloid-beta protein 28
FT                   aggregation."
FT                   /evidence="ECO:0000269|PubMed:10413512"
FT   MUTAGEN         695
FT                   /note="V->C: Causes formation of an artifactual disulfide
FT                   bond with PSEN1."
FT                   /evidence="ECO:0000269|PubMed:30630874"
FT   MUTAGEN         704
FT                   /note="G->V: Reduced protein oxidation. No hippocampal
FT                   neuron toxicity."
FT   MUTAGEN         706
FT                   /note="M->L: Reduced lipid peroxidation inhibition."
FT                   /evidence="ECO:0000269|PubMed:10535332,
FT                   ECO:0000269|PubMed:9168929"
FT   MUTAGEN         706
FT                   /note="M->V: No free radical production. No hippocampal
FT                   neuron toxicity."
FT                   /evidence="ECO:0000269|PubMed:10535332,
FT                   ECO:0000269|PubMed:9168929"
FT   MUTAGEN         717
FT                   /note="V->C,S: Unchanged amyloid-beta protein 42/total
FT                   amyloid-beta ratio."
FT                   /evidence="ECO:0000269|PubMed:8886002"
FT   MUTAGEN         717
FT                   /note="V->K: Decreased amyloid-beta protein 42/total
FT                   amyloid-beta ratio."
FT                   /evidence="ECO:0000269|PubMed:8886002"
FT   MUTAGEN         717
FT                   /note="V->M: Increased amyloid-beta protein 42/40 ratio. No
FT                   change in apoptosis after caspase cleavage."
FT                   /evidence="ECO:0000269|PubMed:8886002"
FT   MUTAGEN         728
FT                   /note="Y->A: No effect on APBA1 nor APBB1 binding. Greatly
FT                   reduces the binding to APPBP2. APP internalization
FT                   unchanged. No change in amyloid-beta protein 42 secretion."
FT                   /evidence="ECO:0000269|PubMed:10383380,
FT                   ECO:0000269|PubMed:8887653, ECO:0000269|PubMed:9843960"
FT   MUTAGEN         739
FT                   /note="D->A: No cleavage by caspases during apoptosis."
FT                   /evidence="ECO:0000269|PubMed:10319819,
FT                   ECO:0000269|PubMed:10742146, ECO:0000269|PubMed:12214090"
FT   MUTAGEN         739
FT                   /note="D->N: No effect on FADD-induced apoptosis."
FT                   /evidence="ECO:0000269|PubMed:10319819,
FT                   ECO:0000269|PubMed:10742146, ECO:0000269|PubMed:12214090"
FT   MUTAGEN         743
FT                   /note="T->A: Greatly reduces the binding to SHC1 and APBB
FT                   family members; no effect on NGF-stimulated neurite
FT                   extension. Loss of phosphorylation by LRRK2."
FT                   /evidence="ECO:0000269|PubMed:10341243,
FT                   ECO:0000269|PubMed:11146006, ECO:0000269|PubMed:11517218,
FT                   ECO:0000269|PubMed:11877420, ECO:0000269|PubMed:28720718"
FT   MUTAGEN         743
FT                   /note="T->E: Reduced NGF-stimulated neurite extension. No
FT                   effect on APP maturation."
FT                   /evidence="ECO:0000269|PubMed:10341243,
FT                   ECO:0000269|PubMed:11146006, ECO:0000269|PubMed:11517218,
FT                   ECO:0000269|PubMed:11877420"
FT   MUTAGEN         756
FT                   /note="G->A: APP internalization unchanged. No change in
FT                   amyloid-beta protein 42 secretion."
FT                   /evidence="ECO:0000269|PubMed:10383380"
FT   MUTAGEN         757..762
FT                   /note="YENPTY->AENPTA: No effect on C99 interaction with
FT                   SORL1."
FT                   /evidence="ECO:0000269|PubMed:16407538"
FT   MUTAGEN         757
FT                   /note="Y->A: Little APP internalization. Reduced amyloid-
FT                   beta protein 42 secretion."
FT                   /evidence="ECO:0000269|PubMed:10383380,
FT                   ECO:0000269|PubMed:11724784, ECO:0000269|PubMed:11877420,
FT                   ECO:0000269|PubMed:8887653"
FT   MUTAGEN         757
FT                   /note="Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1,
FT                   APPBP2 and SHC1."
FT                   /evidence="ECO:0000269|PubMed:10383380,
FT                   ECO:0000269|PubMed:11724784, ECO:0000269|PubMed:11877420,
FT                   ECO:0000269|PubMed:8887653"
FT   MUTAGEN         759
FT                   /note="N->A: No binding to APBA1, no effect on APBB1
FT                   binding. Little APP internalization. Reduced amyloid-beta
FT                   protein 42 secretion."
FT                   /evidence="ECO:0000269|PubMed:10383380,
FT                   ECO:0000269|PubMed:8887653"
FT   MUTAGEN         760
FT                   /note="P->A: Little APP internalization. Reduced amyloid-
FT                   beta protein 42 secretion."
FT                   /evidence="ECO:0000269|PubMed:10383380"
FT   MUTAGEN         762
FT                   /note="Y->A: Loss of binding to APBA1 and APBB1. APP
FT                   internalization unchanged. No change in amyloid-beta
FT                   protein 42 secretion."
FT                   /evidence="ECO:0000269|PubMed:10383380,
FT                   ECO:0000269|PubMed:8887653"
FT   CONFLICT        15..16
FT                   /note="AR -> VW (in Ref. 3; CAA31830)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        647
FT                   /note="D -> E (in Ref. 36; AAA51722)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        724
FT                   /note="Missing (in Ref. 23; AAB26263/AAB26264)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        731
FT                   /note="I -> N (in Ref. 23; AAB26263/AAB26264/AAB26265)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        757
FT                   /note="Y -> S (in Ref. 31; AAA35540)"
FT                   /evidence="ECO:0000305"
FT   HELIX           26..28
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          33..35
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          43..45
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   TURN            47..49
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          52..54
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          56..58
FT                   /evidence="ECO:0007829|PDB:4PWQ"
FT   HELIX           66..76
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          82..87
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          92..94
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          97..99
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   TURN            100..102
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          103..106
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          110..112
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          115..119
FT                   /evidence="ECO:0007829|PDB:4PQD"
FT   STRAND          134..139
FT                   /evidence="ECO:0007829|PDB:2FMA"
FT   HELIX           147..160
FT                   /evidence="ECO:0007829|PDB:2FMA"
FT   STRAND          163..174
FT                   /evidence="ECO:0007829|PDB:2FMA"
FT   TURN            175..177
FT                   /evidence="ECO:0007829|PDB:2FMA"
FT   STRAND          178..188
FT                   /evidence="ECO:0007829|PDB:2FMA"
FT   HELIX           288..292
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   STRAND          299..301
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   STRAND          304..310
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   TURN            311..314
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   STRAND          315..321
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   STRAND          323..325
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   STRAND          331..333
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   HELIX           334..341
FT                   /evidence="ECO:0007829|PDB:1AAP"
FT   HELIX           374..380
FT                   /evidence="ECO:0007829|PDB:3NYL"
FT   HELIX           389..418
FT                   /evidence="ECO:0007829|PDB:3UMH"
FT   STRAND          421..423
FT                   /evidence="ECO:0007829|PDB:3UMH"
FT   HELIX           425..480
FT                   /evidence="ECO:0007829|PDB:3UMH"
FT   STRAND          482..484
FT                   /evidence="ECO:0007829|PDB:3NYJ"
FT   HELIX           487..518
FT                   /evidence="ECO:0007829|PDB:3UMH"
FT   HELIX           520..546
FT                   /evidence="ECO:0007829|PDB:3UMH"
FT   HELIX           547..550
FT                   /evidence="ECO:0007829|PDB:3UMH"
FT   HELIX           552..566
FT                   /evidence="ECO:0007829|PDB:3UMH"
FT   HELIX           615..618
FT                   /evidence="ECO:0007829|PDB:5BUO"
FT   STRAND          620..622
FT                   /evidence="ECO:0007829|PDB:5BUO"
FT   HELIX           673..675
FT                   /evidence="ECO:0007829|PDB:4OJF"
FT   TURN            677..679
FT                   /evidence="ECO:0007829|PDB:7OW1"
FT   STRAND          682..684
FT                   /evidence="ECO:0007829|PDB:7OXN"
FT   STRAND          688..691
FT                   /evidence="ECO:0007829|PDB:6O4J"
FT   STRAND          692..694
FT                   /evidence="ECO:0007829|PDB:4MVI"
FT   TURN            695..698
FT                   /evidence="ECO:0007829|PDB:4MVI"
FT   STRAND          701..703
FT                   /evidence="ECO:0007829|PDB:3PZZ"
FT   STRAND          707..712
FT                   /evidence="ECO:0007829|PDB:2Y3K"
FT   HELIX           713..715
FT                   /evidence="ECO:0007829|PDB:6IYC"
FT   STRAND          718..720
FT                   /evidence="ECO:0007829|PDB:8X52"
FT   STRAND          721..725
FT                   /evidence="ECO:0007829|PDB:6IYC"
FT   HELIX           744..754
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   STRAND          756..758
FT                   /evidence="ECO:0007829|PDB:6ITU"
FT   STRAND          763..765
FT                   /evidence="ECO:0007829|PDB:3L81"
SQ   SEQUENCE   770 AA;  86943 MW;  A12EE761403740F5 CRC64;
     MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
     TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
     EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
     GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
     EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
     RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD
     PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
     KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
     QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
     MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
     KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
     IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL
     VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
//
ID   ADDG_HUMAN              Reviewed;         706 AA.
AC   Q9UEY8; D3DRA8; O43243; Q5VU09; Q92773; Q9UEY7;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   28-JAN-2026, entry version 196.
DE   RecName: Full=Gamma-adducin;
DE   AltName: Full=Adducin-like protein 70;
GN   Name=ADD3; Synonyms=ADDL;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX   PubMed=8893809; DOI=10.1159/000134389;
RA   Katagiri T., Ozaki K., Fujiwara T., Shimizu F., Kawai A., Okuno S.,
RA   Suzuki M., Nakamura Y., Takahashi E., Hirai Y.;
RT   "Cloning, expression and chromosome mapping of adducin-like 70 (ADDL), a
RT   human cDNA highly homologous to human erythrocyte adducin.";
RL   Cytogenet. Cell Genet. 74:90-95(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Moorthy S., Bennett V.;
RT   "Cloning in the gamma quadrant.";
RL   Submitted (SEP-1995) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX   PubMed=10581174; DOI=10.1006/bbrc.1999.1769;
RA   Citterio L., Azzani T., Duga S., Bianchi G.;
RT   "Genomic organization of the human gamma adducin gene.";
RL   Biochem. Biophys. Res. Commun. 266:110-114(1999).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Endometrium;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164054; DOI=10.1038/nature02462;
RA   Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA   Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA   Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA   Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA   Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA   Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA   Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA   Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA   Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA   Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA   Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA   Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA   McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA   Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA   Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA   Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA   Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA   Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA   Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA   Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 10.";
RL   Nature 429:375-381(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Ovary;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [8]
RP   SUMOYLATION.
RX   PubMed=15561718; DOI=10.1074/jbc.m411718200;
RA   Gocke C.B., Yu H., Kang J.;
RT   "Systematic identification and analysis of mammalian small ubiquitin-like
RT   modifier substrates.";
RL   J. Biol. Chem. 280:5004-5012(2005).
RN   [9]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-673, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA   Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT   networks.";
RL   Cell 127:635-648(2006).
RN   [10]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-42, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Platelet;
RX   PubMed=18088087; DOI=10.1021/pr0704130;
RA   Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA   Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT   "Phosphoproteome of resting human platelets.";
RL   J. Proteome Res. 7:526-534(2008).
RN   [11]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-64; SER-423; SER-442;
RP   SER-673; SER-677 AND SER-681, AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [12]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [13]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-402; SER-423 AND SER-681, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [14]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE
RP   ANALYSIS] AT SER-42; SER-673 AND SER-677, CLEAVAGE OF INITIATOR METHIONINE
RP   [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE
RP   SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [15]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [16]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-677 AND SER-681, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA   Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA   Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT   "System-wide temporal characterization of the proteome and phosphoproteome
RT   of human embryonic stem cell differentiation.";
RL   Sci. Signal. 4:RS3-RS3(2011).
RN   [17]
RP   INVOLVEMENT IN CPSQ3, VARIANT CPSQ3 ASP-367, CHARACTERIZATION OF VARIANT
RP   CPSQ3 ASP-367, AND FUNCTION.
RX   PubMed=23836506; DOI=10.1002/ana.23971;
RA   Kruer M.C., Jepperson T., Dutta S., Steiner R.D., Cottenie E., Sanford L.,
RA   Merkens M., Russman B.S., Blasco P.A., Fan G., Pollock J., Green S.,
RA   Woltjer R.L., Mooney C., Kretzschmar D., Paisan-Ruiz C., Houlden H.;
RT   "Mutations in gamma adducin are associated with inherited cerebral palsy.";
RL   Ann. Neurol. 74:805-814(2013).
RN   [18]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-42; SER-64; SER-442; SER-461;
RP   SER-673; SER-677; SER-681 AND SER-683, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [19]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-64, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [20]
RP   SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-484, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=28112733; DOI=10.1038/nsmb.3366;
RA   Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA   Nielsen M.L.;
RT   "Site-specific mapping of the human SUMO proteome reveals co-modification
RT   with phosphorylation.";
RL   Nat. Struct. Mol. Biol. 24:325-336(2017).
RN   [21]
RP   TISSUE SPECIFICITY.
RX   PubMed=33992672; DOI=10.1016/j.pneurobio.2021.102074;
RA   Xiong M., Zou L., Meng L., Zhang X., Tian Y., Zhang G., Yang J., Chen G.,
RA   Xiong J., Ye K., Zhang Z.;
RT   "A gamma-adducin cleavage fragment induces neurite deficits and synaptic
RT   dysfunction in Alzheimer's disease.";
RL   Prog. Neurobiol. 203:102074-102074(2021).
CC   -!- FUNCTION: Membrane-cytoskeleton-associated protein that promotes the
CC       assembly of the spectrin-actin network. Plays a role in actin filament
CC       capping (PubMed:23836506). Binds to calmodulin (Probable). Involved in
CC       myogenic reactivity of the renal afferent arteriole (Af-art), renal
CC       interlobular arteries and middle cerebral artery (MCA) to increased
CC       perfusion pressure. Involved in regulation of potassium channels in the
CC       vascular smooth muscle cells (VSMCs) of the Af-art and MCA ex vivo.
CC       Involved in regulation of glomerular capillary pressure, glomerular
CC       filtration rate (GFR) and glomerular nephrin expression in response to
CC       hypertension. Involved in renal blood flow (RBF) autoregulation. Plays
CC       a role in podocyte structure and function. Regulates globular monomer
CC       actin (G-actin) and filamentous polymer actin (F-actin) ratios in the
CC       primary podocytes affecting actin cytoskeleton organization. Regulates
CC       expression of synaptopodin, RhoA, Rac1 and CDC42 in the renal cortex
CC       and the primary podocytes. Regulates expression of nephrin in the
CC       glomeruli and in the primary podocytes, expression of nephrin and
CC       podocinin in the renal cortex, and expression of focal adhesion
CC       proteins integrin alpha-3 and integrin beta-1 in the glomeruli.
CC       Involved in cell migration and cell adhesion of podocytes, and in
CC       podocyte foot process effacement. Regulates expression of profibrotics
CC       markers MMP2, MMP9, TGF beta-1, tubular tight junction protein E-
CC       cadherin, and mesenchymal markers vimentin and alpha-SMA (By
CC       similarity). Promotes the growth of neurites (By similarity).
CC       {ECO:0000250|UniProtKB:Q62847, ECO:0000250|UniProtKB:Q9QYB5,
CC       ECO:0000269|PubMed:23836506, ECO:0000305}.
CC   -!- SUBUNIT: Heterodimer of an alpha and a gamma subunit.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
CC       {ECO:0000250|UniProtKB:Q62847}. Cell membrane
CC       {ECO:0000250|UniProtKB:Q62847}; Peripheral membrane protein;
CC       Cytoplasmic side. Cytoplasm {ECO:0000250|UniProtKB:Q9QYB5}. Note=Full-
CC       length protein and the cleavage fragment 358-706 localize mainly to the
CC       cytoplasm, while cleavage fragment 1-357 translocates from the
CC       cytoplasm to the nucleus. {ECO:0000250|UniProtKB:Q9QYB5}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC         Comment=Additional isoforms seem to exist.;
CC       Name=2; Synonyms=Long;
CC         IsoId=Q9UEY8-1; Sequence=Displayed;
CC       Name=1; Synonyms=Short;
CC         IsoId=Q9UEY8-2; Sequence=VSP_000188;
CC   -!- TISSUE SPECIFICITY: [Isoform 1]: ubiquitously expressed.
CC       {ECO:0000269|PubMed:8893809}.
CC   -!- TISSUE SPECIFICITY: Cleavage fragment 1-357 is abundantly expressed in
CC       the brain of patients with Alzheimer disease (AD), but hardly
CC       detectable in age-matched control individuals (at protein level).
CC       {ECO:0000269|PubMed:33992672}.
CC   -!- DOMAIN: Comprised of three regions: a N-terminal protease-resistant
CC       globular head region, a short connecting subdomain, and a protease-
CC       sensitive tail region.
CC   -!- PTM: Sumoylated. {ECO:0000269|PubMed:15561718}.
CC   -!- PTM: Proteolytically cleaved by asparagine endopeptidase (AEP) into 2
CC       fragments. Overexpression of the 1-357 fragment induces neuronal
CC       apoptosis, and overexpression of either 1-357 or 358-706 fragment
CC       increases the degeneration of dendritic spines. Overexpression of the
CC       1-357 fragment impairs neurite outgrowth by downregulating the
CC       expression of Rac2, and induces synaptic dysfunction and cognitive
CC       impairments in tau P301S transgenic mice, a mouse model for Alzheimer
CC       disease (AD). {ECO:0000250|UniProtKB:Q9QYB5}.
CC   -!- DISEASE: Cerebral palsy, spastic quadriplegic 3 (CPSQ3) [MIM:617008]: A
CC       form of cerebral palsy, a group of non-progressive disorders of
CC       movement and/or posture resulting from defects in the developing
CC       central nervous system. CPSQ3 is an autosomal recessive
CC       neurodevelopmental disorder characterized by variable spasticity and
CC       cognitive impairment. {ECO:0000269|PubMed:23836506}. Note=The disease
CC       is caused by variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the aldolase class II family. Adducin subfamily.
CC       {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/520/ADD3";
CC   ---------------------------------------------------------------------------
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DR   EMBL; D67031; BAA23783.1; -; mRNA.
DR   EMBL; U37122; AAB17126.1; -; mRNA.
DR   EMBL; Y14372; CAB51805.1; -; Genomic_DNA.
DR   EMBL; Y14373; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14374; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14375; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14376; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14377; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14378; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14379; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14380; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14381; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14382; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14383; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14384; CAB51805.1; JOINED; Genomic_DNA.
DR   EMBL; Y14372; CAB51806.1; -; Genomic_DNA.
DR   EMBL; Y14373; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14374; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14375; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14376; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14377; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14378; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14379; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14380; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14381; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14382; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; Y14384; CAB51806.1; JOINED; Genomic_DNA.
DR   EMBL; BX647403; CAI46048.1; -; mRNA.
DR   EMBL; AL590628; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471066; EAW49573.1; -; Genomic_DNA.
DR   EMBL; CH471066; EAW49574.1; -; Genomic_DNA.
DR   EMBL; BC062559; AAH62559.1; -; mRNA.
DR   CCDS; CCDS7561.1; -. [Q9UEY8-1]
DR   CCDS; CCDS7562.1; -. [Q9UEY8-2]
DR   PIR; JC7164; JC7164.
DR   RefSeq; NP_001112.2; NM_001121.3. [Q9UEY8-2]
DR   RefSeq; NP_001307520.1; NM_001320591.2. [Q9UEY8-1]
DR   RefSeq; NP_001307521.1; NM_001320592.2. [Q9UEY8-1]
DR   RefSeq; NP_001307522.1; NM_001320593.2. [Q9UEY8-1]
DR   RefSeq; NP_001307523.1; NM_001320594.1.
DR   RefSeq; NP_058432.1; NM_016824.5. [Q9UEY8-1]
DR   RefSeq; NP_063968.1; NM_019903.5. [Q9UEY8-2]
DR   RefSeq; XP_024303562.1; XM_024447794.2. [Q9UEY8-1]
DR   RefSeq; XP_024303563.1; XM_024447795.1. [Q9UEY8-1]
DR   RefSeq; XP_024303564.1; XM_024447796.2. [Q9UEY8-1]
DR   RefSeq; XP_024303565.1; XM_024447797.2. [Q9UEY8-1]
DR   RefSeq; XP_024303566.1; XM_024447798.1. [Q9UEY8-1]
DR   RefSeq; XP_024303567.1; XM_024447799.2. [Q9UEY8-1]
DR   RefSeq; XP_024303568.1; XM_024447800.2. [Q9UEY8-1]
DR   RefSeq; XP_024303569.1; XM_024447801.1. [Q9UEY8-1]
DR   RefSeq; XP_024303570.1; XM_024447802.2. [Q9UEY8-1]
DR   RefSeq; XP_024303571.1; XM_024447803.2. [Q9UEY8-2]
DR   RefSeq; XP_024303572.1; XM_024447804.1. [Q9UEY8-2]
DR   RefSeq; XP_024303573.1; XM_024447805.2. [Q9UEY8-2]
DR   RefSeq; XP_024303574.1; XM_024447806.2. [Q9UEY8-2]
DR   RefSeq; XP_024303575.1; XM_024447807.1. [Q9UEY8-2]
DR   RefSeq; XP_047280543.1; XM_047424587.1. [Q9UEY8-1]
DR   RefSeq; XP_047280544.1; XM_047424588.1. [Q9UEY8-1]
DR   RefSeq; XP_047280545.1; XM_047424589.1. [Q9UEY8-1]
DR   RefSeq; XP_047280546.1; XM_047424590.1. [Q9UEY8-1]
DR   RefSeq; XP_047280547.1; XM_047424591.1. [Q9UEY8-1]
DR   RefSeq; XP_047280548.1; XM_047424592.1. [Q9UEY8-2]
DR   RefSeq; XP_047280549.1; XM_047424593.1. [Q9UEY8-2]
DR   RefSeq; XP_047280550.1; XM_047424594.1. [Q9UEY8-2]
DR   RefSeq; XP_047280551.1; XM_047424595.1. [Q9UEY8-2]
DR   RefSeq; XP_054220742.1; XM_054364767.1. [Q9UEY8-1]
DR   RefSeq; XP_054220743.1; XM_054364768.1. [Q9UEY8-1]
DR   RefSeq; XP_054220744.1; XM_054364769.1. [Q9UEY8-1]
DR   RefSeq; XP_054220745.1; XM_054364770.1. [Q9UEY8-1]
DR   RefSeq; XP_054220746.1; XM_054364771.1. [Q9UEY8-1]
DR   RefSeq; XP_054220747.1; XM_054364772.1. [Q9UEY8-1]
DR   RefSeq; XP_054220748.1; XM_054364773.1. [Q9UEY8-1]
DR   RefSeq; XP_054220749.1; XM_054364774.1. [Q9UEY8-1]
DR   RefSeq; XP_054220750.1; XM_054364775.1. [Q9UEY8-1]
DR   RefSeq; XP_054220751.1; XM_054364776.1. [Q9UEY8-1]
DR   RefSeq; XP_054220752.1; XM_054364777.1. [Q9UEY8-1]
DR   RefSeq; XP_054220753.1; XM_054364778.1. [Q9UEY8-1]
DR   RefSeq; XP_054220754.1; XM_054364779.1. [Q9UEY8-1]
DR   RefSeq; XP_054220755.1; XM_054364780.1. [Q9UEY8-1]
DR   RefSeq; XP_054220756.1; XM_054364781.1. [Q9UEY8-2]
DR   RefSeq; XP_054220757.1; XM_054364782.1. [Q9UEY8-2]
DR   RefSeq; XP_054220758.1; XM_054364783.1. [Q9UEY8-2]
DR   RefSeq; XP_054220759.1; XM_054364784.1. [Q9UEY8-2]
DR   RefSeq; XP_054220760.1; XM_054364785.1. [Q9UEY8-2]
DR   RefSeq; XP_054220761.1; XM_054364786.1. [Q9UEY8-2]
DR   RefSeq; XP_054220762.1; XM_054364787.1. [Q9UEY8-2]
DR   RefSeq; XP_054220763.1; XM_054364788.1. [Q9UEY8-2]
DR   RefSeq; XP_054220764.1; XM_054364789.1. [Q9UEY8-2]
DR   AlphaFoldDB; Q9UEY8; -.
DR   SMR; Q9UEY8; -.
DR   BioGRID; 106633; 175.
DR   ComplexPortal; CPX-2643; Adducin complex, alpha-gamma variant.
DR   FunCoup; Q9UEY8; 1492.
DR   IntAct; Q9UEY8; 70.
DR   MINT; Q9UEY8; -.
DR   STRING; 9606.ENSP00000348381; -.
DR   GlyCosmos; Q9UEY8; 2 sites, 1 glycan.
DR   GlyGen; Q9UEY8; 3 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; Q9UEY8; -.
DR   MetOSite; Q9UEY8; -.
DR   PhosphoSitePlus; Q9UEY8; -.
DR   SwissPalm; Q9UEY8; -.
DR   BioMuta; ADD3; -.
DR   DMDM; 12643881; -.
DR   jPOST; Q9UEY8; -.
DR   MassIVE; Q9UEY8; -.
DR   PaxDb; 9606-ENSP00000348381; -.
DR   PeptideAtlas; Q9UEY8; -.
DR   ProteomicsDB; 84160; -. [Q9UEY8-1]
DR   ProteomicsDB; 84161; -. [Q9UEY8-2]
DR   Pumba; Q9UEY8; -.
DR   Antibodypedia; 4067; 206 antibodies from 32 providers.
DR   DNASU; 120; -.
DR   Ensembl; ENST00000277900.12; ENSP00000277900.8; ENSG00000148700.16. [Q9UEY8-2]
DR   Ensembl; ENST00000356080.9; ENSP00000348381.4; ENSG00000148700.16. [Q9UEY8-1]
DR   Ensembl; ENST00000360162.7; ENSP00000353286.3; ENSG00000148700.16. [Q9UEY8-2]
DR   GeneID; 120; -.
DR   KEGG; hsa:120; -.
DR   MANE-Select; ENST00000356080.9; ENSP00000348381.4; NM_016824.5; NP_058432.1.
DR   UCSC; uc001kys.5; human. [Q9UEY8-1]
DR   AGR; HGNC:245; -.
DR   ClinPGx; PA24567; -.
DR   CTD; 120; -.
DR   DisGeNET; 120; -.
DR   GeneCards; ADD3; -.
DR   HGNC; HGNC:245; ADD3.
DR   HPA; ENSG00000148700; Low tissue specificity.
DR   MalaCards; ADD3; -.
DR   MIM; 601568; gene.
DR   MIM; 617008; phenotype.
DR   OpenTargets; ENSG00000148700; -.
DR   Orphanet; 210141; Inherited congenital spastic tetraplegia.
DR   VEuPathDB; HostDB:ENSG00000148700; -.
DR   eggNOG; KOG3699; Eukaryota.
DR   GeneTree; ENSGT00940000155257; -.
DR   HOGENOM; CLU_006033_9_2_1; -.
DR   InParanoid; Q9UEY8; -.
DR   OMA; XVRISKE; -.
DR   OrthoDB; 3238794at2759; -.
DR   PAN-GO; Q9UEY8; 5 GO annotations based on evolutionary models.
DR   PhylomeDB; Q9UEY8; -.
DR   PathwayCommons; Q9UEY8; -.
DR   Reactome; R-HSA-5223345; Miscellaneous transport and binding events.
DR   Reactome; R-HSA-9013405; RHOD GTPase cycle.
DR   Reactome; R-HSA-9035034; RHOF GTPase cycle.
DR   SignaLink; Q9UEY8; -.
DR   SIGNOR; Q9UEY8; -.
DR   Agora; ENSG00000148700; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 120; 16 hits in 1164 CRISPR screens.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; ADD3; human.
DR   GeneWiki; ADD3; -.
DR   GenomeRNAi; 120; -.
DR   Pharos; Q9UEY8; Tbio.
DR   PRO; PR:Q9UEY8; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; Q9UEY8; protein.
DR   Bgee; ENSG00000148700; Expressed in secondary oocyte and 213 other cell types or tissues.
DR   ExpressionAtlas; Q9UEY8; baseline and differential.
DR   GO; GO:0005903; C:brush border; IEA:Ensembl.
DR   GO; GO:0005938; C:cell cortex; IEA:Ensembl.
DR   GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
DR   GO; GO:0000794; C:condensed nuclear chromosome; IEA:Ensembl.
DR   GO; GO:0005856; C:cytoskeleton; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0016020; C:membrane; TAS:ProtInc.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0014069; C:postsynaptic density; IBA:GO_Central.
DR   GO; GO:0051015; F:actin filament binding; IBA:GO_Central.
DR   GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW.
DR   GO; GO:0005080; F:protein kinase C binding; IEA:Ensembl.
DR   GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR   GO; GO:0051016; P:barbed-end actin filament capping; IBA:GO_Central.
DR   GO; GO:0051495; P:positive regulation of cytoskeleton organization; IEA:Ensembl.
DR   GO; GO:0045907; P:positive regulation of vasoconstriction; IEA:Ensembl.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR   FunFam; 3.40.225.10:FF:000004; gamma-adducin isoform X1; 1.
DR   Gene3D; 3.40.225.10; Class II aldolase/adducin N-terminal domain; 1.
DR   InterPro; IPR051017; Aldolase-II_Adducin_sf.
DR   InterPro; IPR001303; Aldolase_II/adducin_N.
DR   InterPro; IPR036409; Aldolase_II/adducin_N_sf.
DR   PANTHER; PTHR10672; ADDUCIN; 1.
DR   PANTHER; PTHR10672:SF5; GAMMA-ADDUCIN; 1.
DR   Pfam; PF00596; Aldolase_II; 1.
DR   SMART; SM01007; Aldolase_II; 1.
DR   SUPFAM; SSF53639; AraD/HMP-PK domain-like; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Actin-binding; Alternative splicing; Calmodulin-binding;
KW   Cell membrane; Cytoplasm; Cytoskeleton; Disease variant; Isopeptide bond;
KW   Membrane; Phosphoprotein; Proteomics identification; Reference proteome;
KW   Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:19413330,
FT                   ECO:0007744|PubMed:20068231"
FT   CHAIN           2..706
FT                   /note="Gamma-adducin"
FT                   /id="PRO_0000218536"
FT   REGION          1..20
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          471..497
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          535..555
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          575..610
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          666..706
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          684..701
FT                   /note="Interaction with calmodulin"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        1..10
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        589..602
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        682..706
FT                   /note="Basic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            357
FT                   /note="Cleavage by asparagine endopeptidase (AEP)"
FT                   /evidence="ECO:0000250|UniProtKB:Q9QYB5"
FT   MOD_RES         2
FT                   /note="N-acetylserine"
FT                   /evidence="ECO:0007744|PubMed:19413330,
FT                   ECO:0007744|PubMed:20068231"
FT   MOD_RES         42
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18088087,
FT                   ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT   MOD_RES         64
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT   MOD_RES         402
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         414
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9QYB5"
FT   MOD_RES         423
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:19690332"
FT   MOD_RES         442
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         461
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         585
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9QYB5"
FT   MOD_RES         590
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9QYB5"
FT   MOD_RES         673
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17081983,
FT                   ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         677
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         679
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9QYB5"
FT   MOD_RES         681
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:21406692,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         683
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   CROSSLNK        484
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2)"
FT                   /evidence="ECO:0007744|PubMed:28112733"
FT   VAR_SEQ         576..607
FT                   /note="Missing (in isoform 1)"
FT                   /evidence="ECO:0000303|PubMed:17974005,
FT                   ECO:0000303|PubMed:8893809, ECO:0000303|Ref.2"
FT                   /id="VSP_000188"
FT   VARIANT         367
FT                   /note="G -> D (in CPSQ3; decreased actin capping activity;
FT                   increased fibroblast proliferation and migration; decreased
FT                   colocalization with alpha subunit ADD1; dbSNP:rs564185858)"
FT                   /evidence="ECO:0000269|PubMed:23836506"
FT                   /id="VAR_076996"
FT   CONFLICT        49..50
FT                   /note="FN -> SS (in Ref. 1; BAA23783)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        60
FT                   /note="Q -> R (in Ref. 1; BAA23783)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        362
FT                   /note="Q -> P (in Ref. 2; AAB17126)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        420
FT                   /note="V -> M (in Ref. 2; AAB17126)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        421
FT                   /note="P -> L (in Ref. 1; BAA23783)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        426..433
FT                   /note="KYMAQRQQ -> QIHGTRGNK (in Ref. 2; AAB17126)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        484
FT                   /note="K -> Q (in Ref. 2; AAB17126)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   706 AA;  79155 MW;  EB8EAF602A4D7B41 CRC64;
     MSSDASQGVI TTPPPPSMPH KERYFDRINE NDPEYIRERN MSPDLRQDFN MMEQRKRVTQ
     ILQSPAFRED LECLIQEQMK KGHNPTGLLA LQQIADYIMA NSFSGFSSPP LSLGMVTPIN
     DLPGADTSSY VKGEKLTRCK LASLYRLVDL FGWAHLANTY ISVRISKEQD HIIIIPRGLS
     FSEATASNLV KVNIIGEVVD QGSTNLKIDH TGFSPHAAIY STRPDVKCVI HIHTLATAAV
     SSMKCGILPI SQESLLLGDV AYYDYQGSLE EQEERIQLQK VLGPSCKVLV LRNHGVVALG
     ETLEEAFHYI FNVQLACEIQ VQALAGAGGV DNLHVLDFQK YKAFTYTVAA SGGGGVNMGS
     HQKWKVGEIE FEGLMRTLDN LGYRTGYAYR HPLIREKPRH KSDVEIPATV TAFSFEDDTV
     PLSPLKYMAQ RQQREKTRWL NSPNTYMKVN VPEESRNGET SPRTKITWMK AEDSSKVSGG
     TPIKIEDPNQ FVPLNTNPNE VLEKRNKIRE QNRYDLKTAG PQSQLLAGIV VDKPPSTMQF
     EDDDHGPPAP PNPFSHLTEG ELEEYKRTIE RKQQGLEDAE QELLSDDASS VSQIQSQTQS
     PQNVPEKLEE NHELFSKSFI SMEVPVMVVN GKDDMHDVED ELAKRVSRLS TSTTIENIEI
     TIKSPEKIEE VLSPEGSPSK SPSKKKKKFR TPSFLKKNKK KEKVEA
//
ID   APBB1_HUMAN             Reviewed;         710 AA.
AC   O00213; A1E379; A6NH82; A6NL69; B7Z1J5; B7Z1J6; B7Z2Y0; D3DQT2; Q7Z324;
AC   Q96A93; V9GYK0; V9GYT4;
DT   11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-1998, sequence version 2.
DT   28-JAN-2026, entry version 216.
DE   RecName: Full=Amyloid beta precursor protein binding family B member 1 {ECO:0000312|HGNC:HGNC:581};
DE   AltName: Full=Amyloid-beta A4 precursor protein-binding family B member 1 {ECO:0000250|UniProtKB:Q9QXJ1};
DE   AltName: Full=Protein Fe65 {ECO:0000250|UniProtKB:Q9QXJ1};
GN   Name=APBB1 {ECO:0000312|HGNC:HGNC:581};
GN   Synonyms=FE65 {ECO:0000303|PubMed:8894693},
GN   RIR {ECO:0000312|HGNC:HGNC:581};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=8894693; DOI=10.1093/hmg/5.10.1589;
RA   Bressler S.L., Gray M.D., Sopher B.L., Hu Q., Hearn M.G., Pham D.G.,
RA   Dinulos M.B., Fukuchi K., Sisodia S.S., Miller M.A., Disteche C.M.,
RA   Martin G.M.;
RT   "cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of
RT   the conserved cytoplasmic domains of the human beta-amyloid precursor
RT   protein and its homologues with the mouse Fe65 protein.";
RL   Hum. Mol. Genet. 5:1589-1598(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=9799084; DOI=10.1007/s004390050820;
RA   Hu Q., Kukull W.A., Bressler S.L., Gray M.D., Cam J.A., Larson E.B.,
RA   Martin G.M., Deeb S.S.;
RT   "The human FE65 gene: genomic structure and an intronic biallelic
RT   polymorphism associated with sporadic dementia of the Alzheimer type.";
RL   Hum. Genet. 103:295-303(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=21824145; DOI=10.1111/j.1471-4159.2011.07420.x;
RA   Domingues S.C., Henriques A.G., Fardilha M., da Cruz E Silva E.F.,
RA   da Cruz E Silva O.A.;
RT   "Identification and characterization of a neuronal enriched novel
RT   transcript encoding the previously described p60Fe65 isoform.";
RL   J. Neurochem. 119:1086-1098(2011).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3; 4 AND 6).
RC   TISSUE=Caudate nucleus, and Cerebellum;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC   TISSUE=Fetal brain;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16554811; DOI=10.1038/nature04632;
RA   Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA   Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA   Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA   Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA   Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA   Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT   "Human chromosome 11 DNA sequence and analysis including novel gene
RT   identification.";
RL   Nature 440:497-500(2006).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Uterus;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   FUNCTION, INTERACTION WITH ABL1, SUBCELLULAR LOCATION, PHOSPHORYLATION AT
RP   TYR-547 BY ABL1, AND MUTAGENESIS OF TYR-117; TYR-234; TYR-269; TYR-270;
RP   TYR-403; TYR-467; 269-TYR--TRP-271; TYR-546; TYR-547 AND TYR-658.
RX   PubMed=15031292; DOI=10.1074/jbc.m311479200;
RA   Perkinton M.S., Standen C.L., Lau K.F., Kesavapany S., Byers H.L., Ward M.,
RA   McLoughlin D.M., Miller C.C.;
RT   "The c-Abl tyrosine kinase phosphorylates the Fe65 adaptor protein to
RT   stimulate Fe65/amyloid precursor protein nuclear signaling.";
RL   J. Biol. Chem. 279:22084-22091(2004).
RN   [10]
RP   SUBCELLULAR LOCATION, AND INTERACTION WITH NEK6.
RX   PubMed=17512906; DOI=10.1016/j.bbrc.2007.04.203;
RA   Lee E.J., Hyun S.H., Chun J., Kang S.S.;
RT   "Human NIMA-related kinase 6 is one of the Fe65 WW domain binding
RT   proteins.";
RL   Biochem. Biophys. Res. Commun. 358:783-788(2007).
RN   [11]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH APP.
RX   PubMed=18468999; DOI=10.1074/jbc.m801827200;
RA   Nakaya T., Kawai T., Suzuki T.;
RT   "Regulation of FE65 nuclear translocation and function by amyloid beta-
RT   protein precursor in osmotically stressed cells.";
RL   J. Biol. Chem. 283:19119-19131(2008).
RN   [12]
RP   FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-547, INTERACTION
RP   WITH RASD1, AND MUTAGENESIS OF TYR-547.
RX   PubMed=18922798; DOI=10.1074/jbc.m801874200;
RA   Lau K.-F., Chan W.-M., Perkinton M.S., Tudor E.L., Chang R.C.C.,
RA   Chan H.-Y., McLoughlin D.M., Miller C.C.J.;
RT   "Dexras1 interacts with FE65 to regulate FE65-amyloid precursor protein-
RT   dependent transcription.";
RL   J. Biol. Chem. 283:34728-34737(2008).
RN   [13]
RP   FUNCTION, AND INTERACTION WITH H2AX AND MAPK8.
RX   PubMed=19234442; DOI=10.1038/nature07849;
RA   Cook P.J., Ju B.G., Telese F., Wang X., Glass C.K., Rosenfeld M.G.;
RT   "Tyrosine dephosphorylation of H2AX modulates apoptosis and survival
RT   decisions.";
RL   Nature 458:591-596(2009).
RN   [14]
RP   FUNCTION, INTERACTION WITH SET AND TSHZ3, IDENTIFICATION IN A TRIMERIC
RP   COMPLEX WITH HDAC1 AND TSHZ3, CHROMATIN-BINDING, SUBCELLULAR LOCATION, AND
RP   TISSUE SPECIFICITY.
RX   PubMed=19343227; DOI=10.1371/journal.pone.0005071;
RA   Kajiwara Y., Akram A., Katsel P., Haroutunian V., Schmeidler J.,
RA   Beecham G., Haines J.L., Pericak-Vance M.A., Buxbaum J.D.;
RT   "FE65 binds Teashirt, inhibiting expression of the primate-specific
RT   caspase-4.";
RL   PLoS ONE 4:E5071-E5071(2009).
RN   [15]
RP   INTERACTION WITH RNF157, UBIQUITINATION BY RNF157, AND FUNCTION.
RX   PubMed=25342469; DOI=10.1038/cdd.2014.163;
RA   Matz A., Lee S.J., Schwedhelm-Domeyer N., Zanini D., Holubowska A.,
RA   Kannan M., Farnworth M., Jahn O., Goepfert M.C., Stegmueller J.;
RT   "Regulation of neuronal survival and morphology by the E3 ubiquitin ligase
RT   RNF157.";
RL   Cell Death Differ. 22:626-642(2015).
RN   [16]
RP   FUNCTION, INTERACTION WITH KAT5, ACETYLATION AT LYS-204 AND LYS-701, AND
RP   MUTAGENESIS OF LYS-204 AND LYS-701.
RX   PubMed=33938178; DOI=10.1515/hsz-2020-0279;
RA   Probst S., Riese F., Kaegi L., Krueger M., Russi N., Nitsch R.M.,
RA   Konietzko U.;
RT   "Lysine acetyltransferase Tip60 acetylates the APP adaptor Fe65 to increase
RT   its transcriptional activity.";
RL   Biol. Chem. 402:481-499(2021).
RN   [17]
RP   FUNCTION, INTERACTION WITH ARF6, MUTAGENESIS OF SER-459, AND
RP   PHOSPHORYLATION AT SER-459.
RX   PubMed=36250347; DOI=10.1096/fj.202200757r;
RA   Chau D.D., Li W., Chan W.W.R., Sun J.K., Zhai Y., Chow H.M., Lau K.F.;
RT   "Insulin stimulates atypical protein kinase C-mediated phosphorylation of
RT   the neuronal adaptor FE65 to potentiate neurite outgrowth by activating
RT   ARF6-Rac1 signaling.";
RL   FASEB J. 36:e22594-e22594(2022).
RN   [18]
RP   X-RAY CRYSTALLOGRAPHY (1.33 ANGSTROMS) OF 253-289 IN COMPLEX WITH ENAH.
RX   PubMed=17686488; DOI=10.1016/j.jmb.2007.06.064;
RA   Meiyappan M., Birrane G., Ladias J.A.A.;
RT   "Structural basis for polyproline recognition by the FE65 WW domain.";
RL   J. Mol. Biol. 372:970-980(2007).
RN   [19]
RP   X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 534-667 IN COMPLEX WITH APP.
RX   PubMed=18833287; DOI=10.1038/embor.2008.188;
RA   Radzimanowski J., Simon B., Sattler M., Beyreuther K., Sinning I., Wild K.;
RT   "Structure of the intracellular domain of the amyloid precursor protein in
RT   complex with Fe65-PTB2.";
RL   EMBO Rep. 9:1134-1140(2008).
RN   [20]
RP   X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 366-505.
RX   PubMed=18550529; DOI=10.1074/jbc.m800861200;
RA   Radzimanowski J., Ravaud S., Schlesinger S., Koch J., Beyreuther K.,
RA   Sinning I., Wild K.;
RT   "Crystal structure of the human Fe65-PTB1 domain.";
RL   J. Biol. Chem. 283:23113-23120(2008).
CC   -!- FUNCTION: Transcription coregulator that can have both coactivator and
CC       corepressor functions (PubMed:15031292, PubMed:18468999,
CC       PubMed:18922798, PubMed:25342469, PubMed:33938178). Adapter protein
CC       that forms a transcriptionally active complex with the gamma-secretase-
CC       derived amyloid precursor protein (APP) intracellular domain
CC       (PubMed:15031292, PubMed:18468999, PubMed:18922798, PubMed:25342469).
CC       Plays a central role in the response to DNA damage by translocating to
CC       the nucleus and inducing apoptosis (PubMed:15031292, PubMed:18468999,
CC       PubMed:18922798, PubMed:25342469). May act by specifically recognizing
CC       and binding histone H2AX phosphorylated on 'Tyr-142' (H2AXY142ph) at
CC       double-strand breaks (DSBs), recruiting other pro-apoptosis factors
CC       such as MAPK8/JNK1 (PubMed:19234442). Required for histone H4
CC       acetylation at double-strand breaks (DSBs) (PubMed:19234442). Its
CC       ability to specifically bind modified histones and chromatin modifying
CC       enzymes such as KAT5/TIP60, probably explains its transcription
CC       activation activity (PubMed:33938178). Functions in association with
CC       TSHZ3, SET and HDAC factors as a transcriptional repressor, that
CC       inhibits the expression of CASP4 (PubMed:19343227). Associates with
CC       chromatin in a region surrounding the CASP4 transcriptional start
CC       site(s) (PubMed:19343227). Involved in hippocampal neurite branching
CC       and neuromuscular junction formation, as a result plays a role in
CC       spatial memory functioning (By similarity). Plays a role in the
CC       maintenance of lens transparency (By similarity). May play a role in
CC       muscle cell strength (By similarity). Acts as a molecular adapter that
CC       functions in neurite outgrowth by activating the RAC1-ARF6 axis upon
CC       insulin treatment (PubMed:36250347). {ECO:0000250|UniProtKB:Q9QXJ1,
CC       ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:18468999,
CC       ECO:0000269|PubMed:18922798, ECO:0000269|PubMed:19234442,
CC       ECO:0000269|PubMed:19343227, ECO:0000269|PubMed:25342469,
CC       ECO:0000269|PubMed:33938178, ECO:0000269|PubMed:36250347}.
CC   -!- SUBUNIT: Component of a complex, at least composed of APBB1,
CC       RASD1/DEXRAS1 and APP (PubMed:18468999, PubMed:18833287,
CC       PubMed:18922798). Interacts (via PID domain 2) with APP (with the
CC       intracellular domain of the amyloid-beta precursor protein)
CC       (PubMed:18468999, PubMed:18833287). Interacts (via PID domain 2) with
CC       RASD1/DEXRAS1; impairs the transcription activation activity
CC       (PubMed:18922798). Interacts (via PID domain 1) with KAT5/TIP60
CC       (PubMed:33938178). Interacts (via the WW domain) with the proline-rich
CC       region of APBB1IP (By similarity). Interacts with TSHZ1 and TSHZ2 (By
CC       similarity). Interacts (via the WW domain) with histone H2AX (when
CC       phosphorylated on 'Tyr-142') and the proline-rich region of ENAH
CC       (PubMed:17686488). Interacts with MAPK8 (PubMed:19234442). Interacts
CC       (via PID domain 1) with TSHZ3 (via homeobox domain) (PubMed:19343227).
CC       Interacts with SET (PubMed:19343227). Found in a trimeric complex with
CC       HDAC1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by
CC       TSHZ3 (PubMed:19343227). Interacts (via WWW domain) with NEK6
CC       (PubMed:17512906). Interacts (via WWW domain) with ABL1
CC       (PubMed:15031292). Interacts with RNF157 (PubMed:25342469). Interacts
CC       with ARF6 (PubMed:36250347). {ECO:0000250|UniProtKB:Q9QXJ1,
CC       ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:17512906,
CC       ECO:0000269|PubMed:17686488, ECO:0000269|PubMed:18468999,
CC       ECO:0000269|PubMed:18833287, ECO:0000269|PubMed:18922798,
CC       ECO:0000269|PubMed:19234442, ECO:0000269|PubMed:19343227,
CC       ECO:0000269|PubMed:25342469, ECO:0000269|PubMed:33938178,
CC       ECO:0000269|PubMed:36250347}.
CC   -!- INTERACTION:
CC       O00213; Q06481: APLP2; NbExp=3; IntAct=EBI-81694, EBI-79306;
CC       O00213; P05067: APP; NbExp=10; IntAct=EBI-81694, EBI-77613;
CC       O00213; P05067-4: APP; NbExp=5; IntAct=EBI-81694, EBI-302641;
CC       O00213; P62330: ARF6; NbExp=9; IntAct=EBI-81694, EBI-638181;
CC       O00213; P00533: EGFR; NbExp=4; IntAct=EBI-81694, EBI-297353;
CC       O00213; P04626: ERBB2; NbExp=2; IntAct=EBI-81694, EBI-641062;
CC       O00213; Q07954: LRP1; NbExp=4; IntAct=EBI-81694, EBI-1046087;
CC       O00213; Q02563: Sv2a; Xeno; NbExp=3; IntAct=EBI-81694, EBI-466194;
CC       O00213-2; P05067: APP; NbExp=6; IntAct=EBI-13307975, EBI-77613;
CC       O00213-2; Q86YB2: DHX8; NbExp=3; IntAct=EBI-13307975, EBI-14405236;
CC       O00213-2; Q8NFZ0: FBH1; NbExp=3; IntAct=EBI-13307975, EBI-724767;
CC       O00213-2; Q92993: KAT5; NbExp=3; IntAct=EBI-13307975, EBI-399080;
CC       O00213-2; O15116: LSM1; NbExp=3; IntAct=EBI-13307975, EBI-347619;
CC       O00213-2; Q14141: SEPTIN6; NbExp=3; IntAct=EBI-13307975, EBI-745901;
CC       O00213-2; Q99720-4: SIGMAR1; NbExp=3; IntAct=EBI-13307975, EBI-25831036;
CC       O00213-2; O95416: SOX14; NbExp=3; IntAct=EBI-13307975, EBI-9087806;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:18468999}.
CC       Cytoplasm {ECO:0000269|PubMed:18468999}. Nucleus
CC       {ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:18468999,
CC       ECO:0000269|PubMed:18922798, ECO:0000269|PubMed:19343227}. Cell
CC       projection, growth cone {ECO:0000250|UniProtKB:P46933}. Nucleus speckle
CC       {ECO:0000269|PubMed:17512906}. Note=Colocalizes with TSHZ3 in axonal
CC       growth cone (By similarity). Colocalizes with TSHZ3 in the nucleus
CC       (PubMed:19343227). In normal conditions, it mainly localizes to the
CC       cytoplasm, while a small fraction is tethered to the cell membrane via
CC       its interaction with APP (PubMed:18468999). Following exposure to DNA
CC       damaging agents, it is released from cell membrane and translocates to
CC       the nucleus (PubMed:18468999). Nuclear translocation is under the
CC       regulation of APP (PubMed:18468999). Colocalizes with NEK6 at the
CC       nuclear speckles (PubMed:17512906). Phosphorylation at Ser-610 by SGK1
CC       promotes its localization to the nucleus (By similarity).
CC       {ECO:0000250|UniProtKB:P46933, ECO:0000269|PubMed:17512906,
CC       ECO:0000269|PubMed:18468999, ECO:0000269|PubMed:19343227}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=6;
CC       Name=1;
CC         IsoId=O00213-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O00213-2; Sequence=VSP_011658;
CC       Name=3;
CC         IsoId=O00213-3; Sequence=VSP_045326, VSP_045327, VSP_011658;
CC       Name=4; Synonyms=p60Fe65;
CC         IsoId=O00213-4; Sequence=VSP_047459;
CC       Name=5;
CC         IsoId=O00213-5; Sequence=VSP_045326, VSP_045327;
CC       Name=6;
CC         IsoId=O00213-6; Sequence=VSP_054709;
CC   -!- TISSUE SPECIFICITY: Highly expressed in brain; strongly reduced in
CC       post-mortem elderly subjects with Alzheimer disease.
CC       {ECO:0000269|PubMed:19343227}.
CC   -!- TISSUE SPECIFICITY: [Isoform 4]: Expressed preferentially in the brain.
CC       {ECO:0000269|PubMed:21824145}.
CC   -!- PTM: Phosphorylation at Ser-610 by SGK1 promotes its localization to
CC       the nucleus (By similarity). Phosphorylated following nuclear
CC       translocation (PubMed:15031292, PubMed:18922798). Phosphorylation at
CC       Tyr-547 by ABL1 enhances transcriptional activation activity and
CC       reduces the affinity for RASD1/DEXRAS1 (PubMed:15031292,
CC       PubMed:18922798). Phosphorylated at Ser-459 by PKC upon insulin
CC       activation (PubMed:36250347). {ECO:0000250|UniProtKB:P46933,
CC       ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:18922798,
CC       ECO:0000269|PubMed:36250347}.
CC   -!- PTM: Acetylation at Lys-204 and Lys-701 by KAT5 promotes its
CC       transcription activator activity. {ECO:0000269|PubMed:33938178}.
CC   -!- PTM: Polyubiquitination by RNF157 leads to degradation by the
CC       proteasome (PubMed:25342469). {ECO:0000269|PubMed:25342469}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAD98057.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; L77864; AAB93631.1; -; mRNA.
DR   EMBL; AF029234; AAC79942.1; -; Genomic_DNA.
DR   EMBL; AF047835; AAC79942.1; JOINED; Genomic_DNA.
DR   EMBL; EF103274; ABL07489.3; -; mRNA.
DR   EMBL; AK293550; BAH11531.1; -; mRNA.
DR   EMBL; AK293554; BAH11532.1; -; mRNA.
DR   EMBL; AK293643; BAH11554.1; -; mRNA.
DR   EMBL; AK295241; BAH12016.1; -; mRNA.
DR   EMBL; BX538185; CAD98057.1; ALT_INIT; mRNA.
DR   EMBL; AC068733; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC084337; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471064; EAW68723.1; -; Genomic_DNA.
DR   EMBL; CH471064; EAW68724.1; -; Genomic_DNA.
DR   EMBL; BC010854; AAH10854.1; -; mRNA.
DR   CCDS; CCDS31410.1; -. [O00213-2]
DR   CCDS; CCDS58114.1; -. [O00213-3]
DR   CCDS; CCDS66015.1; -. [O00213-4]
DR   CCDS; CCDS66016.1; -. [O00213-6]
DR   CCDS; CCDS66017.1; -. [O00213-5]
DR   CCDS; CCDS66018.1; -. [O00213-1]
DR   RefSeq; NP_001155.1; NM_001164.5. [O00213-1]
DR   RefSeq; NP_001244248.1; NM_001257319.3. [O00213-5]
DR   RefSeq; NP_001244249.1; NM_001257320.2. [O00213-4]
DR   RefSeq; NP_001244250.1; NM_001257321.2. [O00213-4]
DR   RefSeq; NP_001244252.1; NM_001257323.3. [O00213-3]
DR   RefSeq; NP_001244254.1; NM_001257325.3. [O00213-6]
DR   RefSeq; NP_001244255.1; NM_001257326.2. [O00213-4]
DR   RefSeq; NP_663722.1; NM_145689.3. [O00213-2]
DR   PDB; 2E45; NMR; -; A=241-290.
DR   PDB; 2HO2; X-ray; 1.33 A; A=253-289.
DR   PDB; 2IDH; X-ray; 2.28 A; A/B/C/D/E/F/G/H=253-289.
DR   PDB; 2OEI; X-ray; 1.35 A; A=253-289.
DR   PDB; 3D8D; X-ray; 2.20 A; A/B=366-505.
DR   PDB; 3D8E; X-ray; 2.80 A; A/B/C/D=366-505.
DR   PDB; 3D8F; X-ray; 2.70 A; A/B/C/D=366-505.
DR   PDB; 3DXC; X-ray; 2.10 A; A/C=534-667.
DR   PDB; 3DXD; X-ray; 2.20 A; A/C=534-667.
DR   PDB; 3DXE; X-ray; 2.00 A; A/C=534-667.
DR   PDB; 5NQH; X-ray; 2.60 A; A/B/C/D=534-667.
DR   PDBsum; 2E45; -.
DR   PDBsum; 2HO2; -.
DR   PDBsum; 2IDH; -.
DR   PDBsum; 2OEI; -.
DR   PDBsum; 3D8D; -.
DR   PDBsum; 3D8E; -.
DR   PDBsum; 3D8F; -.
DR   PDBsum; 3DXC; -.
DR   PDBsum; 3DXD; -.
DR   PDBsum; 3DXE; -.
DR   PDBsum; 5NQH; -.
DR   AlphaFoldDB; O00213; -.
DR   BMRB; O00213; -.
DR   SMR; O00213; -.
DR   BioGRID; 106819; 202.
DR   CORUM; O00213; -.
DR   DIP; DIP-30903N; -.
DR   ELM; O00213; -.
DR   FunCoup; O00213; 944.
DR   IntAct; O00213; 188.
DR   MINT; O00213; -.
DR   STRING; 9606.ENSP00000477213; -.
DR   GlyCosmos; O00213; 1 site, 1 glycan.
DR   GlyGen; O00213; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; O00213; -.
DR   PhosphoSitePlus; O00213; -.
DR   BioMuta; APBB1; -.
DR   jPOST; O00213; -.
DR   MassIVE; O00213; -.
DR   PaxDb; 9606-ENSP00000477213; -.
DR   PeptideAtlas; O00213; -.
DR   ProteomicsDB; 47783; -. [O00213-1]
DR   ProteomicsDB; 47784; -. [O00213-2]
DR   ProteomicsDB; 6474; -.
DR   Pumba; O00213; -.
DR   Antibodypedia; 23808; 406 antibodies from 39 providers.
DR   DNASU; 322; -.
DR   Ensembl; ENST00000299402.10; ENSP00000299402.6; ENSG00000166313.21. [O00213-2]
DR   Ensembl; ENST00000311051.7; ENSP00000311912.3; ENSG00000166313.21. [O00213-2]
DR   Ensembl; ENST00000530885.5; ENSP00000433338.1; ENSG00000166313.21. [O00213-3]
DR   Ensembl; ENST00000608394.5; ENSP00000476442.1; ENSG00000166313.21. [O00213-4]
DR   Ensembl; ENST00000608645.5; ENSP00000476646.1; ENSG00000166313.21. [O00213-4]
DR   Ensembl; ENST00000608655.6; ENSP00000476846.1; ENSG00000166313.21. [O00213-5]
DR   Ensembl; ENST00000608704.5; ENSP00000476871.1; ENSG00000166313.21. [O00213-4]
DR   Ensembl; ENST00000609331.5; ENSP00000477069.1; ENSG00000166313.21. [O00213-6]
DR   Ensembl; ENST00000609360.6; ENSP00000477213.1; ENSG00000166313.21. [O00213-1]
DR   GeneID; 322; -.
DR   KEGG; hsa:322; -.
DR   MANE-Select; ENST00000609360.6; ENSP00000477213.1; NM_001164.5; NP_001155.1.
DR   UCSC; uc001mdb.4; human. [O00213-1]
DR   AGR; HGNC:581; -.
DR   ClinPGx; PA24873; -.
DR   CTD; 322; -.
DR   DisGeNET; 322; -.
DR   GeneCards; APBB1; -.
DR   HGNC; HGNC:581; APBB1.
DR   HPA; ENSG00000166313; Tissue enhanced (brain).
DR   MalaCards; APBB1; -.
DR   MIM; 602709; gene.
DR   OpenTargets; ENSG00000166313; -.
DR   VEuPathDB; HostDB:ENSG00000166313; -.
DR   eggNOG; ENOG502QT08; Eukaryota.
DR   GeneTree; ENSGT00390000000002; -.
DR   HOGENOM; CLU_021196_0_0_1; -.
DR   InParanoid; O00213; -.
DR   OMA; ENHQDQD; -.
DR   OrthoDB; 5969782at2759; -.
DR   PAN-GO; O00213; 5 GO annotations based on evolutionary models.
DR   PhylomeDB; O00213; -.
DR   PathwayCommons; O00213; -.
DR   Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR   SignaLink; O00213; -.
DR   SIGNOR; O00213; -.
DR   Agora; ENSG00000166313; -.
DR   BioGRID-ORCS; 322; 8 hits in 1157 CRISPR screens.
DR   ChiTaRS; APBB1; human.
DR   EvolutionaryTrace; O00213; -.
DR   GeneWiki; APBB1; -.
DR   GenomeRNAi; 322; -.
DR   Pharos; O00213; Tbio.
DR   PRO; PR:O00213; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; O00213; protein.
DR   Bgee; ENSG00000166313; Expressed in right hemisphere of cerebellum and 162 other cell types or tissues.
DR   ExpressionAtlas; O00213; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR   GO; GO:0030426; C:growth cone; IDA:UniProtKB.
DR   GO; GO:0030027; C:lamellipodium; IDA:UniProtKB.
DR   GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0045202; C:synapse; IDA:UniProtKB.
DR   GO; GO:0001540; F:amyloid-beta binding; IBA:GO_Central.
DR   GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR   GO; GO:0042393; F:histone binding; IPI:UniProtKB.
DR   GO; GO:0050750; F:low-density lipoprotein particle receptor binding; TAS:ARUK-UCL.
DR   GO; GO:0060090; F:molecular adaptor activity; IDA:UniProt.
DR   GO; GO:0070064; F:proline-rich region binding; IPI:UniProtKB.
DR   GO; GO:0003713; F:transcription coactivator activity; TAS:ARUK-UCL.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0007409; P:axonogenesis; NAS:UniProtKB.
DR   GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR   GO; GO:0006974; P:DNA damage response; IDA:UniProtKB.
DR   GO; GO:1902807; P:negative regulation of cell cycle G1/S phase transition; ISS:UniProtKB.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IGI:ARUK-UCL.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB.
DR   GO; GO:0010976; P:positive regulation of neuron projection development; IDA:UniProt.
DR   GO; GO:0050714; P:positive regulation of protein secretion; TAS:ARUK-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; TAS:ARUK-UCL.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; IBA:GO_Central.
DR   GO; GO:0007165; P:signal transduction; NAS:UniProtKB.
DR   GO; GO:0006939; P:smooth muscle contraction; ISS:UniProtKB.
DR   CDD; cd01272; PTB1_Fe65; 1.
DR   CDD; cd01271; PTB2_Fe65; 1.
DR   CDD; cd00201; WW; 1.
DR   FunFam; 2.30.29.30:FF:000019; Amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65); 1.
DR   FunFam; 2.20.70.10:FF:000003; amyloid beta A4 precursor protein-binding family B member 2; 1.
DR   FunFam; 2.30.29.30:FF:000034; amyloid beta A4 precursor protein-binding family B member 2; 1.
DR   Gene3D; 2.20.70.10; -; 1.
DR   Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 2.
DR   InterPro; IPR039576; APBB1/2/3.
DR   InterPro; IPR011993; PH-like_dom_sf.
DR   InterPro; IPR006020; PTB/PI_dom.
DR   InterPro; IPR001202; WW_dom.
DR   InterPro; IPR036020; WW_dom_sf.
DR   PANTHER; PTHR14058; AMYLOID BETA A4 PRECURSOR PROTEIN-BINDING FAMILY B; 1.
DR   PANTHER; PTHR14058:SF5; AMYLOID BETA PRECURSOR PROTEIN BINDING FAMILY B MEMBER 1; 1.
DR   Pfam; PF00640; PID; 2.
DR   Pfam; PF00397; WW; 1.
DR   SMART; SM00462; PTB; 2.
DR   SMART; SM00456; WW; 1.
DR   SUPFAM; SSF50729; PH domain-like; 2.
DR   SUPFAM; SSF51045; WW domain; 1.
DR   PROSITE; PS01179; PID; 2.
DR   PROSITE; PS01159; WW_DOMAIN_1; 1.
DR   PROSITE; PS50020; WW_DOMAIN_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Activator; Alternative splicing; Apoptosis;
KW   Cell membrane; Cell projection; Chromatin regulator; Cytoplasm; DNA damage;
KW   Membrane; Nucleus; Phosphoprotein; Proteomics identification;
KW   Reference proteome; Repeat; Repressor; Transcription;
KW   Transcription regulation; Ubl conjugation.
FT   CHAIN           1..710
FT                   /note="Amyloid beta precursor protein binding family B
FT                   member 1"
FT                   /id="PRO_0000076049"
FT   DOMAIN          253..285
FT                   /note="WW"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT   DOMAIN          370..509
FT                   /note="PID 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT   DOMAIN          542..699
FT                   /note="PID 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT   REGION          1..24
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          131..254
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          276..299
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          340..365
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..15
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        145..173
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        223..234
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        287..299
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         204
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:33938178"
FT   MOD_RES         459
FT                   /note="Phosphoserine; by PKC"
FT                   /evidence="ECO:0000269|PubMed:36250347"
FT   MOD_RES         517
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9QXJ1"
FT   MOD_RES         547
FT                   /note="Phosphotyrosine; by ABL1"
FT                   /evidence="ECO:0000269|PubMed:15031292,
FT                   ECO:0000269|PubMed:18922798"
FT   MOD_RES         610
FT                   /note="Phosphoserine; by SGK1"
FT                   /evidence="ECO:0000250|UniProtKB:P46933"
FT   MOD_RES         701
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:33938178"
FT   VAR_SEQ         1..259
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:21824145"
FT                   /id="VSP_047459"
FT   VAR_SEQ         1..240
FT                   /note="MSVPSSLSQSAINANSHGGPALSLPLPLHAAHNQLLNAKLQATAVGPKDLRS
FT                   AMGEGGGPEPGPANAKWLKEGQNQLRRAATAHRDQNRNVTLTLAEEASQEPEMAPLGPK
FT                   GLIHLYSELELSAHNAANRGLRGPGLIISTQEQGPDEGEEKAAGEAEEEEEDDDDEEEE
FT                   EDLSSPPGLPEPLESVEAPPRPQALTDGPREHSKSASLLFGMRNSAASDEDSSWATLSQ
FT                   GSPSYGSPEDT -> MTQMR (in isoform 6)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_054709"
FT   VAR_SEQ         1..213
FT                   /note="Missing (in isoform 3 and isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:17974005"
FT                   /id="VSP_045326"
FT   VAR_SEQ         214..240
FT                   /note="NSAASDEDSSWATLSQGSPSYGSPEDT -> MSAMFSQDFFLAIILQDSSA
FT                   (in isoform 3 and isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:17974005"
FT                   /id="VSP_045327"
FT   VAR_SEQ         462..463
FT                   /note="Missing (in isoform 2 and isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:15489334"
FT                   /id="VSP_011658"
FT   VARIANT         327
FT                   /note="M -> V (in dbSNP:rs1800423)"
FT                   /id="VAR_014444"
FT   VARIANT         396
FT                   /note="N -> S (in dbSNP:rs1800425)"
FT                   /id="VAR_014445"
FT   MUTAGEN         117
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         204
FT                   /note="K->Q: Mimics acetylation; leading to increased
FT                   transcription activator activity; when associated with Q-
FT                   701."
FT                   /evidence="ECO:0000269|PubMed:33938178"
FT   MUTAGEN         204
FT                   /note="K->R: Abolished acetylation by KAT5, leading to
FT                   decreased transcription activator activity; when associated
FT                   with R-701."
FT                   /evidence="ECO:0000269|PubMed:33938178"
FT   MUTAGEN         234
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         269..271
FT                   /note="YYW->AAA: Impairs transcriptional activation and
FT                   inhibits binding to ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         269
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         270
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         403
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         459
FT                   /note="S->A: Loss of PKC-mediated phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:36250347"
FT   MUTAGEN         459
FT                   /note="S->E: Increased activation of the RAC1-ARF6 axis."
FT                   /evidence="ECO:0000269|PubMed:36250347"
FT   MUTAGEN         467
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         546
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         547
FT                   /note="Y->F: Abrogates phosphorylation and stimulation of
FT                   transcription by ABL1, and increases the interaction with
FT                   RASD1/DEXRAS1."
FT                   /evidence="ECO:0000269|PubMed:15031292,
FT                   ECO:0000269|PubMed:18922798"
FT   MUTAGEN         658
FT                   /note="Y->F: No effect on phosphorylation by ABL1."
FT                   /evidence="ECO:0000269|PubMed:15031292"
FT   MUTAGEN         701
FT                   /note="K->Q: Mimics acetylation; leading to increased
FT                   transcription activator activity; when associated with Q-
FT                   204."
FT                   /evidence="ECO:0000269|PubMed:33938178"
FT   MUTAGEN         701
FT                   /note="K->R: Abolished acetylation by KAT5, leading to
FT                   decreased transcription activator activity; when associated
FT                   with R-204."
FT                   /evidence="ECO:0000269|PubMed:33938178"
FT   CONFLICT        367
FT                   /note="I -> T (in Ref. 4; BAH11532)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        493
FT                   /note="T -> A (in Ref. 4; BAH11532)"
FT                   /evidence="ECO:0000305"
FT   STRAND          259..263
FT                   /evidence="ECO:0007829|PDB:2HO2"
FT   STRAND          268..272
FT                   /evidence="ECO:0007829|PDB:2HO2"
FT   TURN            273..275
FT                   /evidence="ECO:0007829|PDB:2HO2"
FT   STRAND          278..281
FT                   /evidence="ECO:0007829|PDB:2HO2"
FT   STRAND          368..379
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   HELIX           382..385
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   TURN            387..389
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   HELIX           390..401
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   STRAND          421..427
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   STRAND          430..434
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   TURN            436..438
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   STRAND          441..446
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   HELIX           447..449
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   STRAND          452..455
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   STRAND          458..460
FT                   /evidence="ECO:0007829|PDB:3D8F"
FT   STRAND          464..470
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   TURN            472..474
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   STRAND          477..486
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   HELIX           488..504
FT                   /evidence="ECO:0007829|PDB:3D8D"
FT   STRAND          544..554
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   HELIX           559..571
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   HELIX           575..577
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   STRAND          579..585
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   STRAND          587..594
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   TURN            595..597
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   STRAND          600..605
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   HELIX           606..608
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   STRAND          609..614
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   STRAND          620..628
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   STRAND          631..641
FT                   /evidence="ECO:0007829|PDB:3DXE"
FT   HELIX           644..665
FT                   /evidence="ECO:0007829|PDB:3DXE"
SQ   SEQUENCE   710 AA;  77244 MW;  FD4A2EF7E8D8E884 CRC64;
     MSVPSSLSQS AINANSHGGP ALSLPLPLHA AHNQLLNAKL QATAVGPKDL RSAMGEGGGP
     EPGPANAKWL KEGQNQLRRA ATAHRDQNRN VTLTLAEEAS QEPEMAPLGP KGLIHLYSEL
     ELSAHNAANR GLRGPGLIIS TQEQGPDEGE EKAAGEAEEE EEDDDDEEEE EDLSSPPGLP
     EPLESVEAPP RPQALTDGPR EHSKSASLLF GMRNSAASDE DSSWATLSQG SPSYGSPEDT
     DSFWNPNAFE TDSDLPAGWM RVQDTSGTYY WHIPTGTTQW EPPGRASPSQ GSSPQEESQL
     TWTGFAHGEG FEDGEFWKDE PSDEAPMELG LKEPEEGTLT FPAQSLSPEP LPQEEEKLPP
     RNTNPGIKCF AVRSLGWVEM TEEELAPGRS SVAVNNCIRQ LSYHKNNLHD PMSGGWGEGK
     DLLLQLEDET LKLVEPQSQA LLHAQPIISI RVWGVGRDSG RERDFAYVAR DKLTQMLKCH
     VFRCEAPAKN IATSLHEICS KIMAERRNAR CLVNGLSLDH SKLVDVPFQV EFPAPKNELV
     QKFQVYYLGN VPVAKPVGVD VINGALESVL SSSSREQWTP SHVSVAPATL TILHQQTEAV
     LGECRVRFLS FLAVGRDVHT FAFIMAAGPA SFCCHMFWCE PNAASLSEAV QAACMLRYQK
     CLDARSQAST SCLPAPPAES VARRVGWTVR RGVQSLWGSL KPKRLGAHTP
//
ID   CD5R1_HUMAN             Reviewed;         307 AA.
AC   Q15078; E1P664; Q5U0G3;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1997, sequence version 1.
DT   28-JAN-2026, entry version 229.
DE   RecName: Full=Cyclin-dependent kinase 5 activator 1;
DE            Short=CDK5 activator 1;
DE   AltName: Full=Cyclin-dependent kinase 5 regulatory subunit 1;
DE   AltName: Full=TPKII regulatory subunit;
DE   Contains:
DE     RecName: Full=Cyclin-dependent kinase 5 activator 1, p35;
DE              Short=p35;
DE   Contains:
DE     RecName: Full=Cyclin-dependent kinase 5 activator 1, p25;
DE              Short=p25;
DE     AltName: Full=Tau protein kinase II 23 kDa subunit;
DE              Short=p23;
DE   Flags: Precursor;
GN   Name=CDK5R1; Synonyms=CDK5R, NCK5A;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Brain;
RX   PubMed=8090221; DOI=10.1038/371419a0;
RA   Tsai L.-H., Delalle I., Caviness V.S. Jr., Chae T., Harlow E.;
RT   "p35 is a neural-specific regulatory subunit of cyclin-dependent kinase
RT   5.";
RL   Nature 371:419-423(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   NIEHS SNPs program;
RL   Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Mammary gland;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [6]
RP   MUTAGENESIS OF GLY-2, SUBCELLULAR LOCATION, AND INVOLVEMENT IN
RP   NEURODEGENERATIVE DISEASES.
RX   PubMed=10604467; DOI=10.1038/45159;
RA   Patrick G.N., Zukerberg L., Nikolic M., de la Monte S., Dikkes P.,
RA   Tsai L.H.;
RT   "Conversion of p35 to p25 deregulates Cdk5 activity and promotes
RT   neurodegeneration.";
RL   Nature 402:615-622(1999).
RN   [7]
RP   PHOSPHORYLATION BY CDK5, AND UBIQUITINATION.
RX   PubMed=12393264; DOI=10.1016/s0169-328x(02)00409-6;
RA   Kerokoski P., Suuronen T., Salminen A., Soininen H., Pirttilae T.;
RT   "Influence of phosphorylation of p35, an activator of cyclin-dependent
RT   kinase 5 (cdk5), on the proteolysis of p35.";
RL   Brain Res. Mol. Brain Res. 106:50-56(2002).
RN   [8]
RP   INTERACTION WITH RASGRF2.
RX   PubMed=15128856; DOI=10.1523/jneurosci.0690-04.2004;
RA   Kesavapany S., Amin N., Zheng Y.-L., Nijhara R., Jaffe H., Sihag R.,
RA   Gutkind J.S., Takahashi S., Kulkarni A., Grant P., Pant H.C.;
RT   "p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide
RT   releasing factor 2 (RasGRF2) mediates Rac-dependent extracellular signal-
RT   regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated
RT   protein 1b distribution in neurons.";
RL   J. Neurosci. 24:4421-4431(2004).
RN   [9]
RP   PHOSPHORYLATION AT SER-8 AND THR-138, AND MUTAGENESIS OF SER-8 AND THR-138.
RX   PubMed=17121855; DOI=10.1074/jbc.m610541200;
RA   Kamei H., Saito T., Ozawa M., Fujita Y., Asada A., Bibb J.A., Saido T.C.,
RA   Sorimachi H., Hisanaga S.;
RT   "Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25
RT   by site-specific phosphorylation.";
RL   J. Biol. Chem. 282:1687-1694(2007).
RN   [10]
RP   PHOSPHORYLATION BY CDK5, INTERACTION WITH CDK5, AND SUBCELLULAR LOCATION.
RX   PubMed=17671990; DOI=10.1002/jnr.21438;
RA   Sato K., Zhu Y.-S., Saito T., Yotsumoto K., Asada A., Hasegawa M.,
RA   Hisanaga S.;
RT   "Regulation of membrane association and kinase activity of Cdk5-p35 by
RT   phosphorylation of p35.";
RL   J. Neurosci. Res. 85:3071-3078(2007).
RN   [11]
RP   SUBCELLULAR LOCATION, MYRISTOYLATION, AND MUTAGENESIS OF GLY-2.
RX   PubMed=18507738; DOI=10.1111/j.1471-4159.2008.05500.x;
RA   Asada A., Yamamoto N., Gohda M., Saito T., Hayashi N., Hisanaga S.;
RT   "Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear
RT   localization of active cyclin-dependent kinase 5 complexes.";
RL   J. Neurochem. 106:1325-1336(2008).
RN   [12]
RP   MYRISTOYLATION AT GLY-2.
RX   PubMed=20213681; DOI=10.1002/pmic.200900783;
RA   Suzuki T., Moriya K., Nagatoshi K., Ota Y., Ezure T., Ando E.,
RA   Tsunasawa S., Utsumi T.;
RT   "Strategy for comprehensive identification of human N-myristoylated
RT   proteins using an insect cell-free protein synthesis system.";
RL   Proteomics 10:1780-1793(2010).
RN   [13]
RP   FUNCTION, AND INTERACTION WITH CLOCK.
RX   PubMed=24235147; DOI=10.1074/jbc.m113.494856;
RA   Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H.,
RA   Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.;
RT   "Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein
RT   by direct phosphorylation.";
RL   J. Biol. Chem. 288:36878-36889(2013).
RN   [14]
RP   UBIQUITINATION, AND MUTAGENESIS OF LEU-305.
RX   PubMed=33398170; DOI=10.1038/s41589-020-00703-4;
RA   Yan X., Wang X., Li Y., Zhou M., Li Y., Song L., Mi W., Min J., Dong C.;
RT   "Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-
RT   degron.";
RL   Nat. Chem. Biol. 17:263-271(2021).
RN   [15]
RP   X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 145-293 IN COMPLEX WITH CDK5.
RX   PubMed=16039528; DOI=10.1016/j.chembiol.2005.05.011;
RA   Ahn J.S., Radhakrishnan M.L., Mapelli M., Choi S., Tidor B., Cuny G.D.,
RA   Musacchio A., Yeh L.A., Kosik K.S.;
RT   "Defining Cdk5 ligand chemical space with small molecule inhibitors of tau
RT   phosphorylation.";
RL   Chem. Biol. 12:811-823(2005).
RN   [16]
RP   X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 100-307 IN COMPLEX WITH CDK5 AND
RP   INHIBITORS.
RX   PubMed=15689152; DOI=10.1021/jm049323m;
RA   Mapelli M., Massimiliano L., Crovace C., Seeliger M.A., Tsai L.H.,
RA   Meijer L., Musacchio A.;
RT   "Mechanism of CDK5/p25 binding by CDK inhibitors.";
RL   J. Med. Chem. 48:671-679(2005).
RN   [17] {ECO:0007744|PDB:6LDP, ECO:0007744|PDB:7CNG}
RP   X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 298-307 IN COMPLEX WITH FEM1B,
RP   AND UBIQUITINATION.
RX   PubMed=33398168; DOI=10.1038/s41589-020-00704-3;
RA   Chen X., Liao S., Makaros Y., Guo Q., Zhu Z., Krizelman R., Dahan K.,
RA   Tu X., Yao X., Koren I., Xu C.;
RT   "Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3
RT   ligase.";
RL   Nat. Chem. Biol. 17:254-262(2021).
CC   -!- FUNCTION: p35 is a neuron specific activator of CDK5. The complex
CC       p35/CDK5 is required for neurite outgrowth and cortical lamination.
CC       Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4
CC       signaling. Activator of TPKII. The complex p35/CDK5 participates in the
CC       regulation of the circadian clock by modulating the function of CLOCK
CC       protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates
CC       the transcriptional activity of the CLOCK-BMAL1 heterodimer in
CC       association with altered stability and subcellular distribution.
CC       {ECO:0000269|PubMed:24235147}.
CC   -!- SUBUNIT: Heterodimer composed of a catalytic subunit CDK5 and a
CC       regulatory subunit CDK5R1 (p25) and macromolecular complex composed of
CC       at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3
CC       (PubMed:15689152, PubMed:16039528, PubMed:17671990). Only the
CC       heterodimer shows kinase activity (PubMed:15689152, PubMed:16039528,
CC       PubMed:17671990). Interacts with EPHA4 and NGEF; may mediate the
CC       activation of NGEF by EPHA4 (By similarity). Interacts with RASGRF2
CC       (PubMed:15128856). The complex p35/CDK5 interacts with CLOCK
CC       (PubMed:24235147). {ECO:0000250|UniProtKB:P61809,
CC       ECO:0000269|PubMed:15128856, ECO:0000269|PubMed:15689152,
CC       ECO:0000269|PubMed:16039528, ECO:0000269|PubMed:17671990,
CC       ECO:0000269|PubMed:24235147}.
CC   -!- INTERACTION:
CC       Q15078; Q6ZMQ8-1: AATK; NbExp=2; IntAct=EBI-746189, EBI-2008436;
CC       Q15078; Q6ZMQ8-2: AATK; NbExp=6; IntAct=EBI-746189, EBI-2008441;
CC       Q15078; O94983-5: CAMTA2; NbExp=3; IntAct=EBI-746189, EBI-10176008;
CC       Q15078; Q00535: CDK5; NbExp=15; IntAct=EBI-746189, EBI-1041567;
CC       Q15078; Q6UXH1-2: CRELD2; NbExp=3; IntAct=EBI-746189, EBI-21670927;
CC       Q15078; P49184: DNASE1L1; NbExp=3; IntAct=EBI-746189, EBI-20894690;
CC       Q15078; P16422: EPCAM; NbExp=3; IntAct=EBI-746189, EBI-1171184;
CC       Q15078; P26715: KLRC1; NbExp=3; IntAct=EBI-746189, EBI-9018187;
CC       Q15078; P43356: MAGEA2B; NbExp=3; IntAct=EBI-746189, EBI-5650739;
CC       Q15078; Q8NCR3: MFI; NbExp=3; IntAct=EBI-746189, EBI-744790;
CC       Q15078; Q5JR59: MTUS2; NbExp=3; IntAct=EBI-746189, EBI-742948;
CC       Q15078; A2RUH7: MYBPHL; NbExp=3; IntAct=EBI-746189, EBI-9088235;
CC       Q15078; Q9NPC7: MYNN; NbExp=3; IntAct=EBI-746189, EBI-3446748;
CC       Q15078; Q9HC98-4: NEK6; NbExp=3; IntAct=EBI-746189, EBI-11750983;
CC       Q15078; Q8N2W9: PIAS4; NbExp=3; IntAct=EBI-746189, EBI-473160;
CC       Q15078; Q96QH2: PRAM1; NbExp=3; IntAct=EBI-746189, EBI-2860740;
CC       Q15078; Q96E17: RAB3C; NbExp=3; IntAct=EBI-746189, EBI-4287022;
CC       Q15078; Q02978: SLC25A11; NbExp=3; IntAct=EBI-746189, EBI-359174;
CC       Q15078; Q9BT49: THAP7; NbExp=3; IntAct=EBI-746189, EBI-741350;
CC       Q15078; Q9ULW0: TPX2; NbExp=3; IntAct=EBI-746189, EBI-1037322;
CC       Q15078; Q9BQ29; NbExp=3; IntAct=EBI-746189, EBI-22013570;
CC   -!- SUBCELLULAR LOCATION: [Cyclin-dependent kinase 5 activator 1, p35]:
CC       Cell membrane {ECO:0000305|PubMed:17671990}; Lipid-anchor
CC       {ECO:0000269|PubMed:18507738}; Cytoplasmic side {ECO:0000305}. Cell
CC       projection, neuron projection {ECO:0000269|PubMed:10604467}. Note=In
CC       the primary cortical neurons, p35 is present in the peripheries and
CC       nerve terminals. {ECO:0000269|PubMed:10604467}.
CC   -!- SUBCELLULAR LOCATION: [Cyclin-dependent kinase 5 activator 1, p25]:
CC       Nucleus {ECO:0000269|PubMed:18507738}. Cytoplasm, perinuclear region
CC       {ECO:0000269|PubMed:10604467}. Perikaryon
CC       {ECO:0000269|PubMed:10604467}. Note=The conversion of p35 to p25
CC       relocalizes the protein from the cell periphery to the cytoplasm, in
CC       nuclear and perinuclear regions (PubMed:18507738). In the primary
CC       cortical neurons, p25 is primarily concentrated in the cell soma and is
CC       largely absent from neurites (PubMed:18507738).
CC       {ECO:0000269|PubMed:18507738}.
CC   -!- TISSUE SPECIFICITY: Brain and neuron specific.
CC   -!- PTM: The p35 form is proteolytically cleaved by calpain, giving rise to
CC       the p25 form. P35 has a 5 to 10 fold shorter half-life compared to p25.
CC       The conversion results in deregulation of the CDK5 kinase: p25/CDK5
CC       kinase displays an increased and altered tau phosphorylation in
CC       comparison to the p35/CDK5 kinase in vivo (By similarity).
CC       {ECO:0000250|UniProtKB:P61809}.
CC   -!- PTM: Myristoylated. A proper myristoylation signal is essential for the
CC       proper distribution of p35. {ECO:0000269|PubMed:18507738,
CC       ECO:0000269|PubMed:20213681}.
CC   -!- PTM: Ubiquitinated, leading to its degradation: degradation of p35 by
CC       proteasome results in down-regulation of CDK5 activity
CC       (PubMed:12393264). During this process, CDK5 phosphorylates p35 and
CC       induces its ubiquitination and subsequent degradation
CC       (PubMed:12393264). Ubiquitinated by the CRL2(FEM1B) complex, which
CC       recognizes the -Gly-Leu-Asp-Arg C-degron at the C-terminus, leading to
CC       its degradation (PubMed:33398168, PubMed:33398170).
CC       {ECO:0000269|PubMed:12393264, ECO:0000269|PubMed:33398168,
CC       ECO:0000269|PubMed:33398170}.
CC   -!- PTM: Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-
CC       mediated proteolysis. {ECO:0000269|PubMed:17121855}.
CC   -!- MISCELLANEOUS: Cleavage of p35 to p25 may be involved in the
CC       pathogenesis of cytoskeletal abnormalities and neuronal death in
CC       neurodegenerative diseases. The p25 form accumulates in neurons in the
CC       brain of patients with Alzheimer disease, but not in normal brain. This
CC       accumulation correlates with an increase in CDK5 kinase activity.
CC       Application of amyloid beta peptide A-beta(1-42) induced the conversion
CC       of p35 to p25 in primary cortical neurons. Expression of the p25/Cdk5
CC       complex in cultured primary neurons induces cytoskeletal disruption,
CC       morphological degeneration and apoptosis.
CC   -!- SIMILARITY: Belongs to the cyclin-dependent kinase 5 activator family.
CC       {ECO:0000305}.
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DR   EMBL; X80343; CAA56587.1; -; mRNA.
DR   EMBL; AY376350; AAQ74776.1; -; Genomic_DNA.
DR   EMBL; BT019573; AAV38380.1; -; mRNA.
DR   EMBL; CH471147; EAW80227.1; -; Genomic_DNA.
DR   EMBL; CH471147; EAW80228.1; -; Genomic_DNA.
DR   EMBL; BC020580; AAH20580.1; -; mRNA.
DR   CCDS; CCDS11273.1; -.
DR   PIR; S50861; S50861.
DR   RefSeq; NP_003876.1; NM_003885.3.
DR   PDB; 1H4L; X-ray; 2.65 A; D/E=147-293.
DR   PDB; 1UNG; X-ray; 2.30 A; D/E=100-307.
DR   PDB; 1UNH; X-ray; 2.35 A; D/E=100-307.
DR   PDB; 1UNL; X-ray; 2.20 A; D/E=100-307.
DR   PDB; 3O0G; X-ray; 1.95 A; D/E=145-293.
DR   PDB; 6LDP; X-ray; 2.35 A; A/B=298-307.
DR   PDB; 7CNG; X-ray; 3.49 A; A/B=298-307.
DR   PDB; 7VDP; X-ray; 2.09 A; C/D=100-307.
DR   PDB; 7VDQ; X-ray; 2.91 A; C/D=100-307.
DR   PDB; 7VDR; X-ray; 2.55 A; C/D=100-307.
DR   PDB; 7VDS; X-ray; 3.05 A; C/D=100-307.
DR   PDBsum; 1H4L; -.
DR   PDBsum; 1UNG; -.
DR   PDBsum; 1UNH; -.
DR   PDBsum; 1UNL; -.
DR   PDBsum; 3O0G; -.
DR   PDBsum; 6LDP; -.
DR   PDBsum; 7CNG; -.
DR   PDBsum; 7VDP; -.
DR   PDBsum; 7VDQ; -.
DR   PDBsum; 7VDR; -.
DR   PDBsum; 7VDS; -.
DR   AlphaFoldDB; Q15078; -.
DR   SMR; Q15078; -.
DR   BioGRID; 114376; 58.
DR   ComplexPortal; CPX-2201; Cyclin-dependent protein kinase 5 holoenzyme complex, p35 variant.
DR   ComplexPortal; CPX-3142; Cyclin-dependent protein kinase 5 holoenzyme complex, p25 variant.
DR   DIP; DIP-24222N; -.
DR   ELM; Q15078; -.
DR   FunCoup; Q15078; 436.
DR   IntAct; Q15078; 44.
DR   MINT; Q15078; -.
DR   STRING; 9606.ENSP00000318486; -.
DR   BindingDB; Q15078; -.
DR   ChEMBL; CHEMBL2783; -.
DR   DrugBank; DB07364; 6-PHENYL[5H]PYRROLO[2,3-B]PYRAZINE.
DR   DrugBank; DB02052; Indirubin-3'-monoxime.
DR   DrugCentral; Q15078; -.
DR   GlyGen; Q15078; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q15078; -.
DR   PhosphoSitePlus; Q15078; -.
DR   BioMuta; CDK5R1; -.
DR   DMDM; 2498217; -.
DR   MassIVE; Q15078; -.
DR   PaxDb; 9606-ENSP00000318486; -.
DR   PeptideAtlas; Q15078; -.
DR   ProteomicsDB; 60429; -.
DR   ABCD; Q15078; 1 sequenced antibody.
DR   Antibodypedia; 15411; 280 antibodies from 34 providers.
DR   DNASU; 8851; -.
DR   Ensembl; ENST00000313401.4; ENSP00000318486.3; ENSG00000176749.10.
DR   GeneID; 8851; -.
DR   KEGG; hsa:8851; -.
DR   MANE-Select; ENST00000313401.4; ENSP00000318486.3; NM_003885.3; NP_003876.1.
DR   UCSC; uc002hhn.4; human.
DR   AGR; HGNC:1775; -.
DR   ClinPGx; PA26311; -.
DR   CTD; 8851; -.
DR   DisGeNET; 8851; -.
DR   GeneCards; CDK5R1; -.
DR   HGNC; HGNC:1775; CDK5R1.
DR   HPA; ENSG00000176749; Tissue enriched (brain).
DR   MalaCards; CDK5R1; -.
DR   MIM; 603460; gene.
DR   OpenTargets; ENSG00000176749; -.
DR   VEuPathDB; HostDB:ENSG00000176749; -.
DR   eggNOG; KOG3932; Eukaryota.
DR   GeneTree; ENSGT00390000008812; -.
DR   HOGENOM; CLU_034132_2_0_1; -.
DR   InParanoid; Q15078; -.
DR   OMA; QHCNQNQ; -.
DR   OrthoDB; 7676799at2759; -.
DR   PAN-GO; Q15078; 6 GO annotations based on evolutionary models.
DR   PhylomeDB; Q15078; -.
DR   PathwayCommons; Q15078; -.
DR   Reactome; R-HSA-399956; CRMPs in Sema3A signaling.
DR   Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   Reactome; R-HSA-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
DR   Reactome; R-HSA-9031628; NGF-stimulated transcription.
DR   Reactome; R-HSA-9032845; Activated NTRK2 signals through CDK5.
DR   Reactome; R-HSA-9768919; NPAS4 regulates expression of target genes.
DR   SignaLink; Q15078; -.
DR   SIGNOR; Q15078; -.
DR   Agora; ENSG00000176749; -.
DR   BioGRID-ORCS; 8851; 8 hits in 1154 CRISPR screens.
DR   EvolutionaryTrace; Q15078; -.
DR   GeneWiki; CDK5R1; -.
DR   GenomeRNAi; 8851; -.
DR   Pharos; Q15078; Tchem.
DR   PRO; PR:Q15078; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; Q15078; protein.
DR   Bgee; ENSG00000176749; Expressed in cortical plate and 161 other cell types or tissues.
DR   ExpressionAtlas; Q15078; baseline and differential.
DR   GO; GO:0030424; C:axon; ISS:UniProtKB.
DR   GO; GO:0043292; C:contractile muscle fiber; ISS:UniProtKB.
DR   GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IPI:ComplexPortal.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR   GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
DR   GO; GO:0030426; C:growth cone; ISS:UniProtKB.
DR   GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR   GO; GO:0031594; C:neuromuscular junction; ISS:UniProtKB.
DR   GO; GO:0043005; C:neuron projection; ISS:ARUK-UCL.
DR   GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR   GO; GO:0016533; C:protein kinase 5 complex; IPI:ComplexPortal.
DR   GO; GO:0051015; F:actin filament binding; IEA:Ensembl.
DR   GO; GO:0043014; F:alpha-tubulin binding; ISS:ARUK-UCL.
DR   GO; GO:0048487; F:beta-tubulin binding; ISS:ARUK-UCL.
DR   GO; GO:0045296; F:cadherin binding; ISS:UniProtKB.
DR   GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR   GO; GO:0061575; F:cyclin-dependent protein serine/threonine kinase activator activity; IGI:ARUK-UCL.
DR   GO; GO:0035255; F:ionotropic glutamate receptor binding; IEA:Ensembl.
DR   GO; GO:0016301; F:kinase activity; ISS:UniProtKB.
DR   GO; GO:0002020; F:protease binding; IEA:Ensembl.
DR   GO; GO:0030295; F:protein kinase activator activity; TAS:GO_Central.
DR   GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
DR   GO; GO:0007411; P:axon guidance; ISS:UniProtKB.
DR   GO; GO:0007413; P:axonal fasciculation; ISS:UniProtKB.
DR   GO; GO:0007420; P:brain development; ISS:UniProtKB.
DR   GO; GO:0021549; P:cerebellum development; IEA:Ensembl.
DR   GO; GO:0048013; P:ephrin receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0007213; P:G protein-coupled acetylcholine receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0070315; P:G1 to G0 transition involved in cell differentiation; IEA:Ensembl.
DR   GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR   GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0021819; P:layer formation in cerebral cortex; IEA:Ensembl.
DR   GO; GO:0000226; P:microtubule cytoskeleton organization; TAS:ARUK-UCL.
DR   GO; GO:0045892; P:negative regulation of DNA-templated transcription; IMP:DFLAT.
DR   GO; GO:0007158; P:neuron cell-cell adhesion; ISS:UniProtKB.
DR   GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
DR   GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR   GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR   GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR   GO; GO:0031116; P:positive regulation of microtubule polymerization; ISS:ARUK-UCL.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR   GO; GO:0090314; P:positive regulation of protein targeting to membrane; IEA:Ensembl.
DR   GO; GO:0032956; P:regulation of actin cytoskeleton organization; IEA:Ensembl.
DR   GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; TAS:ProtInc.
DR   GO; GO:0061001; P:regulation of dendritic spine morphogenesis; ISS:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0045664; P:regulation of neuron differentiation; NAS:UniProtKB.
DR   GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR   GO; GO:0021722; P:superior olivary nucleus maturation; IEA:Ensembl.
DR   FunFam; 1.10.472.10:FF:000025; Cyclin-dependent kinase 5 activator; 1.
DR   Gene3D; 1.10.472.10; Cyclin-like; 1.
DR   InterPro; IPR004944; CDK5_activator.
DR   InterPro; IPR036915; Cyclin-like_sf.
DR   PANTHER; PTHR23401; CYCLIN DEPENDANT KINASE-5 ACTIVATOR; 1.
DR   PANTHER; PTHR23401:SF2; CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1; 1.
DR   Pfam; PF03261; CDK5_activator; 1.
DR   PIRSF; PIRSF009324; Cdk5_activator; 1.
DR   SUPFAM; SSF47954; Cyclin-like; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Biological rhythms; Cell membrane; Cell projection;
KW   Cytoplasm; Lipoprotein; Membrane; Myristate; Nucleus; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT   CHAIN           2..307
FT                   /note="Cyclin-dependent kinase 5 activator 1, p35"
FT                   /id="PRO_0000004794"
FT   CHAIN           99..307
FT                   /note="Cyclin-dependent kinase 5 activator 1, p25"
FT                   /id="PRO_0000004795"
FT   REGION          97..136
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        100..110
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        111..124
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            98..99
FT                   /note="Cleavage; by calpain"
FT                   /evidence="ECO:0000250|UniProtKB:P61809"
FT   MOD_RES         8
FT                   /note="Phosphoserine; by CDK5"
FT                   /evidence="ECO:0000269|PubMed:17121855"
FT   MOD_RES         138
FT                   /note="Phosphothreonine; by CDK5"
FT                   /evidence="ECO:0000269|PubMed:17121855"
FT   LIPID           2
FT                   /note="N-myristoyl glycine"
FT                   /evidence="ECO:0000269|PubMed:20213681"
FT   MUTAGEN         2
FT                   /note="G->A: Absent from the cell periphery."
FT                   /evidence="ECO:0000269|PubMed:10604467,
FT                   ECO:0000269|PubMed:18507738"
FT   MUTAGEN         8
FT                   /note="S->A: Increased susceptibility to calpain."
FT                   /evidence="ECO:0000269|PubMed:17121855"
FT   MUTAGEN         8
FT                   /note="S->E: Reduced susceptibility to calpain."
FT                   /evidence="ECO:0000269|PubMed:17121855"
FT   MUTAGEN         138
FT                   /note="T->A: Increased susceptibility to calpain."
FT                   /evidence="ECO:0000269|PubMed:17121855"
FT   MUTAGEN         138
FT                   /note="T->E: Reduced susceptibility to calpain."
FT                   /evidence="ECO:0000269|PubMed:17121855"
FT   MUTAGEN         305
FT                   /note="L->A: In L-3A mutant; abolished recognition and
FT                   ubiquitination by the CRL2(FEM1B) complex."
FT                   /evidence="ECO:0000269|PubMed:33398170"
FT   MUTAGEN         305
FT                   /note="L->R: In L-3R mutant; abolished recognition and
FT                   ubiquitination by the CRL2(FEM1B) complex, while promoting
FT                   recognition and ubiquitination by the CRL2(FEM1B) complex."
FT                   /evidence="ECO:0000269|PubMed:33398170"
FT   HELIX           148..162
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   TURN            163..165
FT                   /evidence="ECO:0007829|PDB:7VDQ"
FT   HELIX           172..187
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   HELIX           198..211
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   HELIX           219..237
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   STRAND          239..241
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   HELIX           246..248
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   HELIX           254..277
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   HELIX           279..290
FT                   /evidence="ECO:0007829|PDB:3O0G"
FT   TURN            301..304
FT                   /evidence="ECO:0007829|PDB:6LDP"
SQ   SEQUENCE   307 AA;  34060 MW;  D1C29A07AFF1B644 CRC64;
     MGTVLSLSPS YRKATLFEDG AATVGHYTAV QNSKNAKDKN LKRHSIISVL PWKRIVAVSA
     KKKNSKKVQP NSSYQNNITH LNNENLKKSL SCANLSTFAQ PPPAQPPAPP ASQLSGSQTG
     GSSSVKKAPH PAVTSAGTPK RVIVQASTSE LLRCLGEFLC RRCYRLKHLS PTDPVLWLRS
     VDRSLLLQGW QDQGFITPAN VVFLYMLCRD VISSEVGSDH ELQAVLLTCL YLSYSYMGNE
     ISYPLKPFLV ESCKEAFWDR CLSVINLMSS KMLQINADPH YFTQVFSDLK NESGQEDKKR
     LLLGLDR
//
ID   CDK5_HUMAN              Reviewed;         292 AA.
AC   Q00535; A1XKG3;
DT   01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT   15-DEC-1998, sequence version 3.
DT   28-JAN-2026, entry version 248.
DE   RecName: Full=Cyclin-dependent kinase 5 {ECO:0000312|HGNC:HGNC:1774};
DE            EC=2.7.11.1;
DE   AltName: Full=Cell division protein kinase 5 {ECO:0000305};
DE   AltName: Full=Cyclin-dependent-like kinase 5;
DE   AltName: Full=Serine/threonine-protein kinase PSSALRE {ECO:0000250|UniProtKB:Q03114};
DE   AltName: Full=Tau protein kinase II catalytic subunit {ECO:0000250|UniProtKB:Q02399};
DE            Short=TPKII catalytic subunit {ECO:0000250|UniProtKB:Q02399};
GN   Name=CDK5 {ECO:0000312|HGNC:HGNC:1774};
GN   Synonyms=CDKN5 {ECO:0000312|HGNC:HGNC:1774},
GN   PSSALRE {ECO:0000250|UniProtKB:P49615};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Fetal brain;
RX   PubMed=1639063; DOI=10.1002/j.1460-2075.1992.tb05360.x;
RA   Meyerson M., Enders G.H., Wu C.-L., Su L.-K., Gorka C., Nelson C.,
RA   Harlow E., Tsai L.-H.;
RT   "A family of human cdc2-related protein kinases.";
RL   EMBO J. 11:2909-2917(1992).
RN   [2]
RP   SEQUENCE REVISION.
RA   Meyerson M.;
RL   Submitted (FEB-1993) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, INTERACTION WITH CTNNB1, AND FUNCTION IN WNT/B-CATENIN
RP   SIGNALING PATHWAY.
RC   TISSUE=Testis;
RX   PubMed=19693690; DOI=10.1007/s11033-009-9752-7;
RA   Li Q., Liu X., Zhang M., Ye G., Qiao Q., Ling Y., Wu Y., Zhang Y., Yu L.;
RT   "Characterization of a novel human CDK5 splicing variant that inhibits
RT   Wnt/beta-catenin signaling.";
RL   Mol. Biol. Rep. 37:2415-2421(2010).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Hu X., Xu Y., Zhang B., Peng X., Yuan J., Qiang B.;
RL   Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12853948; DOI=10.1038/nature01782;
RA   Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA   Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA   Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA   Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA   Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA   Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA   Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA   Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA   Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA   Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA   Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA   Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA   Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA   Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA   Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA   Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA   Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA   McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA   Wilson R.K.;
RT   "The DNA sequence of human chromosome 7.";
RL   Nature 424:157-164(2003).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [8]
RP   ACTIVITY REGULATION BY ROSCOVITINE AND OLOMOUCINE.
RX   PubMed=9030781; DOI=10.1111/j.1432-1033.1997.t01-2-00527.x;
RA   Meijer L., Borgne A., Mulner O., Chong J.P.J., Blow J.J., Inagaki N.,
RA   Inagaki M., Delcros J.-G., Moulinoux J.-P.;
RT   "Biochemical and cellular effects of roscovitine, a potent and selective
RT   inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5.";
RL   Eur. J. Biochem. 243:527-536(1997).
RN   [9]
RP   FUNCTION IN AXON GROWTH.
RX   PubMed=9822744; DOI=10.1523/jneurosci.18-23-09858.1998;
RA   Paglini G., Pigino G., Kunda P., Morfini G., Maccioni R., Quiroga S.,
RA   Ferreira A., Caceres A.;
RT   "Evidence for the participation of the neuron-specific CDK5 activator P35
RT   during laminin-enhanced axonal growth.";
RL   J. Neurosci. 18:9858-9869(1998).
RN   [10]
RP   PHOSPHORYLATION AT SER-159.
RX   PubMed=10500146; DOI=10.1073/pnas.96.20.11156;
RA   Sharma P., Sharma M., Amin N.D., Albers R.W., Pant H.C.;
RT   "Regulation of cyclin-dependent kinase 5 catalytic activity by
RT   phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:11156-11160(1999).
RN   [11]
RP   FUNCTION AS P35/CDK5R1 KINASE.
RX   PubMed=12393264; DOI=10.1016/s0169-328x(02)00409-6;
RA   Kerokoski P., Suuronen T., Salminen A., Soininen H., Pirttilae T.;
RT   "Influence of phosphorylation of p35, an activator of cyclin-dependent
RT   kinase 5 (cdk5), on the proteolysis of p35.";
RL   Brain Res. Mol. Brain Res. 106:50-56(2002).
RN   [12]
RP   INTERACTION WITH AATK.
RX   PubMed=14521924; DOI=10.1016/j.bbrc.2003.08.143;
RA   Honma N., Asada A., Takeshita S., Enomoto M., Yamakawa E., Tsutsumi K.,
RA   Saito T., Satoh T., Itoh H., Kaziro Y., Kishimoto T., Hisanaga S.;
RT   "Apoptosis-associated tyrosine kinase is a Cdk5 activator p35 binding
RT   protein.";
RL   Biochem. Biophys. Res. Commun. 310:398-404(2003).
RN   [13]
RP   FUNCTION AS MEF2A KINASE, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RX   PubMed=12691662; DOI=10.1016/s0896-6273(03)00191-0;
RA   Gong X., Tang X., Wiedmann M., Wang X., Peng J., Zheng D., Blair L.A.C.,
RA   Marshall J., Mao Z.;
RT   "Cdk5-mediated inhibition of the protective effects of transcription factor
RT   MEF2 in neurotoxicity-induced apoptosis.";
RL   Neuron 38:33-46(2003).
RN   [14]
RP   FUNCTION AS P35 KINASE, SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX   PubMed=15992363; DOI=10.1111/j.1471-4159.2005.03301.x;
RA   Zhu Y.-S., Saito T., Asada A., Maekawa S., Hisanaga S.;
RT   "Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by
RT   membrane dissociation.";
RL   J. Neurochem. 94:1535-1545(2005).
RN   [15]
RP   FUNCTION AS P35/CDK5R KINASE.
RX   PubMed=17121855; DOI=10.1074/jbc.m610541200;
RA   Kamei H., Saito T., Ozawa M., Fujita Y., Asada A., Bibb J.A., Saido T.C.,
RA   Sorimachi H., Hisanaga S.;
RT   "Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25
RT   by site-specific phosphorylation.";
RL   J. Biol. Chem. 282:1687-1694(2007).
RN   [16]
RP   FUNCTION AS CTNNB1 AND CTNND2 KINASE, INTERACTION WITH CTNNB1 AND CTNND2,
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=17009320; DOI=10.1002/jcb.21041;
RA   Munoz J.P., Huichalaf C.H., Orellana D., Maccioni R.B.;
RT   "cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal
RT   cells.";
RL   J. Cell. Biochem. 100:738-749(2007).
RN   [17]
RP   FUNCTION AS P53/TP53 KINASE, INTERACTION WITH P53/TP53, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=17591690; DOI=10.1242/jcs.03468;
RA   Lee J.-H., Kim H.-S., Lee S.-J., Kim K.-T.;
RT   "Stabilization and activation of p53 induced by Cdk5 contributes to
RT   neuronal cell death.";
RL   J. Cell Sci. 120:2259-2271(2007).
RN   [18]
RP   FUNCTION AS PXN KINASE.
RX   PubMed=18042622; DOI=10.1242/jcs.018218;
RA   Miyamoto Y., Yamauchi J., Chan J.R., Okada A., Tomooka Y., Hisanaga S.,
RA   Tanoue A.;
RT   "Cdk5 regulates differentiation of oligodendrocyte precursor cells through
RT   the direct phosphorylation of paxillin.";
RL   J. Cell Sci. 120:4355-4366(2007).
RN   [19]
RP   FUNCTION AS HUNTINGTIN KINASE, AND ACTIVITY REGULATION BY ROSCOVITINE.
RX   PubMed=17611284; DOI=10.1523/jneurosci.1831-07.2007;
RA   Anne S.L., Saudou F., Humbert S.;
RT   "Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by
RT   DNA damage and regulates wild-type and mutant huntingtin toxicity in
RT   neurons.";
RL   J. Neurosci. 27:7318-7328(2007).
RN   [20]
RP   FUNCTION AS P35/CDK5R KINASE, INTERACTION WITH P35/CDK5R, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=17671990; DOI=10.1002/jnr.21438;
RA   Sato K., Zhu Y.-S., Saito T., Yotsumoto K., Asada A., Hasegawa M.,
RA   Hisanaga S.;
RT   "Regulation of membrane association and kinase activity of Cdk5-p35 by
RT   phosphorylation of p35.";
RL   J. Neurosci. Res. 85:3071-3078(2007).
RN   [21]
RP   PHOSPHORYLATION AT TYR-15 BY EPHA4.
RX   PubMed=17143272; DOI=10.1038/nn1811;
RA   Fu W.Y., Chen Y., Sahin M., Zhao X.S., Shi L., Bikoff J.B., Lai K.O.,
RA   Yung W.H., Fu A.K., Greenberg M.E., Ip N.Y.;
RT   "Cdk5 regulates EphA4-mediated dendritic spine retraction through an
RT   ephexin1-dependent mechanism.";
RL   Nat. Neurosci. 10:67-76(2007).
RN   [22]
RP   SUBCELLULAR LOCATION.
RX   PubMed=18507738; DOI=10.1111/j.1471-4159.2008.05500.x;
RA   Asada A., Yamamoto N., Gohda M., Saito T., Hayashi N., Hisanaga S.;
RT   "Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear
RT   localization of active cyclin-dependent kinase 5 complexes.";
RL   J. Neurochem. 106:1325-1336(2008).
RN   [23]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [24]
RP   FUNCTION AS HDAC REGULATOR.
RX   PubMed=19081376; DOI=10.1016/j.neuron.2008.10.015;
RA   Kim D., Frank C.L., Dobbin M.M., Tsunemoto R.K., Tu W., Peng P.L.,
RA   Guan J.S., Lee B.H., Moy L.Y., Giusti P., Broodie N., Mazitschek R.,
RA   Delalle I., Haggarty S.J., Neve R.L., Lu Y., Tsai L.H.;
RT   "Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.";
RL   Neuron 60:803-817(2008).
RN   [25]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [26]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [27]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-56, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19608861; DOI=10.1126/science.1175371;
RA   Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA   Olsen J.V., Mann M.;
RT   "Lysine acetylation targets protein complexes and co-regulates major
RT   cellular functions.";
RL   Science 325:834-840(2009).
RN   [28]
RP   FUNCTION IN ANGIOGENESIS.
RX   PubMed=20826806; DOI=10.1074/jbc.m110.126177;
RA   Liebl J., Weitensteiner S.B., Vereb G., Takacs L., Fuerst R., Vollmar A.M.,
RA   Zahler S.;
RT   "Cyclin-dependent kinase 5 regulates endothelial cell migration and
RT   angiogenesis.";
RL   J. Biol. Chem. 285:35932-35943(2010).
RN   [29]
RP   FUNCTION AS NOS3 KINASE.
RX   PubMed=20213743; DOI=10.1002/jcb.22515;
RA   Lee C.-H., Wei Y.-W., Huang Y.-T., Lin Y.-T., Lee Y.-C., Lee K.-H.,
RA   Lu P.-J.;
RT   "CDK5 phosphorylates eNOS at Ser-113 and regulates NO production.";
RL   J. Cell. Biochem. 110:112-117(2010).
RN   [30]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [31]
RP   INHIBITORS.
RX   PubMed=21144757; DOI=10.1016/j.bmc.2010.11.022;
RA   Jain P., Flaherty P.T., Yi S., Chopra I., Bleasdell G., Lipay J.,
RA   Ferandin Y., Meijer L., Madura J.D.;
RT   "Design, synthesis, and testing of an 6-O-linked series of benzimidazole
RT   based inhibitors of CDK5/p25.";
RL   Bioorg. Med. Chem. 19:359-373(2011).
RN   [32]
RP   FUNCTION AS SRC KINASE.
RX   PubMed=21442427; DOI=10.1007/s00018-011-0638-1;
RA   Pan Q., Qiao F., Gao C., Norman B., Optican L., Zelenka P.S.;
RT   "Cdk5 targets active Src for ubiquitin-dependent degradation by
RT   phosphorylating Src(S75).";
RL   Cell. Mol. Life Sci. 68:3425-3436(2011).
RN   [33]
RP   FUNCTION AS VIM KINASE, AND SUBCELLULAR LOCATION.
RX   PubMed=21465480; DOI=10.1002/jcp.22782;
RA   Lee K.Y., Liu L., Jin Y., Fu S.B., Rosales J.L.;
RT   "Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion
RT   by neutrophils.";
RL   J. Cell. Physiol. 227:739-750(2012).
RN   [34]
RP   ACTIVITY REGULATION, AND INTERACTION WITH GSTP1.
RX   PubMed=21668448; DOI=10.1111/j.1471-4159.2011.07343.x;
RA   Sun K.H., Chang K.H., Clawson S., Ghosh S., Mirzaei H., Regnier F.,
RA   Shah K.;
RT   "Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase
RT   activity.";
RL   J. Neurochem. 118:902-914(2011).
RN   [35]
RP   FUNCTION AS TONEBP/NFAT5 KINASE.
RX   PubMed=21209322; DOI=10.1091/mbc.e10-08-0681;
RA   Gallazzini M., Heussler G.E., Kunin M., Izumi Y., Burg M.B., Ferraris J.D.;
RT   "High NaCl-induced activation of CDK5 increases phosphorylation of the
RT   osmoprotective transcription factor TonEBP/OREBP at threonine 135, which
RT   contributes to its rapid nuclear localization.";
RL   Mol. Biol. Cell 22:703-714(2011).
RN   [36]
RP   FUNCTION AS SH3GLB1 KINASE.
RX   PubMed=21499257; DOI=10.1038/ncb2217;
RA   Wong A.S., Lee R.H., Cheung A.Y., Yeung P.K., Chung S.K., Cheung Z.H.,
RA   Ip N.Y.;
RT   "Cdk5-mediated phosphorylation of endophilin B1 is required for induced
RT   autophagy in models of Parkinson's disease.";
RL   Nat. Cell Biol. 13:568-579(2011).
RN   [37]
RP   FUNCTION AS EPRS KINASE.
RX   PubMed=21220307; DOI=10.1073/pnas.1011275108;
RA   Arif A., Jia J., Moodt R.A., DiCorleto P.E., Fox P.L.;
RT   "Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent
RT   kinase 5 dictates transcript-selective translational control.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:1415-1420(2011).
RN   [38]
RP   REVIEW.
RX   PubMed=11584302; DOI=10.1038/35096019;
RA   Dhavan R., Tsai L.H.;
RT   "A decade of CDK5.";
RL   Nat. Rev. Mol. Cell Biol. 2:749-759(2001).
RN   [39]
RP   REVIEW ON INHIBITORS, AND GENE FAMILY.
RX   PubMed=19238148; DOI=10.1038/nrc2602;
RA   Malumbres M., Barbacid M.;
RT   "Cell cycle, CDKs and cancer: a changing paradigm.";
RL   Nat. Rev. Cancer 9:153-166(2009).
RN   [40]
RP   REVIEW ON NEURONAL PHYSIOLOGY.
RX   PubMed=19782409; DOI=10.1016/j.tins.2009.07.002;
RA   Jessberger S., Gage F.H., Eisch A.J., Lagace D.C.;
RT   "Making a neuron: Cdk5 in embryonic and adult neurogenesis.";
RL   Trends Neurosci. 32:575-582(2009).
RN   [41]
RP   FUNCTION.
RX   PubMed=20061803; DOI=10.4161/cc.9.2.10466;
RA   Lalioti V., Pulido D., Sandoval I.V.;
RT   "Cdk5, the multifunctional surveyor.";
RL   Cell Cycle 9:284-311(2010).
RN   [42]
RP   REVIEW ON REGULATION.
RX   PubMed=21044075; DOI=10.1111/j.1471-4159.2010.07050.x;
RA   Hisanaga S., Endo R.;
RT   "Regulation and role of cyclin-dependent kinase activity in neuronal
RT   survival and death.";
RL   J. Neurochem. 115:1309-1321(2010).
RN   [43]
RP   REVIEW ON NEURON DEVELOPMENT.
RX   PubMed=21415596; DOI=10.4161/cc.10.8.15328;
RA   Zhang J., Herrup K.;
RT   "Nucleocytoplasmic Cdk5 is involved in neuronal cell cycle and death in
RT   post-mitotic neurons.";
RL   Cell Cycle 10:1208-1214(2011).
RN   [44]
RP   REVIEW ON NEURON DEVELOPMENT.
RX   PubMed=21600237; DOI=10.1016/j.mad.2011.04.011;
RA   Zhu J., Li W., Mao Z.;
RT   "Cdk5: Mediator of neuronal development, death and the response to DNA
RT   damage.";
RL   Mech. Ageing Dev. 132:389-394(2011).
RN   [45]
RP   REVIEW ON NEURONS.
RX   PubMed=21473899; DOI=10.1016/j.pneurobio.2011.03.006;
RA   Lopes J.P., Agostinho P.;
RT   "Cdk5: multitasking between physiological and pathological conditions.";
RL   Prog. Neurobiol. 94:49-63(2011).
RN   [46]
RP   FUNCTION, AND INTERACTION WITH CLOCK.
RX   PubMed=24235147; DOI=10.1074/jbc.m113.494856;
RA   Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H.,
RA   Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.;
RT   "Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein
RT   by direct phosphorylation.";
RL   J. Biol. Chem. 288:36878-36889(2013).
RN   [47]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-17, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [48]
RP   INVOLVEMENT IN LIS7.
RX   PubMed=25560765; DOI=10.1007/s00439-014-1522-5;
RA   Magen D., Ofir A., Berger L., Goldsher D., Eran A., Katib N., Nijem Y.,
RA   Vlodavsky E., Tzur S., Zur S., Behar D.M., Fellig Y., Mandel H.;
RT   "Autosomal recessive lissencephaly with cerebellar hypoplasia is associated
RT   with a loss-of-function mutation in CDK5.";
RL   Hum. Genet. 134:305-314(2015).
RN   [49]
RP   X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH P25, AND MUTAGENESIS
RP   OF SER-159.
RX   PubMed=11583627; DOI=10.1016/s1097-2765(01)00343-4;
RA   Tarricone C., Dhavan R., Peng J., Areces L.B., Tsai L.-H., Musacchio A.;
RT   "Structure and regulation of the CDK5-p25(nck5a) complex.";
RL   Mol. Cell 8:657-669(2001).
RN   [50]
RP   X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
RX   PubMed=16039528; DOI=10.1016/j.chembiol.2005.05.011;
RA   Ahn J.S., Radhakrishnan M.L., Mapelli M., Choi S., Tidor B., Cuny G.D.,
RA   Musacchio A., Yeh L.A., Kosik K.S.;
RT   "Defining Cdk5 ligand chemical space with small molecule inhibitors of tau
RT   phosphorylation.";
RL   Chem. Biol. 12:811-823(2005).
RN   [51]
RP   X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEX WITH INHIBITORS AND P25,
RP   AND PHOSPHORYLATION AT TYR-15.
RX   PubMed=15689152; DOI=10.1021/jm049323m;
RA   Mapelli M., Massimiliano L., Crovace C., Seeliger M.A., Tsai L.H.,
RA   Meijer L., Musacchio A.;
RT   "Mechanism of CDK5/p25 binding by CDK inhibitors.";
RL   J. Med. Chem. 48:671-679(2005).
RN   [52]
RP   VARIANT [LARGE SCALE ANALYSIS] ASP-225.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
CC   -!- FUNCTION: Proline-directed serine/threonine-protein kinase essential
CC       for neuronal cell cycle arrest and differentiation and may be involved
CC       in apoptotic cell death in neuronal diseases by triggering abortive
CC       cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins.
CC       Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1,
CC       SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16,
CC       RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53,
CC       HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM.
CC       Regulates several neuronal development and physiological processes
CC       including neuronal survival, migration and differentiation, axonal and
CC       neurite growth, synaptogenesis, oligodendrocyte differentiation,
CC       synaptic plasticity and neurotransmission, by phosphorylating key
CC       proteins. Negatively regulates the CACNA1B/CAV2.2 -mediated Ca(2+)
CC       release probability at hippocampal neuronal soma and synaptic terminals
CC       (By similarity). Activated by interaction with CDK5R1 (p35) and CDK5R2
CC       (p39), especially in postmitotic neurons, and promotes CDK5R1 (p35)
CC       expression in an autostimulation loop. Phosphorylates many downstream
CC       substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1,
CC       RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2,
CC       MAP1B), and modulates actin dynamics to regulate neurite growth and/or
CC       spine morphogenesis. Also phosphorylates exocytosis associated proteins
CC       such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as
CC       endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at
CC       synaptic terminals. In the mature central nervous system (CNS),
CC       regulates neurotransmitter movements by phosphorylating substrates
CC       associated with neurotransmitter release and synapse plasticity;
CC       synaptic vesicle exocytosis, vesicles fusion with the presynaptic
CC       membrane, and endocytosis. Promotes cell survival by activating anti-
CC       apoptotic proteins BCL2 and STAT3, and negatively regulating of
CC       JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to
CC       genotoxic and oxidative stresses enhances its stabilization by
CC       preventing ubiquitin ligase-mediated proteasomal degradation, and
CC       induces transactivation of p53/TP53 target genes, thus regulating
CC       apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by
CC       preventing calpain-mediated proteolysis producing p25/CDK5R1 and
CC       avoiding ubiquitin ligase-mediated proteasomal degradation. During
CC       aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits
CC       cell-cycle activity and double-strand DNA breaks that precedes neuronal
CC       death by deregulating HDAC1. DNA damage triggered phosphorylation of
CC       huntingtin/HTT in nuclei of neurons protects neurons against
CC       polyglutamine expansion as well as DNA damage mediated toxicity.
CC       Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in
CC       matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs)
CC       differentiation. Negative regulator of Wnt/beta-catenin signaling
CC       pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of
CC       translation) pathway, which suppresses expression of a post-
CC       transcriptional regulon of proinflammatory genes in myeloid cells;
CC       phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase
CC       (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly
CC       of the GAIT complex. Phosphorylation of SH3GLB1 is required for
CC       autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5
CC       in response to osmotic stress mediates its rapid nuclear localization.
CC       MEF2 is inactivated by phosphorylation in nucleus in response to
CC       neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-
CC       endodeoxyribonuclease is repressed by phosphorylation, resulting in
CC       accumulation of DNA damage and contributing to neuronal death. NOS3
CC       phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC
CC       phosphorylation mediates its ubiquitin-dependent degradation and thus
CC       leads to cytoskeletal reorganization. May regulate endothelial cell
CC       migration and angiogenesis via the modulation of lamellipodia
CC       formation. Involved in dendritic spine morphogenesis by mediating the
CC       EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the
CC       regulation of the circadian clock by modulating the function of CLOCK
CC       protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates
CC       the transcriptional activity of the CLOCK-BMAL1 heterodimer in
CC       association with altered stability and subcellular distribution.
CC       {ECO:0000250|UniProtKB:Q03114, ECO:0000269|PubMed:12393264,
CC       ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363,
CC       ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:17121855,
CC       ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17611284,
CC       ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:18042622,
CC       ECO:0000269|PubMed:19081376, ECO:0000269|PubMed:19693690,
CC       ECO:0000269|PubMed:20061803, ECO:0000269|PubMed:20213743,
CC       ECO:0000269|PubMed:20826806, ECO:0000269|PubMed:21209322,
CC       ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:21442427,
CC       ECO:0000269|PubMed:21465480, ECO:0000269|PubMed:21499257,
CC       ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:9822744}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC   -!- ACTIVITY REGULATION: Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-
CC       benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-
CC       6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine.
CC       Activated by CDK5R1 (p35) and CDK5R2 (p39) during the development of
CC       the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (p39) by
CC       proteasome result in down regulation of kinase activity, during this
CC       process, CDK5 phosphorylates p35 and induces its ubiquitination and
CC       subsequent degradation. Kinase activity is mainly determined by the
CC       amount of p35 available and subcellular location; reversible
CC       association to plasma membrane inhibits activity. Long-term
CC       inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5
CC       triggers cell death. The pro-death activity of hyperactivated CDK5 is
CC       suppressed by membrane association of CDK5, via myristoylation of p35.
CC       Brain-derived neurotrophic factor, glial-derived neurotrophic factor,
CC       nerve growth factor (NGF), retinoic acid, laminin and neuregulin
CC       promote activity. Neurotoxicity enhances nuclear activity, thus leading
CC       to MEF2 phosphorylation and inhibition prior to apoptosis of cortical
CC       neurons. Repression by GSTP1 via p25/p35 translocation prevents
CC       neurodegeneration. {ECO:0000269|PubMed:12691662,
CC       ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17611284,
CC       ECO:0000269|PubMed:21668448, ECO:0000269|PubMed:9030781}.
CC   -!- SUBUNIT: Heterodimer composed of a catalytic subunit CDK5 and a
CC       regulatory subunit CDK5R1 (p25) and macromolecular complex composed of
CC       at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only
CC       the heterodimer shows kinase activity. Under neurotoxic stress and
CC       neuronal injury conditions, p35 is cleaved by calpain to generate p25
CC       that hyperactivates CDK5, that becomes functionally disabled and often
CC       toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts
CC       with CABLES1 and CABLES2 (By similarity). Interacts with AATK and
CC       GSTP1. Binds to HDAC1 when in complex with p25. Interaction with
CC       myristoylation p35 promotes CDK5 association with membranes. Both
CC       isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with
CC       delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons.
CC       Interacts with EPHA4; may mediate the activation of NGEF by EPHA4.
CC       Interacts with PTK2/FAK1 (By similarity). The complex p35/CDK5
CC       interacts with CLOCK. Interacts with HTR6 (By similarity).
CC       {ECO:0000250, ECO:0000250|UniProtKB:P49615,
CC       ECO:0000269|PubMed:11583627, ECO:0000269|PubMed:14521924,
CC       ECO:0000269|PubMed:15689152, ECO:0000269|PubMed:17009320,
CC       ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17671990,
CC       ECO:0000269|PubMed:19693690, ECO:0000269|PubMed:21668448,
CC       ECO:0000269|PubMed:24235147}.
CC   -!- INTERACTION:
CC       Q00535; P61158: ACTR3; NbExp=3; IntAct=EBI-1041567, EBI-351428;
CC       Q00535; P05067: APP; NbExp=3; IntAct=EBI-1041567, EBI-77613;
CC       Q00535; P23560-2: BDNF; NbExp=3; IntAct=EBI-1041567, EBI-12275524;
CC       Q00535; Q8TDN4: CABLES1; NbExp=8; IntAct=EBI-1041567, EBI-604615;
CC       Q00535; P14635: CCNB1; NbExp=8; IntAct=EBI-1041567, EBI-495332;
CC       Q00535; P24863: CCNC; NbExp=2; IntAct=EBI-1041567, EBI-395261;
CC       Q00535; P30279: CCND2; NbExp=18; IntAct=EBI-1041567, EBI-748789;
CC       Q00535; P30281: CCND3; NbExp=12; IntAct=EBI-1041567, EBI-375013;
CC       Q00535; Q14094: CCNI; NbExp=6; IntAct=EBI-1041567, EBI-1104653;
CC       Q00535; Q15078: CDK5R1; NbExp=15; IntAct=EBI-1041567, EBI-746189;
CC       Q00535; P38936: CDKN1A; NbExp=7; IntAct=EBI-1041567, EBI-375077;
CC       Q00535; P46527: CDKN1B; NbExp=14; IntAct=EBI-1041567, EBI-519280;
CC       Q00535; Q9UJC3: HOOK1; NbExp=3; IntAct=EBI-1041567, EBI-746704;
CC       Q00535; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-1041567, EBI-16439278;
CC       Q00535; Q9Y6R0: NUMBL; NbExp=3; IntAct=EBI-1041567, EBI-945925;
CC       Q00535; P37231-2: PPARG; NbExp=2; IntAct=EBI-1041567, EBI-781416;
CC       Q00535; P62937: PPIA; NbExp=3; IntAct=EBI-1041567, EBI-437708;
CC       Q00535; O60260-5: PRKN; NbExp=3; IntAct=EBI-1041567, EBI-21251460;
CC       Q00535; Q5MJ70: SPDYA; NbExp=3; IntAct=EBI-1041567, EBI-7125479;
CC       Q00535; A6NLX3: SPDYE4; NbExp=4; IntAct=EBI-1041567, EBI-12047907;
CC       Q00535; P20226: TBP; NbExp=3; IntAct=EBI-1041567, EBI-355371;
CC       Q00535; P09936: UCHL1; NbExp=2; IntAct=EBI-1041567, EBI-714860;
CC   -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC       {ECO:0000269|PubMed:12691662}. Nucleus {ECO:0000269|PubMed:12691662}.
CC       Cell membrane {ECO:0000269|PubMed:17009320}; Peripheral membrane
CC       protein. Perikaryon. Cell projection, lamellipodium
CC       {ECO:0000250|UniProtKB:P49615}. Cell projection, growth cone
CC       {ECO:0000250|UniProtKB:P49615}. Postsynaptic density
CC       {ECO:0000250|UniProtKB:Q03114}. Synapse {ECO:0000250|UniProtKB:Q03114}.
CC       Note=In axonal growth cone with extension to the peripheral
CC       lamellipodia (By similarity). Under neurotoxic stress and neuronal
CC       injury conditions, CDK5R (p35) is cleaved by calpain to generate CDK5R1
CC       (p25) in response to increased intracellular calcium. The elevated
CC       level of p25, when in complex with CDK5, leads to its subcellular
CC       misallocation as well as its hyperactivation. Colocalizes with CTNND2
CC       in the cell body of neuronal cells, and with CTNNB1 in the cell-cell
CC       contacts and plasma membrane of undifferentiated and differentiated
CC       neuroblastoma cells. Reversibly attached to the plasma membrane in an
CC       inactive form when complexed to dephosphorylated p35 or CDK5R2 (p39),
CC       p35 phosphorylation releases this attachment and activates CDK5.
CC       {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q00535-1; Sequence=Displayed;
CC       Name=2; Synonyms=CDK5-SV {ECO:0000303|PubMed:19693690};
CC         IsoId=Q00535-2; Sequence=VSP_041948;
CC   -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed
CC       (PubMed:17009320, PubMed:19693690). Accumulates in cortical neurons (at
CC       protein level) (PubMed:17009320). {ECO:0000269|PubMed:17009320,
CC       ECO:0000269|PubMed:19693690}.
CC   -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in the testis, skeletal
CC       muscle, colon, bone marrow and ovary. {ECO:0000269|PubMed:19693690}.
CC   -!- PTM: Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by
CC       casein kinase 1 promotes kinase activity. By contrast, phosphorylation
CC       at Thr-14 inhibits activity. {ECO:0000269|PubMed:10500146,
CC       ECO:0000269|PubMed:15689152, ECO:0000269|PubMed:17143272}.
CC   -!- PTM: Phosphorylation at Ser-159 is essential for maximal catalytic
CC       activity. {ECO:0000269|PubMed:10500146}.
CC   -!- DISEASE: Lissencephaly 7, with cerebellar hypoplasia (LIS7)
CC       [MIM:616342]: A form of lissencephaly, a disorder of cortical
CC       development characterized by agyria or pachygyria and disorganization
CC       of the clear neuronal lamination of normal six-layered cortex. LIS7
CC       patients manifest lack of psychomotor development, facial dysmorphism,
CC       arthrogryposis, and early-onset intractable seizures resulting in death
CC       in infancy. {ECO:0000269|PubMed:25560765}. Note=The disease is caused
CC       by variants affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: Dysregulation of CDK5 is associated with
CC       neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-
CC       Pick type C diseases, ischemia, and amyotrophic lateral sclerosis.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
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DR   EMBL; X66364; CAA47007.1; -; mRNA.
DR   EMBL; DQ411039; ABD66016.1; -; mRNA.
DR   EMBL; AY049778; AAL15435.1; -; mRNA.
DR   EMBL; BT006680; AAP35326.1; -; mRNA.
DR   EMBL; AC010973; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC005115; AAH05115.1; -; mRNA.
DR   CCDS; CCDS47748.1; -. [Q00535-1]
DR   CCDS; CCDS55184.1; -. [Q00535-2]
DR   PIR; S23386; S23386.
DR   RefSeq; NP_001157882.1; NM_001164410.3. [Q00535-2]
DR   RefSeq; NP_004926.1; NM_004935.4. [Q00535-1]
DR   PDB; 1H4L; X-ray; 2.65 A; A/B=1-292.
DR   PDB; 1UNG; X-ray; 2.30 A; A/B=1-292.
DR   PDB; 1UNH; X-ray; 2.35 A; A/B=1-292.
DR   PDB; 1UNL; X-ray; 2.20 A; A/B=1-292.
DR   PDB; 3O0G; X-ray; 1.95 A; A/B=1-292.
DR   PDB; 4AU8; X-ray; 1.90 A; A/B=2-292.
DR   PDB; 7VDP; X-ray; 2.09 A; A/B=2-292.
DR   PDB; 7VDQ; X-ray; 2.91 A; A/B=2-292.
DR   PDB; 7VDR; X-ray; 2.55 A; A/B=2-292.
DR   PDB; 7VDS; X-ray; 3.05 A; A/B=2-292.
DR   PDBsum; 1H4L; -.
DR   PDBsum; 1UNG; -.
DR   PDBsum; 1UNH; -.
DR   PDBsum; 1UNL; -.
DR   PDBsum; 3O0G; -.
DR   PDBsum; 4AU8; -.
DR   PDBsum; 7VDP; -.
DR   PDBsum; 7VDQ; -.
DR   PDBsum; 7VDR; -.
DR   PDBsum; 7VDS; -.
DR   AlphaFoldDB; Q00535; -.
DR   SMR; Q00535; -.
DR   BioGRID; 107455; 220.
DR   ComplexPortal; CPX-2201; Cyclin-dependent protein kinase 5 holoenzyme complex, p35 variant.
DR   ComplexPortal; CPX-3141; Cyclin-dependent protein kinase 5 holoenzyme complex, p39 variant.
DR   ComplexPortal; CPX-3142; Cyclin-dependent protein kinase 5 holoenzyme complex, p25 variant.
DR   CORUM; Q00535; -.
DR   DIP; DIP-24221N; -.
DR   ELM; Q00535; -.
DR   FunCoup; Q00535; 1204.
DR   IntAct; Q00535; 115.
DR   MINT; Q00535; -.
DR   STRING; 9606.ENSP00000419782; -.
DR   BindingDB; Q00535; -.
DR   ChEMBL; CHEMBL4036; -.
DR   DrugBank; DB07364; 6-PHENYL[5H]PYRROLO[2,3-B]PYRAZINE.
DR   DrugBank; DB04014; Alsterpaullone.
DR   DrugBank; DB03496; Alvocidib.
DR   DrugBank; DB02950; Hymenialdisine.
DR   DrugBank; DB02052; Indirubin-3'-monoxime.
DR   DrugBank; DB02116; Olomoucine.
DR   DrugBank; DB02733; Purvalanol.
DR   DrugBank; DB03428; SU9516.
DR   DrugBank; DB15442; Trilaciclib.
DR   DrugCentral; Q00535; -.
DR   GuidetoPHARMACOLOGY; 1977; -.
DR   GlyCosmos; Q00535; 4 sites, 1 glycan.
DR   GlyGen; Q00535; 4 sites, 1 O-linked glycan (4 sites).
DR   iPTMnet; Q00535; -.
DR   PhosphoSitePlus; Q00535; -.
DR   SwissPalm; Q00535; -.
DR   BioMuta; CDK5; -.
DR   DMDM; 4033704; -.
DR   CPTAC; CPTAC-2934; -.
DR   jPOST; Q00535; -.
DR   MassIVE; Q00535; -.
DR   PaxDb; 9606-ENSP00000419782; -.
DR   PeptideAtlas; Q00535; -.
DR   ProteomicsDB; 57852; -. [Q00535-1]
DR   ProteomicsDB; 57853; -. [Q00535-2]
DR   Pumba; Q00535; -.
DR   Antibodypedia; 4556; 1032 antibodies from 44 providers.
DR   DNASU; 1020; -.
DR   Ensembl; ENST00000297518.4; ENSP00000297518.4; ENSG00000164885.14. [Q00535-2]
DR   Ensembl; ENST00000485972.6; ENSP00000419782.1; ENSG00000164885.14. [Q00535-1]
DR   GeneID; 1020; -.
DR   KEGG; hsa:1020; -.
DR   MANE-Select; ENST00000485972.6; ENSP00000419782.1; NM_004935.4; NP_004926.1.
DR   UCSC; uc003wir.3; human. [Q00535-1]
DR   AGR; HGNC:1774; -.
DR   CIViC; 1020; 1 evidence item across 1 molecular profile.
DR   ClinPGx; PA26310; -.
DR   CTD; 1020; -.
DR   DisGeNET; 1020; -.
DR   GeneCards; CDK5; -.
DR   HGNC; HGNC:1774; CDK5.
DR   HPA; ENSG00000164885; Tissue enhanced (brain).
DR   MalaCards; CDK5; -.
DR   MIM; 123831; gene.
DR   MIM; 616342; phenotype.
DR   OpenTargets; ENSG00000164885; -.
DR   VEuPathDB; HostDB:ENSG00000164885; -.
DR   eggNOG; KOG0662; Eukaryota.
DR   GeneTree; ENSGT00940000160805; -.
DR   HOGENOM; CLU_000288_181_1_1; -.
DR   InParanoid; Q00535; -.
DR   OMA; NWQIFVP; -.
DR   OrthoDB; 1732493at2759; -.
DR   PAN-GO; Q00535; 8 GO annotations based on evolutionary models.
DR   PhylomeDB; Q00535; -.
DR   BRENDA; 2.7.11.1; 2681.
DR   BRENDA; 2.7.11.22; 2681.
DR   PathwayCommons; Q00535; -.
DR   Reactome; R-HSA-180024; DARPP-32 events.
DR   Reactome; R-HSA-399956; CRMPs in Sema3A signaling.
DR   Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   Reactome; R-HSA-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
DR   Reactome; R-HSA-9031628; NGF-stimulated transcription.
DR   Reactome; R-HSA-9032845; Activated NTRK2 signals through CDK5.
DR   Reactome; R-HSA-9768919; NPAS4 regulates expression of target genes.
DR   Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR   Reactome; R-HSA-9841922; MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis.
DR   Reactome; R-HSA-9931529; Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK.
DR   Reactome; R-HSA-9931530; Phosphorylation and nuclear translocation of the CRY:PER:kinase complex.
DR   SignaLink; Q00535; -.
DR   SIGNOR; Q00535; -.
DR   Agora; ENSG00000164885; -.
DR   BioGRID-ORCS; 1020; 27 hits in 1199 CRISPR screens.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; CDK5; human.
DR   EvolutionaryTrace; Q00535; -.
DR   GeneWiki; Cyclin-dependent_kinase_5; -.
DR   GenomeRNAi; 1020; -.
DR   Pharos; Q00535; Tchem.
DR   PRO; PR:Q00535; -.
DR   Proteomes; UP000005640; Chromosome 7.
DR   RNAct; Q00535; protein.
DR   Bgee; ENSG00000164885; Expressed in right frontal lobe and 156 other cell types or tissues.
DR   ExpressionAtlas; Q00535; baseline and differential.
DR   GO; GO:0030424; C:axon; ISS:UniProtKB.
DR   GO; GO:0030054; C:cell junction; IDA:HPA.
DR   GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IPI:ComplexPortal.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR   GO; GO:0030175; C:filopodium; IEA:Ensembl.
DR   GO; GO:0030426; C:growth cone; ISS:UniProtKB.
DR   GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR   GO; GO:0031594; C:neuromuscular junction; ISS:UniProtKB.
DR   GO; GO:0043005; C:neuron projection; ISS:ARUK-UCL.
DR   GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR   GO; GO:0098793; C:presynapse; IEA:GOC.
DR   GO; GO:0016533; C:protein kinase 5 complex; IPI:ComplexPortal.
DR   GO; GO:0030549; F:acetylcholine receptor activator activity; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR   GO; GO:0005176; F:ErbB-2 class receptor binding; ISS:UniProtKB.
DR   GO; GO:0043125; F:ErbB-3 class receptor binding; ISS:UniProtKB.
DR   GO; GO:0051879; F:Hsp90 protein binding; IEA:Ensembl.
DR   GO; GO:0035255; F:ionotropic glutamate receptor binding; IPI:ARUK-UCL.
DR   GO; GO:0016301; F:kinase activity; ISS:UniProtKB.
DR   GO; GO:0002039; F:p53 binding; IEA:Ensembl.
DR   GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0030547; F:signaling receptor inhibitor activity; IMP:ARUK-UCL.
DR   GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR   GO; GO:0050321; F:tau-protein kinase activity; ISS:UniProtKB.
DR   GO; GO:0030036; P:actin cytoskeleton organization; TAS:UniProtKB.
DR   GO; GO:0048675; P:axon extension; TAS:UniProtKB.
DR   GO; GO:0007409; P:axonogenesis; IBA:GO_Central.
DR   GO; GO:0048148; P:behavioral response to cocaine; IEA:Ensembl.
DR   GO; GO:0070509; P:calcium ion import; IEA:Ensembl.
DR   GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR   GO; GO:0007160; P:cell-matrix adhesion; IEA:Ensembl.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; ISS:ARUK-UCL.
DR   GO; GO:0021954; P:central nervous system neuron development; IEA:Ensembl.
DR   GO; GO:0021697; P:cerebellar cortex formation; IEA:Ensembl.
DR   GO; GO:0007268; P:chemical synaptic transmission; TAS:UniProtKB.
DR   GO; GO:0022038; P:corpus callosum development; IEA:Ensembl.
DR   GO; GO:0048813; P:dendrite morphogenesis; IEA:Ensembl.
DR   GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl.
DR   GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR   GO; GO:0006886; P:intracellular protein transport; IEA:Ensembl.
DR   GO; GO:0021819; P:layer formation in cerebral cortex; IEA:Ensembl.
DR   GO; GO:0000226; P:microtubule cytoskeleton organization; TAS:ARUK-UCL.
DR   GO; GO:0008045; P:motor neuron axon guidance; IEA:Ensembl.
DR   GO; GO:0030517; P:negative regulation of axon extension; IEA:Ensembl.
DR   GO; GO:1903234; P:negative regulation of calcium ion-dependent exocytosis of neurotransmitter; ISS:ARUK-UCL.
DR   GO; GO:0045786; P:negative regulation of cell cycle; IEA:Ensembl.
DR   GO; GO:0045892; P:negative regulation of DNA-templated transcription; IMP:DFLAT.
DR   GO; GO:0046826; P:negative regulation of protein export from nucleus; IEA:Ensembl.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; IEA:Ensembl.
DR   GO; GO:0045861; P:negative regulation of proteolysis; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0031914; P:negative regulation of synaptic plasticity; IEA:Ensembl.
DR   GO; GO:0051402; P:neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
DR   GO; GO:0001764; P:neuron migration; TAS:UniProtKB.
DR   GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR   GO; GO:0048709; P:oligodendrocyte differentiation; IDA:UniProtKB.
DR   GO; GO:0045956; P:positive regulation of calcium ion-dependent exocytosis; IEA:Ensembl.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR   GO; GO:0099533; P:positive regulation of presynaptic cytosolic calcium concentration; ISS:ARUK-UCL.
DR   GO; GO:0090314; P:positive regulation of protein targeting to membrane; IEA:Ensembl.
DR   GO; GO:0035418; P:protein localization to synapse; IEA:Ensembl.
DR   GO; GO:0032801; P:receptor catabolic process; IEA:Ensembl.
DR   GO; GO:0043113; P:receptor clustering; IEA:Ensembl.
DR   GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB.
DR   GO; GO:0051726; P:regulation of cell cycle; TAS:UniProtKB.
DR   GO; GO:1901987; P:regulation of cell cycle phase transition; IBA:GO_Central.
DR   GO; GO:0030334; P:regulation of cell migration; IEA:Ensembl.
DR   GO; GO:0061001; P:regulation of dendritic spine morphogenesis; ISS:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR   GO; GO:1903076; P:regulation of protein localization to plasma membrane; ISS:ARUK-UCL.
DR   GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR   GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; ISS:ARUK-UCL.
DR   GO; GO:1903421; P:regulation of synaptic vesicle recycling; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR   GO; GO:0014044; P:Schwann cell development; IEA:Ensembl.
DR   GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR   GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl.
DR   GO; GO:0007416; P:synapse assembly; TAS:UniProtKB.
DR   GO; GO:0001963; P:synaptic transmission, dopaminergic; IEA:Ensembl.
DR   GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl.
DR   GO; GO:0048488; P:synaptic vesicle endocytosis; TAS:UniProtKB.
DR   GO; GO:0016079; P:synaptic vesicle exocytosis; TAS:UniProtKB.
DR   GO; GO:0048489; P:synaptic vesicle transport; IBA:GO_Central.
DR   GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR   CDD; cd07839; STKc_CDK5; 1.
DR   FunFam; 3.30.200.20:FF:000144; Cyclin-dependent kinase 5; 1.
DR   FunFam; 1.10.510.10:FF:000184; cyclin-dependent kinase 5 homolog; 1.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR050108; CDK.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR24056; CELL DIVISION PROTEIN KINASE; 1.
DR   PANTHER; PTHR24056:SF46; CYCLIN-DEPENDENT KINASE 5; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding;
KW   Biological rhythms; Cell cycle; Cell division; Cell membrane;
KW   Cell projection; Cytoplasm; Kinase; Lissencephaly; Membrane;
KW   Neurodegeneration; Neurogenesis; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Proteomics identification; Reference proteome;
KW   Serine/threonine-protein kinase; Synapse; Transferase.
FT   CHAIN           1..292
FT                   /note="Cyclin-dependent kinase 5"
FT                   /id="PRO_0000085784"
FT   DOMAIN          4..286
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   ACT_SITE        126
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         10..18
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         33
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         15
FT                   /note="Phosphotyrosine; by ABL1, EPHA4 and FYN"
FT                   /evidence="ECO:0000269|PubMed:15689152,
FT                   ECO:0000269|PubMed:17143272"
FT   MOD_RES         17
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         56
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         72
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976,
FT                   ECO:0007744|PubMed:19369195"
FT   MOD_RES         159
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:10500146"
FT   VAR_SEQ         105..136
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:19693690"
FT                   /id="VSP_041948"
FT   VARIANT         225
FT                   /note="E -> D (in dbSNP:rs35186917)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041977"
FT   MUTAGEN         159
FT                   /note="S->A: No phenotype."
FT                   /evidence="ECO:0000269|PubMed:11583627"
FT   MUTAGEN         159
FT                   /note="S->T: Impaired p35/p25 (CDK5R1) binding."
FT                   /evidence="ECO:0000269|PubMed:11583627"
FT   STRAND          4..12
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          14..23
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   TURN            24..26
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          29..36
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          40..42
FT                   /evidence="ECO:0007829|PDB:1UNG"
FT   HELIX           46..55
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          66..70
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          76..81
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          84..86
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           87..94
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           100..119
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           129..131
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          132..134
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          140..142
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           145..147
FT                   /evidence="ECO:0007829|PDB:1UNG"
FT   HELIX           165..167
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           170..173
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           182..196
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   TURN            197..199
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           208..219
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   TURN            224..226
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           228..232
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           248..250
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           257..266
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           271..273
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           277..281
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           284..286
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          287..289
FT                   /evidence="ECO:0007829|PDB:7VDQ"
SQ   SEQUENCE   292 AA;  33304 MW;  54D10495F017D527 CRC64;
     MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR EICLLKELKH
     KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP EIVKSFLFQL LKGLGFCHSR
     NVLHRDLKPQ NLLINRNGEL KLADFGLARA FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS
     TSIDMWSAGC IFAELANAGR PLFPGNDVDD QLKRIFRLLG TPTEEQWPSM TKLPDYKPYP
     MYPATTSLVN VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP
//
ID   CSEN_HUMAN              Reviewed;         256 AA.
AC   Q9Y2W7; H7BY46; Q3YAC3; Q3YAC4; Q53TJ5; Q96T40; Q9UJ84; Q9UJ85;
DT   27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1999, sequence version 1.
DT   28-JAN-2026, entry version 209.
DE   RecName: Full=Calsenilin;
DE   AltName: Full=A-type potassium channel modulatory protein 3;
DE   AltName: Full=DRE-antagonist modulator;
DE            Short=DREAM;
DE   AltName: Full=Kv channel-interacting protein 3;
DE            Short=KChIP3;
GN   Name=KCNIP3; Synonyms=CSEN, DREAM, KCHIP3;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN PRESENILIN
RP   REGULATION.
RX   PubMed=9771752; DOI=10.1038/2673;
RA   Buxbaum J.D., Choi E.K., Luo Y., Lilliehook C., Crowley A.C., Merriam D.E.,
RA   Wasco W.;
RT   "Calsenilin: a calcium-binding protein that interacts with the presenilins
RT   and regulates the levels of a presenilin fragment.";
RL   Nat. Med. 4:1177-1181(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN TRANSCRIPTION
RP   REGULATION.
RC   TISSUE=Caudate nucleus;
RX   PubMed=10078534; DOI=10.1038/18044;
RA   Carrion A.M., Link W.A., Ledo F., Mellstrom B., Naranjo J.R.;
RT   "DREAM is a Ca2+-regulated transcriptional repressor.";
RL   Nature 398:80-84(1999).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN POTASSIUM
RP   TRANSPORT.
RX   PubMed=10676964; DOI=10.1038/35000592;
RA   An W.F., Bowlby M.R., Betty M., Cao J., Ling H.-P., Mendoza G.,
RA   Hinson J.W., Mattsson K.I., Strassle B.W., Trimmer J.S., Rhodes K.J.;
RT   "Modulation of A-type potassium channels by a family of calcium sensors.";
RL   Nature 403:553-556(2000).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), AND ALTERNATIVE SPLICING.
RX   PubMed=16112838; DOI=10.1016/j.ygeno.2005.07.001;
RA   Pruunsild P., Timmusk T.;
RT   "Structure, alternative splicing, and expression of the human and mouse
RT   KCNIP gene family.";
RL   Genomics 86:581-593(2005).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA   Isbrandt D., Pongs O.;
RL   Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [11]
RP   INTERACTION WITH PSEN2, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND
RP   MUTAGENESIS OF ASP-61 AND ASP-64.
RX   PubMed=11278424; DOI=10.1074/jbc.m008597200;
RA   Choi E.K., Zaidi N.F., Miller J.S., Crowley A.C., Merriam D.E.,
RA   Lilliehook C., Buxbaum J.D., Wasco W.;
RT   "Calsenilin is a substrate for caspase-3 that preferentially interacts with
RT   the familial Alzheimer's disease-associated C-terminal fragment of
RT   presenilin 2.";
RL   J. Biol. Chem. 276:19197-19204(2001).
RN   [12]
RP   FUNCTION IN APOPTOSIS.
RX   PubMed=11259376; DOI=10.1096/fj.00-0541fje;
RA   Jo D.G., Kim M.J., Choi Y.H., Kim I.K., Song Y.H., Woo H.N., Chung C.W.,
RA   Jung Y.K.;
RT   "Pro-apoptotic function of calsenilin/DREAM/KChIP3.";
RL   FASEB J. 15:589-591(2001).
RN   [13]
RP   FUNCTION IN APOPTOSIS.
RX   PubMed=11988022; DOI=10.1006/mcne.2001.1096;
RA   Lilliehook C., Chan S., Choi E.K., Zaidi N.F., Wasco W., Mattson M.P.,
RA   Buxbaum J.D.;
RT   "Calsenilin enhances apoptosis by altering endoplasmic reticulum calcium
RT   signaling.";
RL   Mol. Cell. Neurosci. 19:552-559(2002).
RN   [14]
RP   FUNCTION IN POTASSIUM TRANSPORT.
RX   PubMed=12829703; DOI=10.1074/jbc.m306142200;
RA   Shibata R., Misonou H., Campomanes C.R., Anderson A.E., Schrader L.A.,
RA   Doliveira L.C., Carroll K.I., Sweatt J.D., Rhodes K.J., Trimmer J.S.;
RT   "A fundamental role for KChIPs in determining the molecular properties and
RT   trafficking of Kv4.2 potassium channels.";
RL   J. Biol. Chem. 278:36445-36454(2003).
RN   [15]
RP   PHOSPHORYLATION AT SER-63.
RX   PubMed=12837631; DOI=10.1016/s1044-7431(03)00072-1;
RA   Choi E.K., Miller J.S., Zaidi N.F., Salih E., Buxbaum J.D., Wasco W.;
RT   "Phosphorylation of calsenilin at Ser63 regulates its cleavage by caspase-
RT   3.";
RL   Mol. Cell. Neurosci. 23:495-506(2003).
RN   [16]
RP   INTERACTION WITH KCND2, FUNCTION IN POTASSIUM TRANSPORT, SUBUNIT, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=15485870; DOI=10.1074/jbc.m409721200;
RA   Kunjilwar K., Strang C., DeRubeis D., Pfaffinger P.J.;
RT   "KChIP3 rescues the functional expression of Shal channel tetramerization
RT   mutants.";
RL   J. Biol. Chem. 279:54542-54551(2004).
RN   [17]
RP   TISSUE SPECIFICITY.
RX   PubMed=14720210; DOI=10.1111/j.1471-4159.2004.02159.x;
RA   Jo D.G., Lee J.Y., Hong Y.M., Song S., Mook-Jung I., Koh J.Y., Jung Y.K.;
RT   "Induction of pro-apoptotic calsenilin/DREAM/KChIP3 in Alzheimer's disease
RT   and cultured neurons after amyloid-beta exposure.";
RL   J. Neurochem. 88:604-611(2004).
RN   [18]
RP   FUNCTION IN POTASSIUM TRANSPORT.
RX   PubMed=16123112; DOI=10.1113/jphysiol.2005.087858;
RA   Jerng H.H., Kunjilwar K., Pfaffinger P.J.;
RT   "Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel
RT   complexes with ISA-like properties.";
RL   J. Physiol. (Lond.) 568:767-788(2005).
RN   [19]
RP   FUNCTION IN POTASSIUM TRANSPORT, INTERACTION WITH KCND2, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=18957440; DOI=10.1074/jbc.m806852200;
RA   Jerng H.H., Pfaffinger P.J.;
RT   "Multiple Kv channel-interacting proteins contain an N-terminal
RT   transmembrane domain that regulates Kv4 channel trafficking and gating.";
RL   J. Biol. Chem. 283:36046-36059(2008).
RN   [20]
RP   SUMOYLATION AT LYS-26 AND LYS-90, AND SUBCELLULAR LOCATION.
RX   PubMed=21070824; DOI=10.1016/j.bbamcr.2010.11.001;
RA   Palczewska M., Casafont I., Ghimire K., Rojas A.M., Valencia A.,
RA   Lafarga M., Mellstrom B., Naranjo J.R.;
RT   "Sumoylation regulates nuclear localization of repressor DREAM.";
RL   Biochim. Biophys. Acta 1813:1050-1058(2011).
RN   [21]
RP   STRUCTURE BY NMR OF 161-256, SUBUNIT, AND CALCIUM-BINDING.
RX   PubMed=17962406; DOI=10.1110/ps.072928007;
RA   Yu L., Sun C., Mendoza R., Wang J., Matayoshi E.D., Hebert E.,
RA   Pereda-Lopez A., Hajduk P.J., Olejniczak E.T.;
RT   "Solution structure and calcium-binding properties of EF-hands 3 and 4 of
RT   calsenilin.";
RL   Protein Sci. 16:2502-2509(2007).
RN   [22]
RP   VARIANTS [LARGE SCALE ANALYSIS] SER-170 AND TYR-179.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
CC   -!- FUNCTION: Calcium-dependent transcriptional repressor that binds to the
CC       DRE element of genes including PDYN and FOS. Affinity for DNA is
CC       reduced upon binding to calcium and enhanced by binding to magnesium.
CC       Seems to be involved in nociception (By similarity).
CC       {ECO:0000250|UniProtKB:Q9QXT8}.
CC   -!- FUNCTION: Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly
CC       inactivating A-type potassium channels, such as KCND2/Kv4.2 and
CC       KCND3/Kv4.3. Modulates channel expression at the cell membrane, gating
CC       characteristics, inactivation kinetics and rate of recovery from
CC       inactivation in a calcium-dependent and isoform-specific manner.
CC       {ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:12829703,
CC       ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:16123112,
CC       ECO:0000269|PubMed:18957440}.
CC   -!- FUNCTION: May play a role in the regulation of PSEN2 proteolytic
CC       processing and apoptosis. Together with PSEN2 involved in modulation of
CC       amyloid-beta formation. {ECO:0000269|PubMed:11259376,
CC       ECO:0000269|PubMed:11988022, ECO:0000269|PubMed:9771752}.
CC   -!- SUBUNIT: Binds to DNA as a homomultimer. Dimerization is induced by
CC       binding to calcium (PubMed:17962406). Interacts with the C-terminus of
CC       PSEN1 and PSEN2 and with PSEN2 CTF subunit. Associates with KCN1.
CC       Component of heteromultimeric potassium channels. Identified in
CC       potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1,
CC       KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). Interacts with
CC       KCND2 and KCND3. {ECO:0000250|UniProtKB:Q9QXT8,
CC       ECO:0000269|PubMed:11278424, ECO:0000269|PubMed:15485870,
CC       ECO:0000269|PubMed:17962406, ECO:0000269|PubMed:18957440}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18957440}. Cell
CC       membrane {ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:18957440};
CC       Lipid-anchor {ECO:0000250}. Endoplasmic reticulum
CC       {ECO:0000269|PubMed:11278424, ECO:0000269|PubMed:18957440}. Golgi
CC       apparatus {ECO:0000269|PubMed:11278424}. Nucleus
CC       {ECO:0000269|PubMed:21070824}. Note=Also membrane-bound, associated
CC       with the plasma membrane (PubMed:15485870). In the presence of PSEN2
CC       associated with the endoplasmic reticulum and Golgi. The sumoylated
CC       form is present only in the nucleus. {ECO:0000269|PubMed:11278424,
CC       ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:21070824}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=KChIP3.1;
CC         IsoId=Q9Y2W7-1; Sequence=Displayed;
CC       Name=2; Synonyms=KChIP3.2, KChIP4.2;
CC         IsoId=Q9Y2W7-2; Sequence=VSP_015040;
CC       Name=3; Synonyms=KChip3.x;
CC         IsoId=Q9Y2W7-3; Sequence=VSP_040982, VSP_040983;
CC   -!- TISSUE SPECIFICITY: Highly expressed in brain. Widely expressed at
CC       lower levels. Expression levels are elevated in brain cortex regions
CC       affected by Alzheimer disease. {ECO:0000269|PubMed:14720210}.
CC   -!- PTM: Palmitoylated. Palmitoylation enhances association with the plasma
CC       membrane (By similarity). {ECO:0000250}.
CC   -!- PTM: Proteolytically cleaved by caspase-3.
CC       {ECO:0000269|PubMed:11278424}.
CC   -!- PTM: Phosphorylation at Ser-63 inhibits cleavage by CASP3.
CC       {ECO:0000269|PubMed:11278424, ECO:0000269|PubMed:12837631}.
CC   -!- SIMILARITY: Belongs to the recoverin family. {ECO:0000305}.
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DR   EMBL; AF120102; AAD20350.1; -; mRNA.
DR   EMBL; AJ131730; CAB56836.1; -; mRNA.
DR   EMBL; AJ131730; CAB56835.1; -; mRNA.
DR   EMBL; AF199599; AAF33684.1; -; mRNA.
DR   EMBL; DQ148485; AAZ77802.1; -; mRNA.
DR   EMBL; DQ148486; AAZ77803.1; -; mRNA.
DR   EMBL; AF367022; AAK53711.1; -; mRNA.
DR   EMBL; BT020075; AAV38878.1; -; mRNA.
DR   EMBL; AK315437; BAG37825.1; -; mRNA.
DR   EMBL; AC009238; AAY14752.1; -; Genomic_DNA.
DR   EMBL; CH471219; EAX10724.1; -; Genomic_DNA.
DR   EMBL; BC012850; AAH12850.1; -; mRNA.
DR   CCDS; CCDS2013.1; -. [Q9Y2W7-1]
DR   CCDS; CCDS33245.1; -. [Q9Y2W7-3]
DR   RefSeq; NP_001030086.1; NM_001034914.2. [Q9Y2W7-3]
DR   RefSeq; NP_038462.1; NM_013434.5. [Q9Y2W7-1]
DR   PDB; 2E6W; NMR; -; A=161-256.
DR   PDBsum; 2E6W; -.
DR   AlphaFoldDB; Q9Y2W7; -.
DR   SMR; Q9Y2W7; -.
DR   BioGRID; 119042; 33.
DR   FunCoup; Q9Y2W7; 414.
DR   STRING; 9606.ENSP00000295225; -.
DR   TCDB; 8.A.82.2.5; the calmodulin calcium binding protein (calmodulin) family.
DR   iPTMnet; Q9Y2W7; -.
DR   PhosphoSitePlus; Q9Y2W7; -.
DR   BioMuta; KCNIP3; -.
DR   DMDM; 13431428; -.
DR   MassIVE; Q9Y2W7; -.
DR   PaxDb; 9606-ENSP00000295225; -.
DR   PeptideAtlas; Q9Y2W7; -.
DR   ProteomicsDB; 43500; -.
DR   ProteomicsDB; 85919; -. [Q9Y2W7-1]
DR   ProteomicsDB; 85920; -. [Q9Y2W7-2]
DR   ProteomicsDB; 85921; -. [Q9Y2W7-3]
DR   ABCD; Q9Y2W7; 2 sequenced antibodies.
DR   Antibodypedia; 4181; 544 antibodies from 40 providers.
DR   DNASU; 30818; -.
DR   Ensembl; ENST00000295225.10; ENSP00000295225.5; ENSG00000115041.15. [Q9Y2W7-1]
DR   Ensembl; ENST00000468529.1; ENSP00000417499.1; ENSG00000115041.15. [Q9Y2W7-3]
DR   GeneID; 30818; -.
DR   KEGG; hsa:30818; -.
DR   MANE-Select; ENST00000295225.10; ENSP00000295225.5; NM_013434.5; NP_038462.1.
DR   UCSC; uc002sup.4; human. [Q9Y2W7-1]
DR   AGR; HGNC:15523; -.
DR   ClinPGx; PA26934; -.
DR   CTD; 30818; -.
DR   DisGeNET; 30818; -.
DR   GeneCards; KCNIP3; -.
DR   HGNC; HGNC:15523; KCNIP3.
DR   HPA; ENSG00000115041; Tissue enhanced (brain, lymphoid tissue, parathyroid gland).
DR   MIM; 604662; gene.
DR   OpenTargets; ENSG00000115041; -.
DR   VEuPathDB; HostDB:ENSG00000115041; -.
DR   eggNOG; KOG0044; Eukaryota.
DR   GeneTree; ENSGT00940000158782; -.
DR   HOGENOM; CLU_072366_2_2_1; -.
DR   InParanoid; Q9Y2W7; -.
DR   OMA; TITKKEW; -.
DR   OrthoDB; 191686at2759; -.
DR   PAN-GO; Q9Y2W7; 8 GO annotations based on evolutionary models.
DR   PhylomeDB; Q9Y2W7; -.
DR   PathwayCommons; Q9Y2W7; -.
DR   Reactome; R-HSA-5576894; Phase 1 - inactivation of fast Na+ channels.
DR   Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription.
DR   SignaLink; Q9Y2W7; -.
DR   SIGNOR; Q9Y2W7; -.
DR   Agora; ENSG00000115041; -.
DR   BioGRID-ORCS; 30818; 22 hits in 1155 CRISPR screens.
DR   ChiTaRS; KCNIP3; human.
DR   EvolutionaryTrace; Q9Y2W7; -.
DR   GeneWiki; Calsenilin; -.
DR   GenomeRNAi; 30818; -.
DR   Pharos; Q9Y2W7; Tbio.
DR   PRO; PR:Q9Y2W7; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q9Y2W7; protein.
DR   Bgee; ENSG00000115041; Expressed in right frontal lobe and 110 other cell types or tissues.
DR   ExpressionAtlas; Q9Y2W7; baseline and differential.
DR   GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR   GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0008076; C:voltage-gated potassium channel complex; ISS:UniProtKB.
DR   GO; GO:0005509; F:calcium ion binding; IBA:GO_Central.
DR   GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:ARUK-UCL.
DR   GO; GO:0005267; F:potassium channel activity; IEA:UniProtKB-KW.
DR   GO; GO:0015459; F:potassium channel regulator activity; ISS:UniProtKB.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:ARUK-UCL.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:ARUK-UCL.
DR   GO; GO:0072659; P:protein localization to plasma membrane; ISS:UniProtKB.
DR   GO; GO:1901379; P:regulation of potassium ion transmembrane transport; ISS:UniProtKB.
DR   GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   CDD; cd00051; EFh; 2.
DR   FunFam; 1.10.238.10:FF:000043; Kv channel-interacting protein 1 isoform 2; 1.
DR   Gene3D; 1.10.238.10; EF-hand; 1.
DR   InterPro; IPR011992; EF-hand-dom_pair.
DR   InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR   InterPro; IPR002048; EF_hand_dom.
DR   InterPro; IPR028846; Recoverin.
DR   PANTHER; PTHR23055; CALCIUM BINDING PROTEINS; 1.
DR   PANTHER; PTHR23055:SF165; CALSENILIN; 1.
DR   Pfam; PF13499; EF-hand_7; 1.
DR   Pfam; PF13833; EF-hand_8; 1.
DR   PRINTS; PR00450; RECOVERIN.
DR   SMART; SM00054; EFh; 3.
DR   SUPFAM; SSF47473; EF-hand; 1.
DR   PROSITE; PS00018; EF_HAND_1; 2.
DR   PROSITE; PS50222; EF_HAND_2; 3.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Apoptosis; Calcium; Cell membrane;
KW   Cytoplasm; Endoplasmic reticulum; Golgi apparatus; Ion channel;
KW   Ion transport; Isopeptide bond; Lipoprotein; Membrane; Metal-binding;
KW   Nucleus; Palmitate; Phosphoprotein; Potassium; Potassium channel;
KW   Potassium transport; Proteomics identification; Reference proteome; Repeat;
KW   Repressor; Transcription; Transcription regulation; Transport;
KW   Ubl conjugation; Voltage-gated channel.
FT   CHAIN           1..256
FT                   /note="Calsenilin"
FT                   /id="PRO_0000073814"
FT   DOMAIN          67..123
FT                   /note="EF-hand 1; degenerate"
FT                   /evidence="ECO:0000305"
FT   DOMAIN          126..161
FT                   /note="EF-hand 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   DOMAIN          162..197
FT                   /note="EF-hand 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   DOMAIN          210..245
FT                   /note="EF-hand 4"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   REGION          1..20
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          243..256
FT                   /note="Interaction with KCND2"
FT                   /evidence="ECO:0000250"
FT   BINDING         175
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         177
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         179
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         181
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         186
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         223
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         225
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         227
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         234
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   MOD_RES         14
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9JM47"
FT   MOD_RES         60
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9QXT8"
FT   MOD_RES         63
FT                   /note="Phosphoserine; by CK1"
FT                   /evidence="ECO:0000269|PubMed:12837631"
FT   LIPID           45
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000250"
FT   LIPID           46
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000250"
FT   CROSSLNK        26
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO1)"
FT                   /evidence="ECO:0000269|PubMed:21070824"
FT   CROSSLNK        90
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO1)"
FT                   /evidence="ECO:0000269|PubMed:21070824"
FT   VAR_SEQ         1..26
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:16112838"
FT                   /id="VSP_040982"
FT   VAR_SEQ         27..60
FT                   /note="KEGIKWQRPRLSRQALMRCCLVKWILSSTAPQGS -> MGIQGMELCAMAVV
FT                   VLLFIAVLKQFGILEPISME (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:16112838"
FT                   /id="VSP_040983"
FT   VAR_SEQ         103..124
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.5"
FT                   /id="VSP_015040"
FT   VARIANT         119
FT                   /note="A -> V (in dbSNP:rs35658670)"
FT                   /id="VAR_048663"
FT   VARIANT         170
FT                   /note="A -> S (in a breast cancer sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_035463"
FT   VARIANT         179
FT                   /note="D -> Y (in a breast cancer sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_035464"
FT   MUTAGEN         61
FT                   /note="D->A: Abolishes cleavage by caspase-3."
FT                   /evidence="ECO:0000269|PubMed:11278424"
FT   MUTAGEN         64
FT                   /note="D->A: Abolishes cleavage by caspase-3."
FT                   /evidence="ECO:0000269|PubMed:11278424"
FT   CONFLICT        182
FT                   /note="I -> V (in Ref. 2; CAB56836/CAB56835)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        207
FT                   /note="R -> Q (in Ref. 2; CAB56836/CAB56835)"
FT                   /evidence="ECO:0000305"
FT   HELIX           164..174
FT                   /evidence="ECO:0007829|PDB:2E6W"
FT   STRAND          179..182
FT                   /evidence="ECO:0007829|PDB:2E6W"
FT   HELIX           184..193
FT                   /evidence="ECO:0007829|PDB:2E6W"
FT   STRAND          211..213
FT                   /evidence="ECO:0007829|PDB:2E6W"
FT   HELIX           214..222
FT                   /evidence="ECO:0007829|PDB:2E6W"
FT   STRAND          227..231
FT                   /evidence="ECO:0007829|PDB:2E6W"
FT   HELIX           232..239
FT                   /evidence="ECO:0007829|PDB:2E6W"
FT   HELIX           243..254
FT                   /evidence="ECO:0007829|PDB:2E6W"
SQ   SEQUENCE   256 AA;  29231 MW;  635C3EDF8B91E1C5 CRC64;
     MQPAKEVTKA SDGSLLGDLG HTPLSKKEGI KWQRPRLSRQ ALMRCCLVKW ILSSTAPQGS
     DSSDSELELS TVRHQPEGLD QLQAQTKFTK KELQSLYRGF KNECPTGLVD EDTFKLIYAQ
     FFPQGDATTY AHFLFNAFDA DGNGAIHFED FVVGLSILLR GTVHEKLKWA FNLYDINKDG
     YITKEEMLAI MKSIYDMMGR HTYPILREDA PAEHVERFFE KMDRNQDGVV TIEEFLEACQ
     KDENIMSSMQ LFENVI
//
ID   DHC24_HUMAN             Reviewed;         516 AA.
AC   Q15392; B7Z817; D3DQ51; Q9HBA8;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   31-JAN-2002, sequence version 2.
DT   28-JAN-2026, entry version 214.
DE   RecName: Full=Delta(24)-sterol reductase;
DE            EC=1.3.1.72 {ECO:0000269|PubMed:11519011, ECO:0000269|PubMed:21671375};
DE   AltName: Full=24-dehydrocholesterol reductase;
DE   AltName: Full=3-beta-hydroxysterol Delta-24-reductase;
DE   AltName: Full=Diminuto/dwarf1 homolog;
DE   AltName: Full=Seladin-1 {ECO:0000303|PubMed:11007892};
DE   Flags: Precursor;
GN   Name=DHCR24; Synonyms=KIAA0018;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, AND
RP   TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=11007892; DOI=10.1523/jneurosci.20-19-07345.2000;
RA   Greeve I., Hermans-Borgmeyer I., Brellinger C., Kasper D., Gomez-Isla T.,
RA   Behl C., Levkau B., Nitsch R.M.;
RT   "The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to
RT   Alzheimer's disease-associated neurodegeneration and oxidative stress.";
RL   J. Neurosci. 20:7345-7352(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, TISSUE SPECIFICITY, VARIANTS
RP   DESMOS LYS-191; THR-294; ASN-306 AND SER-471, CATALYTIC ACTIVITY, AND
RP   CHARACTERIZATION OF VARIANTS DESMOS LYS-191; THR-294; ASN-306 AND SER-471.
RX   PubMed=11519011; DOI=10.1086/323473;
RA   Waterham H.R., Koster J., Romeijn G.J., Hennekam R.C.M., Vreken P.,
RA   Andersson H.C., FitzPatrick D.R., Kelley R.I., Wanders R.J.A.;
RT   "Mutations in the 3beta-hydroxysterol delta24-reductase gene cause
RT   desmosterolosis, an autosomal recessive disorder of cholesterol
RT   biosynthesis.";
RL   Am. J. Hum. Genet. 69:685-694(2001).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Bone marrow;
RX   PubMed=7584026; DOI=10.1093/dnares/1.1.27;
RA   Nomura N., Miyajima N., Sazuka T., Tanaka A., Kawarabayasi Y., Sato S.,
RA   Nagase T., Seki N., Ishikawa K., Tabata S.;
RT   "Prediction of the coding sequences of unidentified human genes. I. The
RT   coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of
RT   randomly sampled cDNA clones from human immature myeloid cell line KG-1.";
RL   DNA Res. 1:27-35(1994).
RN   [4]
RP   SEQUENCE REVISION TO C-TERMINUS.
RA   Ohara O., Nagase T., Kikuno R., Nomura N.;
RL   Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Testis;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain, and Placenta;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   VARIANTS DESMOS HIS-94 AND LYS-480, CHARACTERIZATION OF VARIANTS DESMOS
RP   HIS-94 AND LYS-480, CATALYTIC ACTIVITY, AND FUNCTION.
RX   PubMed=21671375; DOI=10.1002/ajmg.a.34040;
RA   Schaaf C.P., Koster J., Katsonis P., Kratz L., Shchelochkov O.A.,
RA   Scaglia F., Kelley R.I., Lichtarge O., Waterham H.R., Shinawi M.;
RT   "Desmosterolosis-phenotypic and molecular characterization of a third case
RT   and review of the literature.";
RL   Am. J. Med. Genet. A 155A:1597-1604(2011).
RN   [10]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [11]
RP   CATALYTIC ACTIVITY, AND FUNCTION.
RX   PubMed=22178193; DOI=10.1016/j.bbalip.2011.11.009;
RA   Zerenturk E.J., Kristiana I., Gill S., Brown A.J.;
RT   "The endogenous regulator 24(S),25-epoxycholesterol inhibits cholesterol
RT   synthesis at DHCR24 (Seladin-1).";
RL   Biochim. Biophys. Acta 1821:1269-1277(2012).
RN   [12]
RP   FUNCTION, SUBCELLULAR LOCATION, AND TOPOLOGY.
RX   PubMed=22010141; DOI=10.1530/jme-11-0132;
RA   Lu X., Li Y., Liu J., Cao X., Wang X., Wang D., Seo H., Gao B.;
RT   "The membrane topological analysis of 3 {beta}-hydroxysteroid-delta24
RT   reductase (DHCR24) on endoplasmic reticulum.";
RL   J. Mol. Endocrinol. 48:1-9(2012).
RN   [13]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [14]
RP   CATALYTIC ACTIVITY, AND INTERACTION WITH DHCR7.
RX   PubMed=25637936; DOI=10.1194/jlr.m056986;
RA   Luu W., Hart-Smith G., Sharpe L.J., Brown A.J.;
RT   "The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact
RT   physically and functionally.";
RL   J. Lipid Res. 56:888-897(2015).
RN   [15]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
CC   -!- FUNCTION: Catalyzes the reduction of the delta-24 double bond of sterol
CC       intermediates during cholesterol biosynthesis (PubMed:11519011,
CC       PubMed:21671375, PubMed:22178193, PubMed:25637936). In addition to its
CC       cholesterol-synthesizing activity, can protect cells from oxidative
CC       stress by reducing caspase 3 activity during apoptosis induced by
CC       oxidative stress (PubMed:11007892, PubMed:22010141). Also protects
CC       against amyloid-beta peptide-induced apoptosis (PubMed:11007892).
CC       {ECO:0000269|PubMed:11007892, ECO:0000269|PubMed:11519011,
CC       ECO:0000269|PubMed:21671375, ECO:0000269|PubMed:22010141,
CC       ECO:0000269|PubMed:22178193, ECO:0000269|PubMed:25637936}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cholesterol + NADP(+) = desmosterol + NADPH + H(+);
CC         Xref=Rhea:RHEA:36391, ChEBI:CHEBI:15378, ChEBI:CHEBI:16113,
CC         ChEBI:CHEBI:17737, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.72;
CC         Evidence={ECO:0000269|PubMed:11519011, ECO:0000269|PubMed:21671375,
CC         ECO:0000269|PubMed:25637936};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:36393;
CC         Evidence={ECO:0000305|PubMed:11519011, ECO:0000305|PubMed:21671375};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=lanosterol + NADPH + H(+) = 24,25-dihydrolanosterol + NADP(+);
CC         Xref=Rhea:RHEA:33919, ChEBI:CHEBI:15378, ChEBI:CHEBI:16521,
CC         ChEBI:CHEBI:28113, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC         Evidence={ECO:0000269|PubMed:22178193};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33920;
CC         Evidence={ECO:0000269|PubMed:22178193};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=5alpha-cholest-8-en-3beta-ol + NADP(+) = zymosterol + NADPH +
CC         H(+); Xref=Rhea:RHEA:36399, ChEBI:CHEBI:15378, ChEBI:CHEBI:16608,
CC         ChEBI:CHEBI:18252, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.72;
CC         Evidence={ECO:0000250|UniProtKB:Q8VCH6};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:36401;
CC         Evidence={ECO:0000250|UniProtKB:Q8VCH6};
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC   -!- PATHWAY: Steroid biosynthesis; cholesterol biosynthesis.
CC       {ECO:0000269|PubMed:11519011, ECO:0000269|PubMed:21671375}.
CC   -!- SUBUNIT: Interacts with DHCR7; this interaction regulates DHCR7
CC       activity. {ECO:0000269|PubMed:25637936}.
CC   -!- INTERACTION:
CC       Q15392; O00264: PGRMC1; NbExp=2; IntAct=EBI-5457558, EBI-1045534;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:11007892, ECO:0000269|PubMed:22010141}; Single-pass
CC       membrane protein {ECO:0000255}. Golgi apparatus membrane
CC       {ECO:0000269|PubMed:11007892}; Single-pass membrane protein
CC       {ECO:0000255}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q15392-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q15392-2; Sequence=VSP_056479;
CC   -!- TISSUE SPECIFICITY: Highly expressed in brain and adrenal gland with
CC       moderate expression in liver, lung, spleen, prostate and spinal cord.
CC       Low expression in heart, uterus and prostate. Undetectable in blood
CC       cells. In the brain, strongly expressed in cortical regions, substantia
CC       nigra, caudate nucleus, hippocampus, medulla oblongata and pons. In
CC       brains affected by Alzheimer disease, expression in the inferior
CC       temporal lobe is substantially lower than in the frontal cortex.
CC       {ECO:0000269|PubMed:11007892, ECO:0000269|PubMed:11519011}.
CC   -!- DISEASE: Desmosterolosis (DESMOS) [MIM:602398]: Rare autosomal
CC       recessive disorder characterized by multiple congenital anomalies and
CC       elevated levels of the cholesterol precursor desmosterol in plasma,
CC       tissue, and cultured cells. {ECO:0000269|PubMed:11519011,
CC       ECO:0000269|PubMed:21671375}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the FAD-binding oxidoreductase/transferase type
CC       4 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA02806.3; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AF261758; AAG17288.1; -; mRNA.
DR   EMBL; AF398342; AAL15644.1; -; Genomic_DNA.
DR   EMBL; AF398336; AAL15644.1; JOINED; Genomic_DNA.
DR   EMBL; AF398337; AAL15644.1; JOINED; Genomic_DNA.
DR   EMBL; AF398338; AAL15644.1; JOINED; Genomic_DNA.
DR   EMBL; AF398339; AAL15644.1; JOINED; Genomic_DNA.
DR   EMBL; AF398340; AAL15644.1; JOINED; Genomic_DNA.
DR   EMBL; AF398341; AAL15644.1; JOINED; Genomic_DNA.
DR   EMBL; D13643; BAA02806.3; ALT_INIT; mRNA.
DR   EMBL; AK302774; BAH13803.1; -; mRNA.
DR   EMBL; AC096536; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471059; EAX06663.1; -; Genomic_DNA.
DR   EMBL; CH471059; EAX06664.1; -; Genomic_DNA.
DR   EMBL; BC004375; AAH04375.1; -; mRNA.
DR   EMBL; BC011669; AAH11669.1; -; mRNA.
DR   CCDS; CCDS600.1; -. [Q15392-1]
DR   RefSeq; NP_055577.1; NM_014762.4. [Q15392-1]
DR   AlphaFoldDB; Q15392; -.
DR   SMR; Q15392; -.
DR   BioGRID; 108064; 217.
DR   CORUM; Q15392; -.
DR   FunCoup; Q15392; 1145.
DR   IntAct; Q15392; 154.
DR   MINT; Q15392; -.
DR   STRING; 9606.ENSP00000360316; -.
DR   BindingDB; Q15392; -.
DR   ChEMBL; CHEMBL2331059; -.
DR   DrugCentral; Q15392; -.
DR   SwissLipids; SLP:000001223; -.
DR   GlyGen; Q15392; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q15392; -.
DR   MetOSite; Q15392; -.
DR   PhosphoSitePlus; Q15392; -.
DR   SwissPalm; Q15392; -.
DR   BioMuta; DHCR24; -.
DR   DMDM; 20141421; -.
DR   jPOST; Q15392; -.
DR   MassIVE; Q15392; -.
DR   PaxDb; 9606-ENSP00000360316; -.
DR   PeptideAtlas; Q15392; -.
DR   ProteomicsDB; 60562; -. [Q15392-1]
DR   ProteomicsDB; 6916; -.
DR   Pumba; Q15392; -.
DR   Antibodypedia; 33226; 239 antibodies from 30 providers.
DR   DNASU; 1718; -.
DR   Ensembl; ENST00000371269.9; ENSP00000360316.3; ENSG00000116133.14. [Q15392-1]
DR   Ensembl; ENST00000436604.2; ENSP00000416585.2; ENSG00000116133.14. [Q15392-1]
DR   GeneID; 1718; -.
DR   KEGG; hsa:1718; -.
DR   MANE-Select; ENST00000371269.9; ENSP00000360316.3; NM_014762.4; NP_055577.1.
DR   UCSC; uc001cyc.2; human. [Q15392-1]
DR   AGR; HGNC:2859; -.
DR   ClinPGx; PA27320; -.
DR   CTD; 1718; -.
DR   DisGeNET; 1718; -.
DR   GeneCards; DHCR24; -.
DR   HGNC; HGNC:2859; DHCR24.
DR   HPA; ENSG00000116133; Tissue enhanced (adrenal gland, liver).
DR   MalaCards; DHCR24; -.
DR   MIM; 602398; phenotype.
DR   MIM; 606418; gene.
DR   OpenTargets; ENSG00000116133; -.
DR   Orphanet; 35107; Desmosterolosis.
DR   VEuPathDB; HostDB:ENSG00000116133; -.
DR   eggNOG; KOG1262; Eukaryota.
DR   GeneTree; ENSGT00390000008338; -.
DR   InParanoid; Q15392; -.
DR   OrthoDB; 415825at2759; -.
DR   PAN-GO; Q15392; 4 GO annotations based on evolutionary models.
DR   PhylomeDB; Q15392; -.
DR   BRENDA; 1.3.1.72; 2681.
DR   PathwayCommons; Q15392; -.
DR   Reactome; R-HSA-191273; Cholesterol biosynthesis.
DR   Reactome; R-HSA-6807047; Cholesterol biosynthesis via desmosterol.
DR   Reactome; R-HSA-6807062; Cholesterol biosynthesis via lathosterol.
DR   SignaLink; Q15392; -.
DR   SIGNOR; Q15392; -.
DR   UniPathway; UPA00063; -.
DR   Agora; ENSG00000116133; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 1718; 22 hits in 1166 CRISPR screens.
DR   ChiTaRS; DHCR24; human.
DR   GeneWiki; 24-dehydrocholesterol_reductase; -.
DR   GenomeRNAi; 1718; -.
DR   Pharos; Q15392; Tchem.
DR   PRO; PR:Q15392; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; Q15392; protein.
DR   Bgee; ENSG00000116133; Expressed in adrenal tissue and 197 other cell types or tissues.
DR   ExpressionAtlas; Q15392; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0000246; F:Delta24(24-1) sterol reductase activity; IMP:UniProtKB.
DR   GO; GO:0050614; F:Delta24-sterol reductase activity; EXP:Reactome.
DR   GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR   GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR   GO; GO:0016628; F:oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor; IDA:MGI.
DR   GO; GO:0042605; F:peptide antigen binding; IPI:UniProtKB.
DR   GO; GO:0042987; P:amyloid precursor protein catabolic process; IEA:Ensembl.
DR   GO; GO:0006695; P:cholesterol biosynthetic process; IMP:MGI.
DR   GO; GO:0033489; P:cholesterol biosynthetic process via desmosterol; IMP:UniProtKB.
DR   GO; GO:0033490; P:cholesterol biosynthetic process via lathosterol; TAS:Reactome.
DR   GO; GO:0008104; P:intracellular protein localization; IEA:Ensembl.
DR   GO; GO:0030539; P:male genitalia development; IEA:Ensembl.
DR   GO; GO:0061024; P:membrane organization; IEA:Ensembl.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl.
DR   GO; GO:0031639; P:plasminogen activation; IEA:Ensembl.
DR   GO; GO:0007265; P:Ras protein signal transduction; IEA:Ensembl.
DR   GO; GO:0009725; P:response to hormone; IEA:Ensembl.
DR   GO; GO:0043588; P:skin development; ISS:UniProtKB.
DR   GO; GO:0008202; P:steroid metabolic process; IBA:GO_Central.
DR   GO; GO:0009888; P:tissue development; IMP:UniProtKB.
DR   FunFam; 3.30.465.10:FF:000032; Delta(24)-sterol reductase; 1.
DR   Gene3D; 3.30.465.10; -; 1.
DR   InterPro; IPR040165; Diminuto-like.
DR   InterPro; IPR016166; FAD-bd_PCMH.
DR   InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR   InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR   InterPro; IPR006094; Oxid_FAD_bind_N.
DR   PANTHER; PTHR10801; 24-DEHYDROCHOLESTEROL REDUCTASE; 1.
DR   PANTHER; PTHR10801:SF0; DELTA(24)-STEROL REDUCTASE; 1.
DR   Pfam; PF01565; FAD_binding_4; 1.
DR   SUPFAM; SSF56176; FAD-binding/transporter-associated domain-like; 1.
DR   PROSITE; PS51387; FAD_PCMH; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cholesterol biosynthesis; Cholesterol metabolism;
KW   Disease variant; Endoplasmic reticulum; FAD; Flavoprotein; Golgi apparatus;
KW   Lipid biosynthesis; Lipid metabolism; Membrane; NADP; Oxidoreductase;
KW   Proteomics identification; Reference proteome; Signal;
KW   Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW   Sterol metabolism; Transmembrane; Transmembrane helix.
FT   SIGNAL          1..22
FT                   /evidence="ECO:0000255"
FT   CHAIN           23..516
FT                   /note="Delta(24)-sterol reductase"
FT                   /id="PRO_0000007230"
FT   TOPO_DOM        23..31
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:22010141"
FT   TRANSMEM        32..52
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        53..516
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:22010141"
FT   DOMAIN          58..234
FT                   /note="FAD-binding PCMH-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT   BINDING         163..175
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000255"
FT   SITE            122..123
FT                   /note="Cleavage; by caspase"
FT                   /evidence="ECO:0000255"
FT   SITE            383..384
FT                   /note="Cleavage; by caspase"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         1..76
FT                   /note="MEPAVSLAVCALLFLLWVRLKGLEFVLIHQRWVFVCLFLLPLSLIFDIYYYV
FT                   RAWVVFKLSSAPRLHEQRVRDIQK -> MGAGEQNRQSAHCVQGICGYLEGDEEGEEGE
FT                   VRST (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_056479"
FT   VARIANT         94
FT                   /note="R -> H (in DESMOS; decreases production of
FT                   cholesterol from desmosterol; dbSNP:rs387906939)"
FT                   /evidence="ECO:0000269|PubMed:21671375"
FT                   /id="VAR_081889"
FT   VARIANT         191
FT                   /note="E -> K (in DESMOS; decreases production of
FT                   cholesterol from desmosterol; dbSNP:rs119475041)"
FT                   /evidence="ECO:0000269|PubMed:11519011"
FT                   /id="VAR_012732"
FT   VARIANT         294
FT                   /note="N -> T (in DESMOS; decreases production of
FT                   cholesterol from desmosterol; dbSNP:rs281797257)"
FT                   /evidence="ECO:0000269|PubMed:11519011"
FT                   /id="VAR_012733"
FT   VARIANT         306
FT                   /note="K -> N (in DESMOS; decreases production of
FT                   cholesterol from desmosterol; dbSNP:rs281797256)"
FT                   /evidence="ECO:0000269|PubMed:11519011"
FT                   /id="VAR_012734"
FT   VARIANT         471
FT                   /note="Y -> S (in DESMOS; complete loss of ability to
FT                   convert desmosterol to cholesterol; dbSNP:rs28939092)"
FT                   /evidence="ECO:0000269|PubMed:11519011,
FT                   ECO:0000269|PubMed:21671375"
FT                   /id="VAR_012735"
FT   VARIANT         480
FT                   /note="E -> K (in DESMOS; decreases production of
FT                   cholesterol from desmosterol; dbSNP:rs387906940)"
FT                   /evidence="ECO:0000269|PubMed:21671375"
FT                   /id="VAR_081890"
SQ   SEQUENCE   516 AA;  60101 MW;  F9A769446FE19E59 CRC64;
     MEPAVSLAVC ALLFLLWVRL KGLEFVLIHQ RWVFVCLFLL PLSLIFDIYY YVRAWVVFKL
     SSAPRLHEQR VRDIQKQVRE WKEQGSKTFM CTGRPGWLTV SLRVGKYKKT HKNIMINLMD
     ILEVDTKKQI VRVEPLVTMG QVTALLTSIG WTLPVLPELD DLTVGGLIMG TGIESSSHKY
     GLFQHICTAY ELVLADGSFV RCTPSENSDL FYAVPWSCGT LGFLVAAEIR IIPAKKYVKL
     RFEPVRGLEA ICAKFTHESQ RQENHFVEGL LYSLDEAVIM TGVMTDEAEP SKLNSIGNYY
     KPWFFKHVEN YLKTNREGLE YIPLRHYYHR HTRSIFWELQ DIIPFGNNPI FRYLFGWMVP
     PKISLLKLTQ GETLRKLYEQ HHVVQDMLVP MKCLQQALHT FQNDIHVYPI WLCPFILPSQ
     PGLVHPKGNE AELYIDIGAY GEPRVKHFEA RSCMRQLEKF VRSVHGFQML YADCYMNREE
     FWEMFDGSLY HKLREKLGCQ DAFPEVYDKI CKAARH
//
ID   DNM1L_HUMAN             Reviewed;         736 AA.
AC   O00429; A8K4X9; B4DGC9; B4DSU8; G8JLD5; J3KPI2; O14541; O60709; Q59GN9;
AC   Q7L6B3; Q8TBT7; Q9BWM1; Q9Y5J2;
DT   10-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT   06-FEB-2007, sequence version 2.
DT   28-JAN-2026, entry version 213.
DE   RecName: Full=Dynamin-1-like protein;
DE            EC=3.6.5.5 {ECO:0000269|PubMed:23977156, ECO:0000269|PubMed:9422767};
DE   AltName: Full=Dnm1p/Vps1p-like protein;
DE            Short=DVLP;
DE   AltName: Full=Dynamin family member proline-rich carboxyl-terminal domain less;
DE            Short=Dymple;
DE   AltName: Full=Dynamin-like protein;
DE   AltName: Full=Dynamin-like protein 4;
DE   AltName: Full=Dynamin-like protein IV;
DE            Short=HdynIV;
DE   AltName: Full=Dynamin-related protein 1;
GN   Name=DNM1L {ECO:0000312|HGNC:HGNC:2973}; Synonyms=DLP1, DRP1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND SUBCELLULAR LOCATION.
RC   TISSUE=Hepatoma;
RX   PubMed=9348079; DOI=10.1093/oxfordjournals.jbchem.a021784;
RA   Shin H.-W., Shinotsuka C., Torii S., Murakami K., Nakayama K.;
RT   "Identification and subcellular localization of a novel mammalian dynamin-
RT   related protein homologous to yeast Vps1p and Dnm1p.";
RL   J. Biochem. 122:525-530(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), VARIANT THR-71, TISSUE SPECIFICITY,
RP   INTERACTION WITH GSK3B, AND REGION.
RC   TISSUE=Liver;
RX   PubMed=9731200; DOI=10.1006/bbrc.1998.9253;
RA   Hong Y.-R., Chen C.-H., Cheng D.-S., Howng S.-L., Chow C.-C.;
RT   "Human dynamin-like protein interacts with the glycogen synthase kinase
RT   3beta.";
RL   Biochem. Biophys. Res. Commun. 249:697-703(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT THR-71, TISSUE SPECIFICITY,
RP   SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-38, AND FUNCTION.
RC   TISSUE=Brain;
RX   PubMed=9570752; DOI=10.1242/jcs.111.10.1341;
RA   Imoto M., Tachibana I., Urrutia R.;
RT   "Identification and functional characterization of a novel human protein
RT   highly related to the yeast dynamin-like GTPase Vps1p.";
RL   J. Cell Sci. 111:1341-1349(1998).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3; 4 AND 5), VARIANT THR-71, TISSUE
RP   SPECIFICITY, AND INTERACTION WITH GSK3B.
RC   TISSUE=Brain;
RX   PubMed=10749171; DOI=10.1089/104454900314573;
RA   Chen C.-H., Howng S.-L., Hwang S.-L., Chou C.-K., Liao C.-H., Hong Y.-R.;
RT   "Differential expression of four human dynamin-like protein variants in
RT   brain tumors.";
RL   DNA Cell Biol. 19:189-194(2000).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3; 6 AND 7).
RC   TISSUE=Amygdala, and Brain;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 8).
RC   TISSUE=Brain;
RA   Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA   Ohara O., Nagase T., Kikuno R.F.;
RT   "Homo sapiens protein coding cDNA.";
RL   Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16541075; DOI=10.1038/nature04569;
RA   Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA   Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA   Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA   Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA   Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA   Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA   Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA   Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA   Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA   Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA   Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA   Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA   Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA   Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA   Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA   Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA   Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA   David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA   D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA   Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA   Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA   Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA   LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA   Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA   Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA   Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA   Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA   Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA   Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA   Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA   Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA   Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA   Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA   Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA   Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA   Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA   Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA   Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA   Gibbs R.A.;
RT   "The finished DNA sequence of human chromosome 12.";
RL   Nature 440:346-351(2006).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP   [LARGE SCALE MRNA] OF 27-736 (ISOFORM 1).
RC   TISSUE=Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   MUTAGENESIS OF SER-39, TISSUE SPECIFICITY, CATALYTIC ACTIVITY, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=9422767; DOI=10.1074/jbc.273.2.1044;
RA   Kamimoto T., Nagai Y., Onogi H., Muro Y., Wakabayashi T., Hagiwara M.;
RT   "Dymple, a novel dynamin-like high molecular weight GTPase lacking a
RT   proline-rich carboxyl-terminal domain in mammalian cells.";
RL   J. Biol. Chem. 273:1044-1051(1998).
RN   [10]
RP   SUBCELLULAR LOCATION.
RX   PubMed=9472031; DOI=10.1083/jcb.140.4.779;
RA   Yoon Y., Pitts K.R., Dahan S., McNiven M.A.;
RT   "A novel dynamin-like protein associates with cytoplasmic vesicles and
RT   tubules of the endoplasmic reticulum in mammalian cells.";
RL   J. Cell Biol. 140:779-793(1998).
RN   [11]
RP   FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX   PubMed=9786947; DOI=10.1083/jcb.143.2.351;
RA   Smirnova E., Shurland D.-L., Ryazantsev S.N., van der Bliek A.M.;
RT   "A human dynamin-related protein controls the distribution of
RT   mitochondria.";
RL   J. Cell Biol. 143:351-358(1998).
RN   [12]
RP   OLIGOMERIZATION.
RX   PubMed=9915810; DOI=10.1074/jbc.274.5.2780;
RA   Shin H.-W., Takatsu H., Mukai H., Munekata E., Murakami K., Nakayama K.;
RT   "Intermolecular and interdomain interactions of a dynamin-related GTP-
RT   binding protein, Dnm1p/Vps1p-like protein.";
RL   J. Biol. Chem. 274:2780-2785(1999).
RN   [13]
RP   FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-38; VAL-41; THR-59 AND
RP   GLY-281, AND OLIGOMERIZATION.
RX   PubMed=11514614; DOI=10.1091/mbc.12.8.2245;
RA   Smirnova E., Griparic L., Shurland D.-L., van der Bliek A.M.;
RT   "Dynamin-related protein Drp1 is required for mitochondrial division in
RT   mammalian cells.";
RL   Mol. Biol. Cell 12:2245-2256(2001).
RN   [14]
RP   FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-38.
RX   PubMed=12499366; DOI=10.1074/jbc.m211761200;
RA   Koch A., Thiemann M., Grabenbauer M., Yoon Y., McNiven M.A., Schrader M.;
RT   "Dynamin-like protein 1 is involved in peroxisomal fission.";
RL   J. Biol. Chem. 278:8597-8605(2003).
RN   [15]
RP   FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF SER-39 AND THR-59.
RX   PubMed=12618434; DOI=10.1074/jbc.m212031200;
RA   Li X., Gould S.J.;
RT   "The dynamin-like GTPase DLP1 is essential for peroxisome division and is
RT   recruited to peroxisomes in part by PEX11.";
RL   J. Biol. Chem. 278:17012-17020(2003).
RN   [16]
RP   OLIGOMERIZATION, SUBCELLULAR LOCATION, DOMAIN, REGION, AND MUTAGENESIS OF
RP   LYS-38 AND LYS-679.
RX   PubMed=15208300; DOI=10.1074/jbc.m404105200;
RA   Zhu P.P., Patterson A., Stadler J., Seeburg D.P., Sheng M., Blackstone C.;
RT   "Intra- and intermolecular domain interactions of the C-terminal GTPase
RT   effector domain of the multimeric dynamin-like GTPase Drp1.";
RL   J. Biol. Chem. 279:35967-35974(2004).
RN   [17]
RP   UBIQUITINATION BY MARCHF5, AND INTERACTION WITH MARCHF5.
RX   PubMed=16874301; DOI=10.1038/sj.emboj.7601249;
RA   Yonashiro R., Ishido S., Kyo S., Fukuda T., Goto E., Matsuki Y.,
RA   Ohmura-Hoshino M., Sada K., Hotta H., Yamamura H., Inatome R., Yanagi S.;
RT   "A novel mitochondrial ubiquitin ligase plays a critical role in
RT   mitochondrial dynamics.";
RL   EMBO J. 25:3618-3626(2006).
RN   [18]
RP   UBIQUITINATION BY MARCHF5, AND INTERACTION WITH MARCHF5.
RX   PubMed=16936636; DOI=10.1038/sj.embor.7400790;
RA   Nakamura N., Kimura Y., Tokuda M., Honda S., Hirose S.;
RT   "MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change
RT   mitochondrial morphology.";
RL   EMBO Rep. 7:1019-1022(2006).
RN   [19]
RP   FUNCTION.
RX   PubMed=17015472; DOI=10.1128/mcb.02282-05;
RA   Parone P.A., James D.I., Da Cruz S., Mattenberger Y., Donze O., Barja F.,
RA   Martinou J.C.;
RT   "Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-
RT   dependent apoptosis.";
RL   Mol. Cell. Biol. 26:7397-7408(2006).
RN   [20]
RP   PHOSPHORYLATION, AND FUNCTION.
RX   PubMed=17301055; DOI=10.1074/jbc.m607279200;
RA   Taguchi N., Ishihara N., Jofuku A., Oka T., Mihara K.;
RT   "Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in
RT   mitochondrial fission.";
RL   J. Biol. Chem. 282:11521-11529(2007).
RN   [21]
RP   PHOSPHORYLATION AT SER-637, FUNCTION, SUBUNIT, AND MUTAGENESIS OF SER-637.
RX   PubMed=17553808; DOI=10.1074/jbc.c700083200;
RA   Chang C.R., Blackstone C.;
RT   "Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its
RT   GTPase activity and mitochondrial morphology.";
RL   J. Biol. Chem. 282:21583-21587(2007).
RN   [22]
RP   SUBCELLULAR LOCATION.
RX   PubMed=17606867; DOI=10.1083/jcb.200611064;
RA   Karbowski M., Neutzner A., Youle R.J.;
RT   "The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1
RT   dependent mitochondrial division.";
RL   J. Cell Biol. 178:71-84(2007).
RN   [23]
RP   FUNCTION, VARIANT EMPF1 ASP-395, AND CHARACTERIZATION OF VARIANT EMPF1
RP   ASP-395.
RX   PubMed=17460227; DOI=10.1056/nejmoa064436;
RA   Waterham H.R., Koster J., van Roermund C.W., Mooyer P.A., Wanders R.J.,
RA   Leonard J.V.;
RT   "A lethal defect of mitochondrial and peroxisomal fission.";
RL   N. Engl. J. Med. 356:1736-1741(2007).
RN   [24]
RP   PHOSPHORYLATION AT SER-637, FUNCTION, INTERACTION WITH FIS1, AND
RP   MUTAGENESIS OF SER-637.
RX   PubMed=18695047; DOI=10.1083/jcb.200802164;
RA   Han X.J., Lu Y.F., Li S.A., Kaitsuka T., Sato Y., Tomizawa K., Nairn A.C.,
RA   Takei K., Matsui H., Matsushita M.;
RT   "CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial
RT   morphology.";
RL   J. Cell Biol. 182:573-585(2008).
RN   [25]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Platelet;
RX   PubMed=18088087; DOI=10.1021/pr0704130;
RA   Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA   Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT   "Phosphoproteome of resting human platelets.";
RL   J. Proteome Res. 7:526-534(2008).
RN   [26]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-548; SER-607 AND SER-616, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [27]
RP   PHOSPHORYLATION AT SER-616 AND SER-637, INTERACTION WITH PPP3CA,
RP   DEPHOSPHORYLATION, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP   SER-616 AND SER-637.
RX   PubMed=18838687; DOI=10.1073/pnas.0808249105;
RA   Cereghetti G.M., Stangherlin A., Martins de Brito O., Chang C.R.,
RA   Blackstone C., Bernardi P., Scorrano L.;
RT   "Dephosphorylation by calcineurin regulates translocation of Drp1 to
RT   mitochondria.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:15803-15808(2008).
RN   [28]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [29]
RP   SUMOYLATION BY MUL1.
RX   PubMed=19407830; DOI=10.1038/embor.2009.86;
RA   Braschi E., Zunino R., McBride H.M.;
RT   "MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial
RT   fission.";
RL   EMBO Rep. 10:748-754(2009).
RN   [30]
RP   SUMOYLATION AT LYS-532; LYS-535; LYS-558; LYS-568; LYS-594; LYS-597;
RP   LYS-606 AND LYS-608, INTERACTION WITH UBE2I, FUNCTION, AND MUTAGENESIS OF
RP   LYS-38; LYS-532; LYS-535; LYS-558; LYS-568; LYS-594; LYS-597; LYS-606 AND
RP   LYS-608.
RX   PubMed=19638400; DOI=10.1096/fj.09-136630;
RA   Figueroa-Romero C., Iniguez-Lluhi J.A., Stadler J., Chang C.R., Arnoult D.,
RA   Keller P.J., Hong Y., Blackstone C., Feldman E.L.;
RT   "SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple
RT   nonconsensus sites within the B domain and is linked to its activity
RT   cycle.";
RL   FASEB J. 23:3917-3927(2009).
RN   [31]
RP   SUMOYLATION, DESUMOYLATION, AND FUNCTION.
RX   PubMed=19411255; DOI=10.1074/jbc.m901902200;
RA   Zunino R., Braschi E., Xu L., McBride H.M.;
RT   "Translocation of SenP5 from the nucleoli to the mitochondria modulates
RT   DRP1-dependent fission during mitosis.";
RL   J. Biol. Chem. 284:17783-17795(2009).
RN   [32]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [33]
RP   S-NITROSYLATION AT CYS-644, FUNCTION, ASSOCIATION WITH ALZHEIMER DISEASE,
RP   AND MUTAGENESIS OF CYS-300; CYS-345; CYS-361; CYS-367; CYS-431; CYS-446;
RP   CYS-470; CYS-505 AND CYS-644.
RX   PubMed=19342591; DOI=10.1126/science.1171091;
RA   Cho D.H., Nakamura T., Fang J., Cieplak P., Godzik A., Gu Z., Lipton S.A.;
RT   "S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial
RT   fission and neuronal injury.";
RL   Science 324:102-105(2009).
RN   [34]
RP   POSSIBLE FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=20688057; DOI=10.1016/j.yexcr.2010.07.020;
RA   Bonekamp N.A., Vormund K., Jacob R., Schrader M.;
RT   "Dynamin-like protein 1 at the Golgi complex: A novel component of the
RT   sorting/targeting machinery en route to the plasma membrane.";
RL   Exp. Cell Res. 316:3454-3467(2010).
RN   [35]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [36]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [37]
RP   INTERACTION WITH MIEF2 AND MIEF1.
RX   PubMed=21508961; DOI=10.1038/embor.2011.54;
RA   Palmer C.S., Osellame L.D., Laine D., Koutsopoulos O.S., Frazier A.E.,
RA   Ryan M.T.;
RT   "MiD49 and MiD51, new components of the mitochondrial fission machinery.";
RL   EMBO Rep. 12:565-573(2011).
RN   [38]
RP   INTERACTION WITH MIEF1.
RX   PubMed=21701560; DOI=10.1038/emboj.2011.198;
RA   Zhao J., Liu T., Jin S., Wang X., Qu M., Uhlen P., Tomilin N.,
RA   Shupliakov O., Lendahl U., Nister M.;
RT   "Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes
RT   mitochondrial fusion rather than fission.";
RL   EMBO J. 30:2762-2778(2011).
RN   [39]
RP   INTERACTION WITH RALBP1, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT
RP   SER-616 BY CDK1.
RX   PubMed=21822277; DOI=10.1038/ncb2310;
RA   Kashatus D.F., Lim K.H., Brady D.C., Pershing N.L., Cox A.D., Counter C.M.;
RT   "RALA and RALBP1 regulate mitochondrial fission at mitosis.";
RL   Nat. Cell Biol. 13:1108-1115(2011).
RN   [40]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA   Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA   Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT   "System-wide temporal characterization of the proteome and phosphoproteome
RT   of human embryonic stem cell differentiation.";
RL   Sci. Signal. 4:RS3-RS3(2011).
RN   [41]
RP   FUNCTION, INTERACTION WITH PGAM5, AND SUBCELLULAR LOCATION.
RX   PubMed=22265414; DOI=10.1016/j.cell.2011.11.030;
RA   Wang Z., Jiang H., Chen S., Du F., Wang X.;
RT   "The mitochondrial phosphatase PGAM5 functions at the convergence point of
RT   multiple necrotic death pathways.";
RL   Cell 148:228-243(2012).
RN   [42]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA   Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA   Giglione C.;
RT   "Comparative large-scale characterisation of plant vs. mammal proteins
RT   reveals similar and idiosyncratic N-alpha acetylation features.";
RL   Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN   [43]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=23921378; DOI=10.1074/jbc.m113.479873;
RA   Palmer C.S., Elgass K.D., Parton R.G., Osellame L.D., Stojanovski D.,
RA   Ryan M.T.;
RT   "MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment
RT   and are specific for mitochondrial fission.";
RL   J. Biol. Chem. 288:27584-27593(2013).
RN   [44]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-529 AND SER-616, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [45]
RP   FUNCTION, INTERACTION WITH MIEF2 AND MIEF1, PHOSPHORYLATION AT SER-637, AND
RP   MUTAGENESIS OF SER-637.
RX   PubMed=23283981; DOI=10.1091/mbc.e12-10-0721;
RA   Loson O.C., Song Z., Chen H., Chan D.C.;
RT   "Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial
RT   fission.";
RL   Mol. Biol. Cell 24:659-667(2013).
RN   [46]
RP   INTERACTION WITH BCL2L1, AND FUNCTION.
RX   PubMed=23792689; DOI=10.1038/ncb2791;
RA   Li H., Alavian K.N., Lazrove E., Mehta N., Jones A., Zhang P.,
RA   Licznerski P., Graham M., Uo T., Guo J., Rahner C., Duman R.S.,
RA   Morrison R.S., Jonas E.A.;
RT   "A Bcl-xL-Drp1 complex regulates synaptic vesicle membrane dynamics during
RT   endocytosis.";
RL   Nat. Cell Biol. 15:773-785(2013).
RN   [47]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [48]
RP   INTERACTION WITH FIS1; CANX; BCAP31.
RX   PubMed=24196833; DOI=10.1091/mbc.e13-09-0525;
RA   Shen Q., Yamano K., Head B.P., Kawajiri S., Cheung J.T., Wang C., Cho J.H.,
RA   Hattori N., Youle R.J., van der Bliek A.M.;
RT   "Mutations in Fis1 disrupt orderly disposal of defective mitochondria.";
RL   Mol. Biol. Cell 25:145-159(2014).
RN   [49]
RP   SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-616 AND SER-637.
RX   PubMed=26122121; DOI=10.1093/brain/awv182;
RA   Shahni R., Cale C.M., Anderson G., Osellame L.D., Hambleton S.,
RA   Jacques T.S., Wedatilake Y., Taanman J.W., Chan E., Qasim W., Plagnol V.,
RA   Chalasani A., Duchen M.R., Gilmour K.C., Rahman S.;
RT   "Signal transducer and activator of transcription 2 deficiency is a novel
RT   disorder of mitochondrial fission.";
RL   Brain 138:2834-2846(2015).
RN   [50]
RP   FUNCTION, INTERACTION WITH MIEF2, AND SUBUNIT.
RX   PubMed=23530241; DOI=10.1073/pnas.1300855110;
RA   Koirala S., Guo Q., Kalia R., Bui H.T., Eckert D.M., Frost A., Shaw J.M.;
RT   "Interchangeable adaptors regulate mitochondrial dynamin assembly for
RT   membrane scission.";
RL   Proc. Natl. Acad. Sci. U.S.A. 110:E1342-E1351(2013).
RN   [51]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FUNDC1.
RX   PubMed=27145933; DOI=10.15252/embj.201593102;
RA   Wu W., Lin C., Wu K., Jiang L., Wang X., Li W., Zhuang H., Zhang X.,
RA   Chen H., Li S., Yang Y., Lu Y., Wang J., Zhu R., Zhang L., Sui S., Tan N.,
RA   Zhao B., Zhang J., Li L., Feng D.;
RT   "FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact
RT   site under hypoxic conditions.";
RL   EMBO J. 35:1368-1384(2016).
RN   [52]
RP   FUNCTION, AND PHOSPHORYLATION AT SER-637.
RX   PubMed=29478834; DOI=10.1016/j.cmet.2018.01.011;
RA   Schmitt K., Grimm A., Dallmann R., Oettinghaus B., Restelli L.M.,
RA   Witzig M., Ishihara N., Mihara K., Ripperger J.A., Albrecht U., Frank S.,
RA   Brown S.A., Eckert A.;
RT   "Circadian control of DRP1 activity regulates mitochondrial dynamics and
RT   bioenergetics.";
RL   Cell Metab. 27:657-666(2018).
RN   [53]
RP   FUNCTION, PHOSPHORYLATION AT SER-616, AND MUTAGENESIS OF SER-616.
RX   PubMed=32484300; DOI=10.15252/embr.201948686;
RA   Han H., Tan J., Wang R., Wan H., He Y., Yan X., Guo J., Gao Q., Li J.,
RA   Shang S., Chen F., Tian R., Liu W., Liao L., Tang B., Zhang Z.;
RT   "PINK1 phosphorylates Drp1S616 to regulate mitophagy-independent
RT   mitochondrial dynamics.";
RL   EMBO Rep. 21:48686-48686(2020).
RN   [54]
RP   FUNCTION, DEPHOSPHORYLATION BY PGAM5, MUTAGENESIS OF LYS-38 AND SER-637,
RP   AND PHOSPHORYLATION AT SER-637.
RX   PubMed=32439975; DOI=10.1038/s41467-020-16312-7;
RA   Yu B., Ma J., Li J., Wang D., Wang Z., Wang S.;
RT   "Mitochondrial phosphatase PGAM5 modulates cellular senescence by
RT   regulating mitochondrial dynamics.";
RL   Nat. Commun. 11:2549-2549(2020).
RN   [55]
RP   FUNCTION, AND PHOSPHORYLATION.
RX   PubMed=33850055; DOI=10.1126/scisignal.abc7931;
RA   Huang S., Li Z., Wu Z., Liu C., Yu M., Wen M., Zhang L., Wang X.;
RT   "DDAH2 suppresses RLR-MAVS-mediated innate antiviral immunity by
RT   stimulating nitric oxide-activated, Drp1-induced mitochondrial fission.";
RL   Sci. Signal. 14:0-0(2021).
RN   [56]
RP   X-RAY CRYSTALLOGRAPHY (3.48 ANGSTROMS), FUNCTION, SUBUNIT, SUBCELLULAR
RP   LOCATION, MUTAGENESIS OF 401-GLY--PRO-404; GLU-490 AND LYS-668,
RP   LIPID-BINDING, AND REGION.
RX   PubMed=23584531; DOI=10.1038/emboj.2013.74;
RA   Frohlich C., Grabiger S., Schwefel D., Faelber K., Rosenbaum E., Mears J.,
RA   Rocks O., Daumke O.;
RT   "Structural insights into oligomerization and mitochondrial remodelling of
RT   dynamin 1-like protein.";
RL   EMBO J. 32:1280-1292(2013).
RN   [57]
RP   X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1-327 AND 711-736 IN COMPLEX WITH
RP   GTP ANALOGS, CATALYTIC ACTIVITY, MUTAGENESIS OF GLN-34; LYS-38; SER-39;
RP   THR-59; ASP-146; GLY-149; LYS-216 AND ASP-218, ACTIVITY REGULATION, AND
RP   SUBUNIT.
RX   PubMed=23977156; DOI=10.1371/journal.pone.0071835;
RA   Wenger J., Klinglmayr E., Frohlich C., Eibl C., Gimeno A., Hessenberger M.,
RA   Puehringer S., Daumke O., Goettig P.;
RT   "Functional mapping of human dynamin-1-like GTPase domain based on x-ray
RT   structure analyses.";
RL   PLoS ONE 8:E71835-E71835(2013).
RN   [58] {ECO:0007744|PDB:5WP9}
RP   STRUCTURE BY ELECTRON MICROSCOPY (4.22 ANGSTROMS) (ISOFORM 2) IN COMPLEX
RP   WITH MIEF2, MUTAGENESIS OF ASP-190; ASP-221 AND SER-637, AND
RP   CHARACTERIZATION OF VARIANT EMPF1 ASP-362.
RX   PubMed=29899447; DOI=10.1038/s41586-018-0211-2;
RA   Kalia R., Wang R.Y., Yusuf A., Thomas P.V., Agard D.A., Shaw J.M.,
RA   Frost A.;
RT   "Structural basis of mitochondrial receptor binding and constriction by
RT   DRP1.";
RL   Nature 558:401-405(2018).
RN   [59]
RP   VARIANT EMPF1 ASP-362, AND CHARACTERIZATION OF VARIANT EMPF1 ASP-362.
RX   PubMed=26604000; DOI=10.1038/ejhg.2015.243;
RG   Care4Rare Consortium;
RA   Vanstone J.R., Smith A.M., McBride S., Naas T., Holcik M., Antoun G.,
RA   Harper M.E., Michaud J., Sell E., Chakraborty P., Tetreault M.,
RA   Majewski J., Baird S., Boycott K.M., Dyment D.A., MacKenzie A., Lines M.A.;
RT   "DNM1L-related mitochondrial fission defect presenting as refractory
RT   epilepsy.";
RL   Eur. J. Hum. Genet. 24:1084-1088(2016).
RN   [60]
RP   VARIANT EMPF1 CYS-403, CHARACTERIZATION OF VARIANTS EMPF1 ASP-395 AND
RP   CYS-403, FUNCTION, SUBUNIT, AND SUBCELLULAR LOCATION.
RX   PubMed=27145208; DOI=10.1002/ajmg.a.37721;
RA   Fahrner J.A., Liu R., Perry M.S., Klein J., Chan D.C.;
RT   "A novel de novo dominant negative mutation in DNM1L impairs mitochondrial
RT   fission and presents as childhood epileptic encephalopathy.";
RL   Am. J. Med. Genet. A 170:2002-2011(2016).
RN   [61]
RP   VARIANT EMPF1 SER-362, CHARACTERIZATION OF VARIANT EMPF1 SER-362, AND
RP   FUNCTION.
RX   PubMed=26992161; DOI=10.1002/ajmg.a.37624;
RA   Sheffer R., Douiev L., Edvardson S., Shaag A., Tamimi K., Soiferman D.,
RA   Meiner V., Saada A.;
RT   "Postnatal microcephaly and pain insensitivity due to a de novo
RT   heterozygous DNM1L mutation causing impaired mitochondrial fission and
RT   function.";
RL   Am. J. Med. Genet. A 170:1603-1607(2016).
RN   [62]
RP   VARIANT EMPF1 SER-406, CHARACTERIZATION OF VARIANT EMPF1 SER-406, AND
RP   FUNCTION.
RX   PubMed=27301544; DOI=10.1111/cge.12805;
RA   Zaha K., Matsumoto H., Itoh M., Saitsu H., Kato K., Kato M., Ogata S.,
RA   Murayama K., Kishita Y., Mizuno Y., Kohda M., Nishino I., Ohtake A.,
RA   Okazaki Y., Matsumoto N., Nonoyama S.;
RT   "DNM1L-related encephalopathy in infancy with Leigh syndrome-like phenotype
RT   and suppression-burst.";
RL   Clin. Genet. 90:472-474(2016).
RN   [63]
RP   VARIANT EMPF1 GLY-36, CHARACTERIZATION OF VARIANT EMPF1 GLY-36, AND
RP   FUNCTION.
RX   PubMed=27328748; DOI=10.1002/humu.23033;
RA   Nasca A., Legati A., Baruffini E., Nolli C., Moroni I., Ardissone A.,
RA   Goffrini P., Ghezzi D.;
RT   "Biallelic Mutations in DNM1L are Associated with a Slowly Progressive
RT   Infantile Encephalopathy.";
RL   Hum. Mutat. 37:898-903(2016).
RN   [64]
RP   INVOLVEMENT IN OPA5, VARIANTS OPA5 ALA-2 AND GLU-192, CHARACTERIZATION OF
RP   VARIANTS OPA5 ALA-2 AND GLU-192, AND SUBCELLULAR LOCATION.
RX   PubMed=28969390; DOI=10.1093/brain/awx219;
RA   Gerber S., Charif M., Chevrollier A., Chaumette T., Angebault C.,
RA   Kane M.S., Paris A., Alban J., Quiles M., Delettre C., Bonneau D.,
RA   Procaccio V., Amati-Bonneau P., Reynier P., Leruez S., Calmon R.,
RA   Boddaert N., Funalot B., Rio M., Bouccara D., Meunier I., Sesaki H.,
RA   Kaplan J., Hamel C.P., Rozet J.M., Lenaers G.;
RT   "Mutations in DNM1L, as in OPA1, result indominant optic atrophy despite
RT   opposite effectson mitochondrial fusion and fission.";
RL   Brain 140:2586-2596(2017).
CC   -!- FUNCTION: Functions in mitochondrial and peroxisomal division
CC       (PubMed:11514614, PubMed:12499366, PubMed:17301055, PubMed:17460227,
CC       PubMed:17553808, PubMed:18695047, PubMed:18838687, PubMed:19342591,
CC       PubMed:19411255, PubMed:19638400, PubMed:23283981, PubMed:23530241,
CC       PubMed:23921378, PubMed:26992161, PubMed:27145208, PubMed:27145933,
CC       PubMed:27301544, PubMed:27328748, PubMed:29478834, PubMed:32439975,
CC       PubMed:32484300, PubMed:9570752, PubMed:9786947). Mediates membrane
CC       fission through oligomerization into membrane-associated tubular
CC       structures that wrap around the scission site to constrict and sever
CC       the mitochondrial membrane through a GTP hydrolysis-dependent mechanism
CC       (PubMed:23530241, PubMed:23584531, PubMed:33850055). The specific
CC       recruitment at scission sites is mediated by membrane receptors like
CC       MFF, MIEF1 and MIEF2 for mitochondrial membranes (PubMed:23283981,
CC       PubMed:23921378, PubMed:29899447). While the recruitment by the
CC       membrane receptors is GTP-dependent, the following hydrolysis of GTP
CC       induces the dissociation from the receptors and allows DNM1L filaments
CC       to curl into closed rings that are probably sufficient to sever a
CC       double membrane (PubMed:29899447). Acts downstream of PINK1 to promote
CC       mitochondrial fission in a PRKN-dependent manner (PubMed:32484300).
CC       Plays an important role in mitochondrial fission during mitosis
CC       (PubMed:19411255, PubMed:26992161, PubMed:27301544, PubMed:27328748).
CC       Through its function in mitochondrial division, ensures the survival of
CC       at least some types of postmitotic neurons, including Purkinje cells,
CC       by suppressing oxidative damage (By similarity). Required for normal
CC       brain development, including that of cerebellum (PubMed:17460227,
CC       PubMed:26992161, PubMed:27145208, PubMed:27301544, PubMed:27328748).
CC       Facilitates developmentally regulated apoptosis during neural tube
CC       formation (By similarity). Required for a normal rate of cytochrome c
CC       release and caspase activation during apoptosis; this requirement may
CC       depend upon the cell type and the physiological apoptotic cues (By
CC       similarity). Required for formation of endocytic vesicles
CC       (PubMed:20688057, PubMed:23792689, PubMed:9570752). Proposed to
CC       regulate synaptic vesicle membrane dynamics through association with
CC       BCL2L1 isoform Bcl-X(L) which stimulates its GTPase activity in
CC       synaptic vesicles; the function may require its recruitment by MFF to
CC       clathrin-containing vesicles (PubMed:17015472, PubMed:23792689).
CC       Required for programmed necrosis execution (PubMed:22265414). Rhythmic
CC       control of its activity following phosphorylation at Ser-637 is
CC       essential for the circadian control of mitochondrial ATP production
CC       (PubMed:29478834). {ECO:0000250|UniProtKB:Q8K1M6,
CC       ECO:0000269|PubMed:11514614, ECO:0000269|PubMed:12499366,
CC       ECO:0000269|PubMed:17015472, ECO:0000269|PubMed:17301055,
CC       ECO:0000269|PubMed:17460227, ECO:0000269|PubMed:17553808,
CC       ECO:0000269|PubMed:18695047, ECO:0000269|PubMed:18838687,
CC       ECO:0000269|PubMed:19342591, ECO:0000269|PubMed:19411255,
CC       ECO:0000269|PubMed:19638400, ECO:0000269|PubMed:20688057,
CC       ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:23283981,
CC       ECO:0000269|PubMed:23530241, ECO:0000269|PubMed:23584531,
CC       ECO:0000269|PubMed:23792689, ECO:0000269|PubMed:23921378,
CC       ECO:0000269|PubMed:26992161, ECO:0000269|PubMed:27145208,
CC       ECO:0000269|PubMed:27145933, ECO:0000269|PubMed:27301544,
CC       ECO:0000269|PubMed:27328748, ECO:0000269|PubMed:29478834,
CC       ECO:0000269|PubMed:29899447, ECO:0000269|PubMed:32439975,
CC       ECO:0000269|PubMed:32484300, ECO:0000269|PubMed:33850055,
CC       ECO:0000269|PubMed:9570752, ECO:0000269|PubMed:9786947}.
CC   -!- FUNCTION: [Isoform 1]: Inhibits peroxisomal division when
CC       overexpressed. {ECO:0000269|PubMed:12618434}.
CC   -!- FUNCTION: [Isoform 4]: Inhibits peroxisomal division when
CC       overexpressed. {ECO:0000269|PubMed:12618434}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565,
CC         ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; EC=3.6.5.5;
CC         Evidence={ECO:0000269|PubMed:23977156, ECO:0000269|PubMed:9422767};
CC   -!- ACTIVITY REGULATION: GTPase activity is increased by binding to
CC       phospholipid membranes. {ECO:0000269|PubMed:23977156}.
CC   -!- SUBUNIT: Homotetramer; dimerizes through the N-terminal GTP-middle
CC       region of one molecule binding to the GED domain of another DNM1L
CC       molecule (PubMed:17553808, PubMed:23530241, PubMed:23584531,
CC       PubMed:23977156). Oligomerizes in a GTP-dependent manner to form
CC       membrane-associated tubules with a spiral pattern (PubMed:23584531).
CC       Interacts with GSK3B and MARCHF5 (PubMed:10749171, PubMed:16874301,
CC       PubMed:16936636, PubMed:9731200). Interacts (via the GTPase and B
CC       domains) with UBE2I; the interaction promotes sumoylation of DNM1L,
CC       mainly in its B domain (PubMed:19638400). Interacts with PPP3CA; the
CC       interaction dephosphorylates DNM1L and regulates its transition to
CC       mitochondria (PubMed:18838687). Interacts with BCL2L1 isoform BCL-X(L)
CC       and CLTA; DNM1L and BCL2L1 isoform BCL-X(L) may form a complex in
CC       synaptic vesicles that also contains clathrin and MFF
CC       (PubMed:23792689). Interacts with MFF; the interaction is inhibited by
CC       C11orf65/MFI (By similarity). Interacts with FIS1; may form part of a
CC       larger protein complex at the endoplasmic reticulum-mitochondrial
CC       interface during mitochondrial fission (PubMed:18695047,
CC       PubMed:24196833). Interacts with CANX (PubMed:24196833). Interacts with
CC       BCAP31 (PubMed:24196833). Interacts with MIEF2 and MIEF1; GTP-
CC       dependent, regulates GTP hydrolysis and DNM1L oligomerization
CC       (PubMed:21508961). Interacts with PGAM5; this interaction leads to
CC       dephosphorylation at Ser-656 and activation of GTPase activity and
CC       eventually to mitochondria fragmentation (PubMed:22265414). Interacts
CC       with RALBP1; during mitosis, recruits DNM1L to the mitochondrion and
CC       mediates its activation by the mitotic kinase cyclin B-CDK1
CC       (PubMed:21822277). Interacts with FUNDC1; this interaction recruits
CC       DNM1L/DRP1 at ER-mitochondria contact sites (PubMed:27145933).
CC       {ECO:0000250|UniProtKB:Q8K1M6, ECO:0000269|PubMed:10749171,
CC       ECO:0000269|PubMed:16874301, ECO:0000269|PubMed:16936636,
CC       ECO:0000269|PubMed:17553808, ECO:0000269|PubMed:18695047,
CC       ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:19638400,
CC       ECO:0000269|PubMed:21508961, ECO:0000269|PubMed:21701560,
CC       ECO:0000269|PubMed:21822277, ECO:0000269|PubMed:22265414,
CC       ECO:0000269|PubMed:23283981, ECO:0000269|PubMed:23530241,
CC       ECO:0000269|PubMed:23584531, ECO:0000269|PubMed:23792689,
CC       ECO:0000269|PubMed:23977156, ECO:0000269|PubMed:27145208,
CC       ECO:0000269|PubMed:27145933, ECO:0000269|PubMed:9731200}.
CC   -!- INTERACTION:
CC       O00429; Q9NVI7: ATAD3A; NbExp=4; IntAct=EBI-724571, EBI-352007;
CC       O00429; Q9NVI7-2: ATAD3A; NbExp=5; IntAct=EBI-724571, EBI-5456381;
CC       O00429; O00429: DNM1L; NbExp=2; IntAct=EBI-724571, EBI-724571;
CC       O00429; P03372: ESR1; NbExp=2; IntAct=EBI-724571, EBI-78473;
CC       O00429; Q9Y3D6: FIS1; NbExp=2; IntAct=EBI-724571, EBI-3385283;
CC       O00429; Q5S007: LRRK2; NbExp=16; IntAct=EBI-724571, EBI-5323863;
CC       O00429; Q9GZY8: MFF; NbExp=3; IntAct=EBI-724571, EBI-11420856;
CC       O00429; Q9NQG6: MIEF1; NbExp=11; IntAct=EBI-724571, EBI-740987;
CC       O00429; Q96C03: MIEF2; NbExp=5; IntAct=EBI-724571, EBI-750153;
CC       O00429; Q9Y512: SAMM50; NbExp=3; IntAct=EBI-724571, EBI-748409;
CC       O00429; Q14160: SCRIB; NbExp=2; IntAct=EBI-724571, EBI-357345;
CC       O00429-3; O00429-3: DNM1L; NbExp=8; IntAct=EBI-6896746, EBI-6896746;
CC       O00429-3; Q5S007: LRRK2; NbExp=2; IntAct=EBI-6896746, EBI-5323863;
CC       O00429-3; Q8N7X4: MAGEB6; NbExp=3; IntAct=EBI-6896746, EBI-6447163;
CC       O00429-3; O95563: MPC2; NbExp=3; IntAct=EBI-6896746, EBI-719403;
CC       O00429-3; P21980-2: TGM2; NbExp=3; IntAct=EBI-6896746, EBI-25842075;
CC       O00429-3; O43257: ZNHIT1; NbExp=3; IntAct=EBI-6896746, EBI-347522;
CC       O00429-4; O00429-4: DNM1L; NbExp=2; IntAct=EBI-4420450, EBI-4420450;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:11514614,
CC       ECO:0000269|PubMed:12618434, ECO:0000269|PubMed:9786947}. Golgi
CC       apparatus {ECO:0000269|PubMed:20688057, ECO:0000269|PubMed:9348079,
CC       ECO:0000269|PubMed:9570752}. Endomembrane system
CC       {ECO:0000269|PubMed:11514614, ECO:0000269|PubMed:9348079,
CC       ECO:0000269|PubMed:9472031, ECO:0000269|PubMed:9570752}; Peripheral
CC       membrane protein. Mitochondrion outer membrane
CC       {ECO:0000269|PubMed:26122121, ECO:0000269|PubMed:27145208,
CC       ECO:0000269|PubMed:27145933, ECO:0000269|PubMed:28969390}; Peripheral
CC       membrane protein. Peroxisome {ECO:0000269|PubMed:12499366,
CC       ECO:0000269|PubMed:12618434}. Membrane, clathrin-coated pit
CC       {ECO:0000250|UniProtKB:O35303}. Cytoplasmic vesicle, secretory vesicle,
CC       synaptic vesicle membrane {ECO:0000250|UniProtKB:O35303}. Note=Mainly
CC       cytosolic. Recruited by RALA and RALBP1 to mitochondrion during mitosis
CC       (PubMed:21822277). Translocated to the mitochondrial membrane through
CC       O-GlcNAcylation and interaction with FIS1. Colocalized with MARCHF5 at
CC       mitochondrial membrane (PubMed:17606867). Localizes to mitochondria at
CC       sites of division (PubMed:15208300). Localizes to mitochondria
CC       following necrosis induction. Recruited to the mitochondrial outer
CC       membrane by interaction with MIEF1. Mitochondrial recruitment is
CC       inhibited by C11orf65/MFI (By similarity). Associated with peroxisomal
CC       membranes, partly recruited there by PEX11B. May also be associated
CC       with endoplasmic reticulum tubules and cytoplasmic vesicles and found
CC       to be perinuclear (PubMed:9422767, PubMed:9570752). In some cell types,
CC       localizes to the Golgi complex (By similarity). Binds to phospholipid
CC       membranes (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q8K1M6,
CC       ECO:0000269|PubMed:15208300, ECO:0000269|PubMed:17606867,
CC       ECO:0000269|PubMed:21822277, ECO:0000269|PubMed:9422767,
CC       ECO:0000269|PubMed:9570752}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=9;
CC       Name=1; Synonyms=HdynIV-WT, DLP1F;
CC         IsoId=O00429-1; Sequence=Displayed;
CC       Name=4; Synonyms=HdynIV-11, DLP1c;
CC         IsoId=O00429-2; Sequence=VSP_013688;
CC       Name=2; Synonyms=DLP1a;
CC         IsoId=O00429-3; Sequence=VSP_013686;
CC       Name=3; Synonyms=HdynIV-37, DLP1b;
CC         IsoId=O00429-4; Sequence=VSP_013685;
CC       Name=5; Synonyms=HdynIV-26;
CC         IsoId=O00429-5; Sequence=VSP_013687;
CC       Name=6;
CC         IsoId=O00429-6; Sequence=VSP_039097;
CC       Name=7;
CC         IsoId=O00429-7; Sequence=VSP_054544, VSP_054545;
CC       Name=8;
CC         IsoId=O00429-8; Sequence=VSP_039097, VSP_013688;
CC       Name=9;
CC         IsoId=O00429-9; Sequence=VSP_039097, VSP_013685;
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed with highest levels found in
CC       skeletal muscles, heart, kidney and brain. Isoform 1 is brain-specific.
CC       Isoform 2 and isoform 3 are predominantly expressed in testis and
CC       skeletal muscles respectively. Isoform 4 is weakly expressed in brain,
CC       heart and kidney. Isoform 5 is dominantly expressed in liver, heart and
CC       kidney. Isoform 6 is expressed in neurons.
CC       {ECO:0000269|PubMed:10749171, ECO:0000269|PubMed:9422767,
CC       ECO:0000269|PubMed:9570752, ECO:0000269|PubMed:9731200,
CC       ECO:0000269|PubMed:9786947}.
CC   -!- DOMAIN: The GED domain folds back to interact, in cis, with the GTP-
CC       binding domain and middle domain, and interacts, in trans, with the GED
CC       domains of other DNM1L molecules, and is thus critical for activating
CC       GTPase activity and for DNM1L dimerization.
CC       {ECO:0000269|PubMed:15208300}.
CC   -!- PTM: Phosphorylation/dephosphorylation events on two sites near the GED
CC       domain regulate mitochondrial fission (PubMed:17301055,
CC       PubMed:17553808, PubMed:18695047, PubMed:18838687, PubMed:23283981,
CC       PubMed:29478834, PubMed:33850055). Phosphorylation on Ser-637 by CAMK1
CC       and PKA inhibits the GTPase activity, leading to a defect in
CC       mitochondrial fission promoting mitochondrial elongation
CC       (PubMed:17553808, PubMed:18695047, PubMed:23283981, PubMed:29478834).
CC       Dephosphorylated on this site by PPP3CA which promotes mitochondrial
CC       fission (PubMed:18838687). Phosphorylation on Ser-616 by CDK1 and PINK1
CC       activates the GTPase activity and promotes mitochondrial fission
CC       (PubMed:18838687, PubMed:21822277, PubMed:32484300). Phosphorylated in
CC       a circadian manner at Ser-637 (PubMed:29478834). Dephosphorylated by
CC       PGAM5 (PubMed:32439975). {ECO:0000269|PubMed:17301055,
CC       ECO:0000269|PubMed:17553808, ECO:0000269|PubMed:18695047,
CC       ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:21822277,
CC       ECO:0000269|PubMed:23283981, ECO:0000269|PubMed:29478834,
CC       ECO:0000269|PubMed:32439975, ECO:0000269|PubMed:32484300,
CC       ECO:0000269|PubMed:33850055}.
CC   -!- PTM: Sumoylated on various lysine residues within the B domain,
CC       probably by MUL1. Sumoylation positively regulates mitochondrial
CC       fission. Desumoylated by SENP5 during G2/M transition of mitosis.
CC       Appears to be linked to its catalytic activity.
CC       {ECO:0000269|PubMed:19407830, ECO:0000269|PubMed:19411255,
CC       ECO:0000269|PubMed:19638400}.
CC   -!- PTM: S-nitrosylation increases DNM1L dimerization, mitochondrial
CC       fission and causes neuronal damage. {ECO:0000269|PubMed:19342591}.
CC   -!- PTM: Ubiquitination by MARCHF5 affects mitochondrial morphology.
CC       {ECO:0000269|PubMed:16874301, ECO:0000269|PubMed:16936636}.
CC   -!- PTM: O-GlcNAcylation augments the level of the GTP-bound active form of
CC       DNM1L and induces translocation from the cytoplasm to mitochondria in
CC       cardiomyocytes. It also decreases phosphorylation at Ser-637 (By
CC       similarity). {ECO:0000250|UniProtKB:O35303}.
CC   -!- DISEASE: Note=May be associated with Alzheimer disease through amyloid-
CC       beta-induced increased S-nitrosylation of DNM1L, which triggers,
CC       directly or indirectly, excessive mitochondrial fission, synaptic loss
CC       and neuronal damage. {ECO:0000269|PubMed:19342591}.
CC   -!- DISEASE: Encephalopathy due to defective mitochondrial and peroxisomal
CC       fission 1 (EMPF1) [MIM:614388]: A rare autosomal dominant systemic
CC       disorder resulting in lack of neurologic development and death in
CC       infancy. After birth, infants present in the first week of life with
CC       poor feeding and neurologic impairment, including hypotonia, little
CC       spontaneous movement, no tendon reflexes, no response to light
CC       stimulation, and poor visual fixation. Other features include mildly
CC       elevated plasma concentration of very-long-chain fatty acids, lactic
CC       acidosis, microcephaly, deep-set eyes, optic atrophy and hypoplasia,
CC       and an abnormal gyral pattern in both frontal lobes associated with
CC       dysmyelination. {ECO:0000269|PubMed:17460227,
CC       ECO:0000269|PubMed:26604000, ECO:0000269|PubMed:26992161,
CC       ECO:0000269|PubMed:27145208, ECO:0000269|PubMed:27301544,
CC       ECO:0000269|PubMed:27328748, ECO:0000269|PubMed:29899447}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Optic atrophy 5 (OPA5) [MIM:610708]: A form of optic atrophy,
CC       a disease characterized by progressive visual loss in association with
CC       a deficiency in the number of nerve fibers which arise in the retina
CC       and converge to form the optic disk, optic nerve, optic chiasm and
CC       optic tracts. OPA5 is an autosomal dominant non-syndromic form that
CC       manifests as slowly progressive visual loss with variable onset from
CC       the first to third decades. Additional ocular abnormalities may include
CC       central scotoma and dyschromatopsia. {ECO:0000269|PubMed:28969390}.
CC       Note=The disease is caused by variants affecting the gene represented
CC       in this entry.
CC   -!- SIMILARITY: Belongs to the TRAFAC class dynamin-like GTPase
CC       superfamily. Dynamin/Fzo/YdjA family. {ECO:0000255|PROSITE-
CC       ProRule:PRU01055}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAD92307.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AB006965; BAA22193.1; -; mRNA.
DR   EMBL; AF061795; AAC35283.1; -; mRNA.
DR   EMBL; AF000430; AAC23724.1; -; mRNA.
DR   EMBL; AF151685; AAD39541.1; -; mRNA.
DR   EMBL; AK299926; BAG61760.1; -; mRNA.
DR   EMBL; AK291094; BAF83783.1; -; mRNA.
DR   EMBL; AK294533; BAG57740.1; -; mRNA.
DR   EMBL; AB209070; BAD92307.1; ALT_INIT; mRNA.
DR   EMBL; AC084824; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC087588; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC024590; AAH24590.1; -; mRNA.
DR   CCDS; CCDS61095.1; -. [O00429-6]
DR   CCDS; CCDS61096.1; -. [O00429-8]
DR   CCDS; CCDS61098.1; -. [O00429-2]
DR   CCDS; CCDS81680.1; -. [O00429-9]
DR   CCDS; CCDS8728.1; -. [O00429-4]
DR   CCDS; CCDS8729.1; -. [O00429-1]
DR   CCDS; CCDS8730.1; -. [O00429-3]
DR   PIR; JC5695; JC5695.
DR   RefSeq; NP_001265392.1; NM_001278463.2. [O00429-2]
DR   RefSeq; NP_001265393.1; NM_001278464.2. [O00429-6]
DR   RefSeq; NP_001265394.1; NM_001278465.2. [O00429-8]
DR   RefSeq; NP_001265395.1; NM_001278466.2. [O00429-7]
DR   RefSeq; NP_001317309.1; NM_001330380.2. [O00429-9]
DR   RefSeq; NP_005681.2; NM_005690.5. [O00429-4]
DR   RefSeq; NP_036192.2; NM_012062.5. [O00429-1]
DR   RefSeq; NP_036193.2; NM_012063.4. [O00429-3]
DR   PDB; 3W6N; X-ray; 2.00 A; A/B=1-329, A/B=709-736.
DR   PDB; 3W6O; X-ray; 1.90 A; A/B=1-329, A/B=709-736.
DR   PDB; 3W6P; X-ray; 1.70 A; A/B=1-329, A/B=709-736.
DR   PDB; 4BEJ; X-ray; 3.48 A; A/B/C/D=1-736.
DR   PDB; 4H1U; X-ray; 2.30 A; A=1-327, A=711-736.
DR   PDB; 4H1V; X-ray; 2.30 A; A=1-327, A=711-736.
DR   PDB; 5WP9; EM; 4.22 A; A/C/E/G/I/K/M/O=1-736.
DR   PDB; 8T1H; EM; 5.97 A; A/B=1-736.
DR   PDB; 8V8T; EM; 14.73 A; A/B/C/D=1-736.
DR   PDBsum; 3W6N; -.
DR   PDBsum; 3W6O; -.
DR   PDBsum; 3W6P; -.
DR   PDBsum; 4BEJ; -.
DR   PDBsum; 4H1U; -.
DR   PDBsum; 4H1V; -.
DR   PDBsum; 5WP9; -.
DR   PDBsum; 8T1H; -.
DR   PDBsum; 8V8T; -.
DR   AlphaFoldDB; O00429; -.
DR   EMDB; EMD-40967; -.
DR   EMDB; EMD-43045; -.
DR   EMDB; EMD-8874; -.
DR   SMR; O00429; -.
DR   BioGRID; 115370; 372.
DR   CORUM; O00429; -.
DR   DIP; DIP-42704N; -.
DR   FunCoup; O00429; 4592.
DR   IntAct; O00429; 273.
DR   MINT; O00429; -.
DR   STRING; 9606.ENSP00000449089; -.
DR   BindingDB; O00429; -.
DR   ChEMBL; CHEMBL4523118; -.
DR   TCDB; 1.N.6.1.2; the mitochondrial inner/outer membrane fusion (mmf) family.
DR   GlyCosmos; O00429; 4 sites, 1 glycan.
DR   GlyGen; O00429; 5 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; O00429; -.
DR   MetOSite; O00429; -.
DR   PhosphoSitePlus; O00429; -.
DR   SwissPalm; O00429; -.
DR   BioMuta; DNM1L; -.
DR   CPTAC; CPTAC-57; -.
DR   jPOST; O00429; -.
DR   MassIVE; O00429; -.
DR   PaxDb; 9606-ENSP00000449089; -.
DR   PeptideAtlas; O00429; -.
DR   ProteomicsDB; 34194; -.
DR   ProteomicsDB; 4122; -.
DR   ProteomicsDB; 47884; -. [O00429-1]
DR   ProteomicsDB; 47885; -. [O00429-2]
DR   ProteomicsDB; 47886; -. [O00429-3]
DR   ProteomicsDB; 47887; -. [O00429-4]
DR   ProteomicsDB; 47888; -. [O00429-5]
DR   ProteomicsDB; 47889; -. [O00429-6]
DR   Pumba; O00429; -.
DR   Antibodypedia; 4096; 735 antibodies from 39 providers.
DR   DNASU; 10059; -.
DR   Ensembl; ENST00000266481.10; ENSP00000266481.6; ENSG00000087470.22. [O00429-4]
DR   Ensembl; ENST00000358214.9; ENSP00000350948.5; ENSG00000087470.22. [O00429-9]
DR   Ensembl; ENST00000381000.8; ENSP00000370388.4; ENSG00000087470.22. [O00429-8]
DR   Ensembl; ENST00000452533.6; ENSP00000415131.2; ENSG00000087470.22. [O00429-3]
DR   Ensembl; ENST00000547312.5; ENSP00000448610.1; ENSG00000087470.22. [O00429-2]
DR   Ensembl; ENST00000549701.6; ENSP00000450399.1; ENSG00000087470.22. [O00429-1]
DR   Ensembl; ENST00000553257.6; ENSP00000449089.1; ENSG00000087470.22. [O00429-6]
DR   GeneID; 10059; -.
DR   KEGG; hsa:10059; -.
DR   MANE-Select; ENST00000549701.6; ENSP00000450399.1; NM_012062.5; NP_036192.2.
DR   UCSC; uc001rld.4; human. [O00429-1]
DR   AGR; HGNC:2973; -.
DR   ClinPGx; PA27441; -.
DR   CTD; 10059; -.
DR   DisGeNET; 10059; -.
DR   GeneCards; DNM1L; -.
DR   HGNC; HGNC:2973; DNM1L.
DR   HPA; ENSG00000087470; Low tissue specificity.
DR   MalaCards; DNM1L; -.
DR   MIM; 603850; gene.
DR   MIM; 610708; phenotype.
DR   MIM; 614388; phenotype.
DR   OpenTargets; ENSG00000087470; -.
DR   Orphanet; 98673; Autosomal dominant optic atrophy, classic form.
DR   Orphanet; 330050; DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect.
DR   VEuPathDB; HostDB:ENSG00000087470; -.
DR   eggNOG; KOG0446; Eukaryota.
DR   GeneTree; ENSGT00940000155504; -.
DR   HOGENOM; CLU_008964_5_4_1; -.
DR   InParanoid; O00429; -.
DR   OMA; KICHNCG; -.
DR   OrthoDB; 5061070at2759; -.
DR   PAN-GO; O00429; 8 GO annotations based on evolutionary models.
DR   PhylomeDB; O00429; -.
DR   BRENDA; 3.6.5.5; 2681.
DR   PathwayCommons; O00429; -.
DR   Reactome; R-HSA-75153; Apoptotic execution phase.
DR   SignaLink; O00429; -.
DR   SIGNOR; O00429; -.
DR   Agora; ENSG00000087470; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 10059; 516 hits in 1170 CRISPR screens.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; DNM1L; human.
DR   EvolutionaryTrace; O00429; -.
DR   GeneWiki; DNM1L; -.
DR   GenomeRNAi; 10059; -.
DR   Pharos; O00429; Tchem.
DR   PRO; PR:O00429; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; O00429; protein.
DR   Bgee; ENSG00000087470; Expressed in lateral nuclear group of thalamus and 209 other cell types or tissues.
DR   ExpressionAtlas; O00429; baseline and differential.
DR   GO; GO:0005903; C:brush border; IEA:Ensembl.
DR   GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR   GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR   GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR   GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR   GO; GO:0030742; F:GTP-dependent protein binding; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005096; F:GTPase activator activity; IC:ParkinsonsUK-UCL.
DR   GO; GO:0003924; F:GTPase activity; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR   GO; GO:0008017; F:microtubule binding; IBA:GO_Central.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0031267; F:small GTPase binding; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR   GO; GO:0006816; P:calcium ion transport; IEA:Ensembl.
DR   GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR   GO; GO:0060047; P:heart contraction; IEA:Ensembl.
DR   GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0000266; P:mitochondrial fission; IDA:UniProtKB.
DR   GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IMP:HGNC-UCL.
DR   GO; GO:0090149; P:mitochondrial membrane fission; IDA:UniProtKB.
DR   GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0160040; P:mitocytosis; IEA:Ensembl.
DR   GO; GO:0016559; P:peroxisome fission; IDA:UniProtKB.
DR   GO; GO:0090141; P:positive regulation of mitochondrial fission; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0090023; P:positive regulation of neutrophil chemotaxis; IMP:CACAO.
DR   GO; GO:0050714; P:positive regulation of protein secretion; IDA:UniProtKB.
DR   GO; GO:0051259; P:protein complex oligomerization; IMP:UniProtKB.
DR   GO; GO:0070585; P:protein localization to mitochondrion; IMP:DisProt.
DR   GO; GO:1903578; P:regulation of ATP metabolic process; IEA:Ensembl.
DR   GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR   GO; GO:1901524; P:regulation of mitophagy; IGI:ParkinsonsUK-UCL.
DR   GO; GO:1900063; P:regulation of peroxisome organization; IEA:Ensembl.
DR   GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR   CDD; cd08771; DLP_1; 1.
DR   DisProt; DP01537; -. [O00429-3]
DR   FunFam; 1.20.120.1240:FF:000034; Dynamin 1 like; 1.
DR   FunFam; 1.20.120.1240:FF:000006; Dynamin-1-like protein isoform 1; 1.
DR   FunFam; 3.40.50.300:FF:000172; Dynamin-1-like protein isoform 1; 1.
DR   Gene3D; 1.20.120.1240; Dynamin, middle domain; 2.
DR   Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1.
DR   InterPro; IPR022812; Dynamin.
DR   InterPro; IPR001401; Dynamin_GTPase.
DR   InterPro; IPR019762; Dynamin_GTPase_CS.
DR   InterPro; IPR045063; Dynamin_N.
DR   InterPro; IPR000375; Dynamin_stalk.
DR   InterPro; IPR030381; G_DYNAMIN_dom.
DR   InterPro; IPR003130; GED.
DR   InterPro; IPR020850; GED_dom.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   PANTHER; PTHR11566; DYNAMIN; 1.
DR   PANTHER; PTHR11566:SF39; DYNAMIN-1-LIKE PROTEIN; 1.
DR   Pfam; PF01031; Dynamin_M; 1.
DR   Pfam; PF00350; Dynamin_N; 1.
DR   Pfam; PF02212; GED; 1.
DR   PRINTS; PR00195; DYNAMIN.
DR   SMART; SM00053; DYNc; 1.
DR   SMART; SM00302; GED; 1.
DR   SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1.
DR   PROSITE; PS00410; G_DYNAMIN_1; 1.
DR   PROSITE; PS51718; G_DYNAMIN_2; 1.
DR   PROSITE; PS51388; GED; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Biological rhythms;
KW   Coated pit; Cytoplasm; Cytoplasmic vesicle; Disease variant; Endocytosis;
KW   Glycoprotein; Golgi apparatus; GTP-binding; Hydrolase; Isopeptide bond;
KW   Lipid-binding; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW   Necrosis; Nucleotide-binding; Peroxisome; Phosphoprotein;
KW   Proteomics identification; Reference proteome; S-nitrosylation; Synapse;
KW   Ubl conjugation.
FT   CHAIN           1..736
FT                   /note="Dynamin-1-like protein"
FT                   /id="PRO_0000206566"
FT   DOMAIN          22..302
FT                   /note="Dynamin-type G"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT   DOMAIN          644..735
FT                   /note="GED"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00720"
FT   REGION          32..39
FT                   /note="G1 motif"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT   REGION          58..60
FT                   /note="G2 motif"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT   REGION          146..149
FT                   /note="G3 motif"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT   REGION          215..218
FT                   /note="G4 motif"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT   REGION          245..248
FT                   /note="G5 motif"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
FT   REGION          344..489
FT                   /note="Middle domain"
FT                   /evidence="ECO:0000269|PubMed:15208300"
FT   REGION          448..685
FT                   /note="Interaction with GSK3B"
FT                   /evidence="ECO:0000269|PubMed:9731200"
FT   REGION          502..569
FT                   /note="B domain"
FT                   /evidence="ECO:0000269|PubMed:15208300"
FT   REGION          523..590
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          654..668
FT                   /note="Important for homodimerization"
FT                   /evidence="ECO:0000269|PubMed:23584531"
FT   COMPBIAS        537..554
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        555..568
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         32..40
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT                   /evidence="ECO:0000305|PubMed:23977156"
FT   BINDING         215..221
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT                   /evidence="ECO:0000305|PubMed:23977156"
FT   BINDING         246..249
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT                   /evidence="ECO:0000305|PubMed:23977156"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0007744|PubMed:19413330,
FT                   ECO:0007744|PubMed:22223895"
FT   MOD_RES         529
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         548
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         597
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q8K1M6"
FT   MOD_RES         607
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         616
FT                   /note="Phosphoserine; by CDK1 and PINK1"
FT                   /evidence="ECO:0000269|PubMed:18838687,
FT                   ECO:0000269|PubMed:21822277, ECO:0000269|PubMed:26122121,
FT                   ECO:0000269|PubMed:32484300, ECO:0007744|PubMed:18088087,
FT                   ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332,
FT                   ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT                   ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT   MOD_RES         637
FT                   /note="Phosphoserine; by CAMK1 and PKA"
FT                   /evidence="ECO:0000269|PubMed:17553808,
FT                   ECO:0000269|PubMed:18695047, ECO:0000269|PubMed:18838687,
FT                   ECO:0000269|PubMed:23283981, ECO:0000269|PubMed:26122121,
FT                   ECO:0000269|PubMed:32439975"
FT   MOD_RES         644
FT                   /note="S-nitrosocysteine"
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   CARBOHYD        585
FT                   /note="O-linked (GlcNAc) threonine"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        586
FT                   /note="O-linked (GlcNAc) threonine"
FT                   /evidence="ECO:0000250"
FT   CROSSLNK        532
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   CROSSLNK        535
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   CROSSLNK        558
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   CROSSLNK        568
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   CROSSLNK        594
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   CROSSLNK        597
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO); alternate"
FT   CROSSLNK        606
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   CROSSLNK        608
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   VAR_SEQ         1..43
FT                   /note="MEALIPVINKLQDVFNTVGADIIQLPQIVVVGTQSSGKSSVLE -> MFHKK
FT                   INGKQQEKKMTLLHGKTQDTFLKGWKQKNGVNFFTPKI (in isoform 7)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_054544"
FT   VAR_SEQ         44..246
FT                   /note="Missing (in isoform 7)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_054545"
FT   VAR_SEQ         83
FT                   /note="N -> NDPATWKNSRHLSK (in isoform 6, isoform 8 and
FT                   isoform 9)"
FT                   /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.6"
FT                   /id="VSP_039097"
FT   VAR_SEQ         533..569
FT                   /note="Missing (in isoform 3 and isoform 9)"
FT                   /evidence="ECO:0000303|PubMed:10749171,
FT                   ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:9731200"
FT                   /id="VSP_013685"
FT   VAR_SEQ         533..558
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_013686"
FT   VAR_SEQ         544..569
FT                   /note="Missing (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:10749171"
FT                   /id="VSP_013687"
FT   VAR_SEQ         559..569
FT                   /note="Missing (in isoform 4 and isoform 8)"
FT                   /evidence="ECO:0000303|PubMed:10749171, ECO:0000303|Ref.6"
FT                   /id="VSP_013688"
FT   VARIANT         2
FT                   /note="E -> A (in OPA5; changed localization to
FT                   mitochondrion; impaired mitochondrial membrane fission;
FT                   dbSNP:rs1555229948)"
FT                   /evidence="ECO:0000269|PubMed:28969390"
FT                   /id="VAR_080869"
FT   VARIANT         36
FT                   /note="S -> G (in EMPF1; autosomal recessive; impaired
FT                   mitochondrial membrane fission; hypomorphic mutation
FT                   retaining partial activity in mitochondrial membrane
FT                   fission; dbSNP:rs879255688)"
FT                   /evidence="ECO:0000269|PubMed:27328748"
FT                   /id="VAR_080870"
FT   VARIANT         71
FT                   /note="S -> T (in dbSNP:rs1064610)"
FT                   /evidence="ECO:0000269|PubMed:10749171,
FT                   ECO:0000269|PubMed:9570752, ECO:0000269|PubMed:9731200"
FT                   /id="VAR_022446"
FT   VARIANT         192
FT                   /note="A -> E (in OPA5; changed localization to
FT                   mitochondrion; impaired mitochondrial membrane fission;
FT                   dbSNP:rs1555119216)"
FT                   /evidence="ECO:0000269|PubMed:28969390"
FT                   /id="VAR_080871"
FT   VARIANT         362
FT                   /note="G -> D (in EMPF1; uncertain significance; unable to
FT                   associate with MIEF2 into filaments forming the tubular
FT                   structures that wrap around the scission site; presence of
FT                   concentric cristae and/or increased dense granules in some
FT                   mitochondria; dbSNP:rs879255685)"
FT                   /evidence="ECO:0000269|PubMed:26604000,
FT                   ECO:0000269|PubMed:29899447"
FT                   /id="VAR_076316"
FT   VARIANT         362
FT                   /note="G -> S (in EMPF1; the mutation acts in a dominant-
FT                   negative manner; defects observed in mitochondrial fission;
FT                   significant decrease in mitochondrial respiratory chain
FT                   complex IV activity; dbSNP:rs886037861)"
FT                   /evidence="ECO:0000269|PubMed:26992161"
FT                   /id="VAR_076317"
FT   VARIANT         395
FT                   /note="A -> D (in EMPF1; the mutation acts in a dominant-
FT                   negative manner; defects observed in both mitochondrial and
FT                   peroxisomal fission; reduced oligomerization, decreased
FT                   mitochondrial recruitment; dbSNP:rs121908531)"
FT                   /evidence="ECO:0000269|PubMed:17460227,
FT                   ECO:0000269|PubMed:27145208"
FT                   /id="VAR_063704"
FT   VARIANT         403
FT                   /note="R -> C (in EMPF1; the mutation acts in a dominant-
FT                   negative manner; reduced oligomerization; decreased
FT                   mitochondrial recruitment; defects observed in
FT                   mitochondrial fission; dbSNP:rs863223953)"
FT                   /evidence="ECO:0000269|PubMed:27145208"
FT                   /id="VAR_076318"
FT   VARIANT         406
FT                   /note="L -> S (in EMPF1; impaired mitochondrial and
FT                   peroxisomal membrane fission)"
FT                   /evidence="ECO:0000269|PubMed:27301544"
FT                   /id="VAR_080872"
FT   VARIANT         426
FT                   /note="E -> D (in dbSNP:rs2389105)"
FT                   /id="VAR_030489"
FT   MUTAGEN         34
FT                   /note="Q->A: Abolishes GTP hydrolysis."
FT                   /evidence="ECO:0000269|PubMed:23977156"
FT   MUTAGEN         38
FT                   /note="K->A: Loss of GTPase activity. Impairs mitochondrial
FT                   division and induces changes in peroxisome morphology. No
FT                   effect on oligomerization. Increase in sumoylation by
FT                   SUMO3."
FT                   /evidence="ECO:0000269|PubMed:11514614,
FT                   ECO:0000269|PubMed:12499366, ECO:0000269|PubMed:15208300,
FT                   ECO:0000269|PubMed:19638400, ECO:0000269|PubMed:23977156,
FT                   ECO:0000269|PubMed:32439975, ECO:0000269|PubMed:9570752"
FT   MUTAGEN         38
FT                   /note="K->E: Overexpression delays protein secretion.
FT                   Rescues fragmented or truncated mitochondria in PRKN- or
FT                   PINK1-depleted cells."
FT                   /evidence="ECO:0000269|PubMed:11514614,
FT                   ECO:0000269|PubMed:12499366, ECO:0000269|PubMed:15208300,
FT                   ECO:0000269|PubMed:19638400, ECO:0000269|PubMed:23977156,
FT                   ECO:0000269|PubMed:9570752"
FT   MUTAGEN         39
FT                   /note="S->A: Abolishes GTP hydrolysis."
FT                   /evidence="ECO:0000269|PubMed:12618434,
FT                   ECO:0000269|PubMed:23977156, ECO:0000269|PubMed:9422767"
FT   MUTAGEN         39
FT                   /note="S->I: Decreased localization to the perinuclear
FT                   region."
FT                   /evidence="ECO:0000269|PubMed:12618434,
FT                   ECO:0000269|PubMed:23977156, ECO:0000269|PubMed:9422767"
FT   MUTAGEN         39
FT                   /note="S->N: Reduces peroxisomal abundance."
FT                   /evidence="ECO:0000269|PubMed:12618434,
FT                   ECO:0000269|PubMed:23977156, ECO:0000269|PubMed:9422767"
FT   MUTAGEN         41
FT                   /note="V->F: Temperature-sensitive. Impairs mitochondrial
FT                   division."
FT                   /evidence="ECO:0000269|PubMed:11514614"
FT   MUTAGEN         59
FT                   /note="T->A: Abolishes GTP hydrolysis. Impairs
FT                   mitochondrial division. Reduces peroxisomal abundance."
FT                   /evidence="ECO:0000269|PubMed:11514614,
FT                   ECO:0000269|PubMed:12618434, ECO:0000269|PubMed:23977156"
FT   MUTAGEN         146
FT                   /note="D->A: Abolishes GTP hydrolysis."
FT                   /evidence="ECO:0000269|PubMed:23977156"
FT   MUTAGEN         149
FT                   /note="G->A: Abolishes GTP hydrolysis."
FT                   /evidence="ECO:0000269|PubMed:23977156"
FT   MUTAGEN         190
FT                   /note="D->A: Unable to homooligomerize. Unable to associate
FT                   with MIEF2 into filaments forming the tubular structures
FT                   that wrap around the scission site."
FT                   /evidence="ECO:0000269|PubMed:29899447"
FT   MUTAGEN         216
FT                   /note="K->A: Abolishes GTP hydrolysis."
FT                   /evidence="ECO:0000269|PubMed:23977156"
FT   MUTAGEN         218
FT                   /note="D->A: Abolishes GTP hydrolysis."
FT                   /evidence="ECO:0000269|PubMed:23977156"
FT   MUTAGEN         221
FT                   /note="D->A: Unable to homooligomerize. Unable to associate
FT                   with MIEF2 into filaments forming the tubular structures
FT                   that wrap around the scission site."
FT                   /evidence="ECO:0000269|PubMed:29899447"
FT   MUTAGEN         281
FT                   /note="G->D: Temperature-sensitive. Impairs mitochondrial
FT                   division."
FT                   /evidence="ECO:0000269|PubMed:11514614"
FT   MUTAGEN         300
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         345
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         361
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         367
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         401..404
FT                   /note="GPRP->AAAA: Impairs formation of higher order
FT                   oligomers, but not homodimerization."
FT                   /evidence="ECO:0000269|PubMed:23584531"
FT   MUTAGEN         431
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         446
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         470
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         490
FT                   /note="E->A: Does not impair homodimerization and formation
FT                   of higher order oligomers."
FT                   /evidence="ECO:0000269|PubMed:23584531"
FT   MUTAGEN         490
FT                   /note="E->R: Impairs homodimerization and formation of
FT                   higher order oligomers."
FT                   /evidence="ECO:0000269|PubMed:23584531"
FT   MUTAGEN         505
FT                   /note="C->A: No effect on S-nitrosylation."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         532
FT                   /note="K->R: Some loss of sumoylation in B domain. Complete
FT                   loss of sumoylation in B domain; when associated with R-
FT                   535; R-558 and R-568."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         535
FT                   /note="K->R: Some loss of sumoylation in B domain. Complete
FT                   loss of sumoylation in B domain; when associated with R-
FT                   532; R-558 and R-568."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         558
FT                   /note="K->R: Some loss of sumoylation in B domain. Complete
FT                   loss of sumoylation in B domain; when associated with R-
FT                   532; R-535 and R-568."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         568
FT                   /note="K->R: Some loss of sumoylation in B domain. Complete
FT                   loss of sumoylation in B domain; when associated with R-
FT                   532; R-535 and R-558."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         594
FT                   /note="K->R: Some loss of sumoylation in the GED domain;
FT                   Complete loss of sumoylation in the GED domain; when
FT                   associated with R-597; R-606 and R-608."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         597
FT                   /note="K->R: Some loss of sumoylation in the GED domain;
FT                   Complete loss of sumoylation in the GED domain; when
FT                   associated with R-594; R-606 and R-608."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         606
FT                   /note="K->R: Some loss of sumoylation in the GED domain;
FT                   Complete loss of sumoylation in the GED domain; when
FT                   associated with R-594; R-597 and R-608."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         608
FT                   /note="K->R: Some loss of sumoylation in the GED domain;
FT                   Complete loss of sumoylation in the GED domain; when
FT                   associated with R-594; R-597 and R-606."
FT                   /evidence="ECO:0000269|PubMed:19638400"
FT   MUTAGEN         616
FT                   /note="S->A: Loss of activity. Little effect on
FT                   mitochondrial morphology. Translocated to mitochondria."
FT                   /evidence="ECO:0000269|PubMed:18838687,
FT                   ECO:0000269|PubMed:32484300"
FT   MUTAGEN         637
FT                   /note="S->A: Abolishes phosphorylation. Reduces interaction
FT                   with MIEF1 and MIEF2. Promotes mitochondrial fission and
FT                   cell vulnerability to apoptotic insults. Mostly
FT                   mitochondrial. Disrupts, in vitro, binding to FIS1."
FT                   /evidence="ECO:0000269|PubMed:17553808,
FT                   ECO:0000269|PubMed:18695047, ECO:0000269|PubMed:18838687,
FT                   ECO:0000269|PubMed:23283981"
FT   MUTAGEN         637
FT                   /note="S->D: Impairs intramolecular interactions but not
FT                   homooligomerization. Does not reduce interaction with MIEF1
FT                   and MIEF2. Impairs formation of higher order oligomers but
FT                   not homodimerization. Unable to associate with MIEF2 into
FT                   filaments forming the tubular structures that wrap around
FT                   the scission site. Slight reduction in GTPase activity.
FT                   Inhibits mitochondrial fission. Retained in the cytoplasm."
FT                   /evidence="ECO:0000269|PubMed:17553808,
FT                   ECO:0000269|PubMed:18695047, ECO:0000269|PubMed:18838687,
FT                   ECO:0000269|PubMed:23283981, ECO:0000269|PubMed:29899447,
FT                   ECO:0000269|PubMed:32439975"
FT   MUTAGEN         644
FT                   /note="C->A: Abolishes S-nitrosylation. Reduced
FT                   dimerization and no enhancement of GTPase activity."
FT                   /evidence="ECO:0000269|PubMed:19342591"
FT   MUTAGEN         668
FT                   /note="K->E: Abolishes homodimerization and formation of
FT                   higher order oligomers."
FT                   /evidence="ECO:0000269|PubMed:23584531"
FT   MUTAGEN         679
FT                   /note="K->A: Diminishes intramolecular interaction between
FT                   GTP-middle domain and GED domain but no effect on
FT                   homooligomerization. Marked reduction in GTPase activity,
FT                   in vitro. Decreased mitochondrial division."
FT                   /evidence="ECO:0000269|PubMed:15208300"
FT   CONFLICT        208
FT                   /note="R -> C (in Ref. 2; AAC35283 and 4; AAD39541)"
FT                   /evidence="ECO:0000305"
FT   HELIX           5..18
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   TURN            21..23
FT                   /evidence="ECO:0007829|PDB:4H1U"
FT   STRAND          27..31
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           34..36
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           38..44
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          55..57
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          63..69
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          86..88
FT                   /evidence="ECO:0007829|PDB:4H1U"
FT   STRAND          90..93
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           94..96
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           104..119
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          121..123
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          130..136
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          141..146
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           155..157
FT                   /evidence="ECO:0007829|PDB:4H1U"
FT   HELIX           162..174
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          179..186
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           191..193
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           195..203
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          205..207
FT                   /evidence="ECO:0007829|PDB:4H1U"
FT   STRAND          210..215
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           217..219
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          222..225
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           227..230
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          233..235
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   STRAND          237..239
FT                   /evidence="ECO:0007829|PDB:4H1V"
FT   STRAND          241..243
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           249..253
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           258..272
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   TURN            274..276
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           277..279
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           282..317
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           338..355
FT                   /evidence="ECO:0007829|PDB:3W6P"
FT   HELIX           363..371
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           373..380
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           389..399
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           409..420
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           421..424
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           425..440
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   TURN            441..443
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           444..446
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           458..493
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           501..504
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           643..673
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           675..690
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           693..699
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           704..727
FT                   /evidence="ECO:0007829|PDB:4BEJ"
FT   HELIX           728..731
FT                   /evidence="ECO:0007829|PDB:3W6P"
SQ   SEQUENCE   736 AA;  81877 MW;  F9521A376B785B71 CRC64;
     MEALIPVINK LQDVFNTVGA DIIQLPQIVV VGTQSSGKSS VLESLVGRDL LPRGTGIVTR
     RPLILQLVHV SQEDKRKTTG EENGVEAEEW GKFLHTKNKL YTDFDEIRQE IENETERISG
     NNKGVSPEPI HLKIFSPNVV NLTLVDLPGM TKVPVGDQPK DIELQIRELI LRFISNPNSI
     ILAVTAANTD MATSEALKIS REVDPDGRRT LAVITKLDLM DAGTDAMDVL MGRVIPVKLG
     IIGVVNRSQL DINNKKSVTD SIRDEYAFLQ KKYPSLANRN GTKYLARTLN RLLMHHIRDC
     LPELKTRINV LAAQYQSLLN SYGEPVDDKS ATLLQLITKF ATEYCNTIEG TAKYIETSEL
     CGGARICYIF HETFGRTLES VDPLGGLNTI DILTAIRNAT GPRPALFVPE VSFELLVKRQ
     IKRLEEPSLR CVELVHEEMQ RIIQHCSNYS TQELLRFPKL HDAIVEVVTC LLRKRLPVTN
     EMVHNLVAIE LAYINTKHPD FADACGLMNN NIEEQRRNRL ARELPSAVSR DKSSKVPSAL
     APASQEPSPA ASAEADGKLI QDSRRETKNV ASGGGGVGDG VQEPTTGNWR GMLKTSKAEE
     LLAEEKSKPI PIMPASPQKG HAVNLLDVPV PVARKLSARE QRDCEVIERL IKSYFLIVRK
     NIQDSVPKAV MHFLVNHVKD TLQSELVGQL YKSSLLDDLL TESEDMAQRR KEAADMLKAL
     QGASQIIAEI RETHLW
//
ID   E2AK2_HUMAN             Reviewed;         551 AA.
AC   P19525; A8K3P0; D6W584; E9PC80; Q52M43; Q7Z6F6; Q9UIR4;
DT   01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1991, sequence version 2.
DT   28-JAN-2026, entry version 260.
DE   RecName: Full=Interferon-induced, double-stranded RNA-activated protein kinase;
DE            EC=2.7.11.1;
DE   AltName: Full=Eukaryotic translation initiation factor 2-alpha kinase 2;
DE            Short=eIF-2A protein kinase 2;
DE   AltName: Full=Interferon-inducible RNA-dependent protein kinase;
DE   AltName: Full=P1/eIF-2A protein kinase;
DE   AltName: Full=Protein kinase RNA-activated;
DE            Short=PKR;
DE            Short=Protein kinase R {ECO:0000303|PubMed:11438532};
DE   AltName: Full=Tyrosine-protein kinase EIF2AK2;
DE            EC=2.7.10.2;
DE   AltName: Full=p68 kinase;
GN   Name=EIF2AK2; Synonyms=PKR, PRKR;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 101-118 AND
RP   309-325, AND INDUCTION.
RX   PubMed=1695551; DOI=10.1016/0092-8674(90)90374-n;
RA   Meurs E., Chong K., Galabru J., Thomas N.S.B., Kerr I.M., Williams B.R.G.,
RA   Hovanessian A.G.;
RT   "Molecular cloning and characterization of the human double-stranded RNA-
RT   activated protein kinase induced by interferon.";
RL   Cell 62:379-390(1990).
RN   [2]
RP   SEQUENCE REVISION.
RA   Meurs E.;
RL   Submitted (AUG-1990) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=1373553; DOI=10.1016/0042-6822(92)90732-5;
RA   Thomis D.C., Doohan J.P., Samuel C.E.;
RT   "Mechanism of interferon action: cDNA structure, expression, and regulation
RT   of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from
RT   human cells.";
RL   Virology 188:33-46(1992).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RX   PubMed=8921913; DOI=10.1016/0378-1119(96)00314-9;
RA   Kuhen K.L., Shen X., Samuel C.E.;
RT   "Mechanism of interferon action sequence of the human interferon-inducible
RT   RNA-dependent protein kinase (PKR) deduced from genomic clones.";
RL   Gene 178:191-193(1996).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   TISSUE=Placenta;
RX   PubMed=8812437; DOI=10.1006/geno.1996.0446;
RA   Kuhen K.L., Shen X., Carlisle E.R., Richardson A.L., Weier H.-U.G.,
RA   Tanaka H., Samuel C.E.;
RT   "Structural organization of the human gene (PKR) encoding an interferon-
RT   inducible RNA-dependent protein kinase (PKR) and differences from its mouse
RT   homolog.";
RL   Genomics 36:197-201(1996).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=9726442; DOI=10.1089/jir.1998.18.609;
RA   Xu Z., Williams B.R.;
RT   "Genomic features of human PKR: alternative splicing and a polymorphic CGG
RT   repeat in the 5'-untranslated region.";
RL   J. Interferon Cytokine Res. 18:609-616(1998).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA   Li H., Huang F., Shen C., Zhou G., Zheng G., Ke R., Lin L., Yang S.;
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain, and Embryo;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   NIEHS SNPs program;
RL   Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [12]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [13]
RP   PROTEIN SEQUENCE OF 2-18; 27-40; 70-77; 414-426 AND 430-440, CLEAVAGE OF
RP   INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RC   TISSUE=Prostatic carcinoma;
RA   Bienvenut W.V., Gao M., Leug H.;
RL   Submitted (JUN-2009) to UniProtKB.
RN   [14]
RP   INTERACTION WITH DNAJC3.
RX   PubMed=8576172; DOI=10.1074/jbc.271.3.1702;
RA   Polyak S.J., Tang N., Wambach M., Barber G.N., Katze M.G.;
RT   "The P58 cellular inhibitor complexes with the interferon-induced, double-
RT   stranded RNA-dependent protein kinase, PKR, to regulate its
RT   autophosphorylation and activity.";
RL   J. Biol. Chem. 271:1702-1707(1996).
RN   [15]
RP   INTERACTION WITH HIV-1 TAT.
RX   PubMed=9079663; DOI=10.1074/jbc.272.13.8388;
RA   Brand S.R., Kobayashi R., Mathews M.B.;
RT   "The Tat protein of human immunodeficiency virus type 1 is a substrate and
RT   inhibitor of the interferon-induced, virally activated protein kinase,
RT   PKR.";
RL   J. Biol. Chem. 272:8388-8395(1997).
RN   [16]
RP   INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX   PubMed=9143277; DOI=10.1006/viro.1997.8493;
RA   Gale M.J. Jr., Korth M.J., Tang N.M., Tan S.-L., Hopkins D.A., Dever T.E.,
RA   Polyak S.J., Gretch D.R., Katze M.G.;
RT   "Evidence that hepatitis C virus resistance to interferon is mediated
RT   through repression of the PKR protein kinase by the nonstructural 5A
RT   protein.";
RL   Virology 230:217-227(1997).
RN   [17]
RP   INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX   PubMed=9710605; DOI=10.1128/mcb.18.9.5208;
RA   Gale M.J. Jr., Blakely C.M., Kwieciszewski B., Tan S.-L., Dossett M.,
RA   Tang N.M., Korth M.J., Polyak S.J., Gretch D.R., Katze M.G.;
RT   "Control of PKR protein kinase by hepatitis C virus nonstructural 5A
RT   protein: molecular mechanisms of kinase regulation.";
RL   Mol. Cell. Biol. 18:5208-5218(1998).
RN   [18]
RP   INTERACTION WITH INFLUENZA A NS1 PROTEIN.
RX   PubMed=9781815; DOI=10.1089/jir.1998.18.757;
RA   Tan S.L., Katze M.G.;
RT   "Biochemical and genetic evidence for complex formation between the
RT   influenza A virus NS1 protein and the interferon-induced PKR protein
RT   kinase.";
RL   J. Interferon Cytokine Res. 18:757-766(1998).
RN   [19]
RP   INTERACTION WITH HCV ENVELOPE GLYCOPROTEIN E2 (MICROBIAL INFECTION).
RX   PubMed=10390359; DOI=10.1126/science.285.5424.107;
RA   Taylor D.R., Shi S.T., Romano P.R., Barber G.N., Lai M.M.C.;
RT   "Inhibition of the interferon-inducible protein kinase PKR by HCV E2
RT   protein.";
RL   Science 285:107-110(1999).
RN   [20]
RP   FUNCTION, AND INTERACTION WITH IKBKB.
RX   PubMed=10848580; DOI=10.1128/mcb.20.13.4532-4542.2000;
RA   Bonnet M.C., Weil R., Dam E., Hovanessian A.G., Meurs E.F.;
RT   "PKR stimulates NF-kappaB irrespective of its kinase function by
RT   interacting with the IkappaB kinase complex.";
RL   Mol. Cell. Biol. 20:4532-4542(2000).
RN   [21]
RP   INTERACTION WITH TARBP2.
RX   PubMed=11438532; DOI=10.1074/jbc.m103584200;
RA   Daher A., Longuet M., Dorin D., Bois F., Segeral E., Bannwarth S.,
RA   Battisti P.-L., Purcell D.F., Benarous R., Vaquero C., Meurs E.F.,
RA   Gatignol A.;
RT   "Two dimerization domains in the trans-activation response RNA-binding
RT   protein (TRBP) individually reverse the protein kinase R inhibition of HIV-
RT   1 long terminal repeat expression.";
RL   J. Biol. Chem. 276:33899-33905(2001).
RN   [22]
RP   PHOSPHORYLATION AT SER-83; THR-88; THR-89; THR-90; SER-242; THR-255 AND
RP   THR-258, MUTAGENESIS OF SER-83; THR-88; THR-89; THR-90; SER-242; THR-255;
RP   THR-258 AND LYS-296, AND INHIBITION BY HCV E2 ENVELOPE PROTEIN.
RX   PubMed=11152499; DOI=10.1128/jvi.75.3.1265-1273.2001;
RA   Taylor D.R., Tian B., Romano P.R., Hinnebusch A.G., Lai M.M.C.,
RA   Mathews M.B.;
RT   "Hepatitis C virus envelope protein E2 does not inhibit PKR by simple
RT   competition with autophosphorylation sites in the RNA-binding domain.";
RL   J. Virol. 75:1265-1273(2001).
RN   [23]
RP   MUTAGENESIS OF LYS-60; ALA-67; THR-446 AND THR-451, AND PHOSPHORYLATION AT
RP   THR-446 AND THR-451.
RX   PubMed=11337501; DOI=10.1074/jbc.m102108200;
RA   Zhang F., Romano P.R., Nagamura-Inoue T., Tian B., Dever T.E.,
RA   Mathews M.B., Ozato K., Hinnebusch A.G.;
RT   "Binding of double-stranded RNA to protein kinase PKR is required for
RT   dimerization and promotes critical autophosphorylation events in the
RT   activation loop.";
RL   J. Biol. Chem. 276:24946-24958(2001).
RN   [24]
RP   INTERACTION WITH HHV-8 PROTEIN VIRF2 (MICROBIAL INFECTION).
RX   PubMed=11160738; DOI=10.1128/jvi.75.5.2345-2352.2001;
RA   Burysek L., Pitha P.M.;
RT   "Latently expressed human herpesvirus 8-encoded interferon regulatory
RT   factor 2 inhibits double-stranded RNA-activated protein kinase.";
RL   J. Virol. 75:2345-2352(2001).
RN   [25]
RP   FUNCTION, AND INTERACTION WITH HHV-1 US11 (MICROBIAL INFECTION).
RX   PubMed=11836380; DOI=10.1128/jvi.76.5.2029-2035.2002;
RA   Cassady K.A., Gross M.;
RT   "The herpes simplex virus type 1 U(S)11 protein interacts with protein
RT   kinase R in infected cells and requires a 30-amino-acid sequence adjacent
RT   to a kinase substrate domain.";
RL   J. Virol. 76:2029-2035(2002).
RN   [26]
RP   INTERACTION WITH NPM1, AND ACTIVITY REGULATION.
RX   PubMed=12882984; DOI=10.1074/jbc.m301392200;
RA   Pang Q., Christianson T.A., Koretsky T., Carlson H., David L., Keeble W.,
RA   Faulkner G.R., Speckhart A., Bagby G.C.;
RT   "Nucleophosmin interacts with and inhibits the catalytic function of
RT   eukaryotic initiation factor 2 kinase PKR.";
RL   J. Biol. Chem. 278:41709-41717(2003).
RN   [27]
RP   FUNCTION, AND INTERACTION WITH MAP2K6.
RX   PubMed=15229216; DOI=10.1074/jbc.m406554200;
RA   Silva A.M., Whitmore M., Xu Z., Jiang Z., Li X., Williams B.R.;
RT   "Protein kinase R (PKR) interacts with and activates mitogen-activated
RT   protein kinase kinase 6 (MKK6) in response to double-stranded RNA
RT   stimulation.";
RL   J. Biol. Chem. 279:37670-37676(2004).
RN   [28]
RP   IDENTIFICATION IN A COMPLEX WITH FANCA; FANCC; FANCG AND HSP70.
RX   PubMed=15299030; DOI=10.1074/jbc.m403884200;
RA   Zhang X., Li J., Sejas D.P., Rathbun K.R., Bagby G.C., Pang Q.;
RT   "The Fanconi anemia proteins functionally interact with the protein kinase
RT   regulated by RNA (PKR).";
RL   J. Biol. Chem. 279:43910-43919(2004).
RN   [29]
RP   FUNCTION, INTERACTION WITH TRAF2; TRAF5 AND TRAF6, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=15121867; DOI=10.1128/mcb.24.10.4502-4512.2004;
RA   Gil J., Garcia M.A., Gomez-Puertas P., Guerra S., Rullas J., Nakano H.,
RA   Alcami J., Esteban M.;
RT   "TRAF family proteins link PKR with NF-kappa B activation.";
RL   Mol. Cell. Biol. 24:4502-4512(2004).
RN   [30]
RP   INHIBITION BY VACCINIA VIRUS PROTEIN E3 (MICROBIAL INFECTION).
RX   PubMed=15207627; DOI=10.1016/j.virol.2004.03.012;
RA   Langland J.O., Jacobs B.L.;
RT   "Inhibition of PKR by vaccinia virus: role of the N- and C-terminal domains
RT   of E3L.";
RL   Virology 324:419-429(2004).
RN   [31]
RP   REVIEW.
RX   PubMed=17158706; DOI=10.1128/mmbr.00027-06;
RA   Garcia M.A., Gil J., Ventoso I., Guerra S., Domingo E., Rivas C.,
RA   Esteban M.;
RT   "Impact of protein kinase PKR in cell biology: from antiviral to
RT   antiproliferative action.";
RL   Microbiol. Mol. Biol. Rev. 70:1032-1060(2006).
RN   [32]
RP   INTERACTION WITH HCMV TRS1 (MICROBIAL INFECTION).
RX   PubMed=16987971; DOI=10.1128/jvi.00957-06;
RA   Hakki M., Marshall E.E., De Niro K.L., Geballe A.P.;
RT   "Binding and nuclear relocalization of protein kinase R by human
RT   cytomegalovirus TRS1.";
RL   J. Virol. 80:11817-11826(2006).
RN   [33]
RP   PHOSPHORYLATION AT TYR-101; TYR-162 AND TYR-293.
RX   PubMed=16373505; DOI=10.1073/pnas.0508207103;
RA   Su Q., Wang S., Baltzis D., Qu L.K., Wong A.H., Koromilas A.E.;
RT   "Tyrosine phosphorylation acts as a molecular switch to full-scale
RT   activation of the eIF2alpha RNA-dependent protein kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:63-68(2006).
RN   [34]
RP   INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX   PubMed=16951545; DOI=10.1016/s1016-8478(23)17385-7;
RA   Liang Y., Kang C.B., Yoon H.S.;
RT   "Molecular and structural characterization of the domain 2 of hepatitis C
RT   virus non-structural protein 5A.";
RL   Mol. Cells 22:13-20(2006).
RN   [35]
RP   INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX   PubMed=17451199; DOI=10.3748/wjg.v13.i8.1195;
RA   Veillon P., Payan C., Le Guillou-Guillemette H., Gaudy C., Lunel F.;
RT   "Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b
RT   during interferon or combined interferon-ribavirin therapy.";
RL   World J. Gastroenterol. 13:1195-1203(2007).
RN   [36]
RP   INTERACTION WITH HCV MATURE CORE PROTEIN (MICROBIAL INFECTION).
RX   PubMed=17267064; DOI=10.1016/j.virusres.2006.12.010;
RA   Yan X.B., Battaglia S., Boucreux D., Chen Z., Brechot C., Pavio N.;
RT   "Mapping of the interacting domains of hepatitis C virus core protein and
RT   the double-stranded RNA-activated protein kinase PKR.";
RL   Virus Res. 125:79-87(2007).
RN   [37]
RP   INTERACTION WITH ADAR.
RX   PubMed=17079286; DOI=10.1128/jvi.01527-06;
RA   Nie Y., Hammond G.L., Yang J.H.;
RT   "Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus
RT   infection.";
RL   J. Virol. 81:917-923(2007).
RN   [38]
RP   REVIEW ON ACTIVITY REGULATION.
RX   PubMed=17196820; DOI=10.1016/j.tibs.2006.12.003;
RA   Cole J.L.;
RT   "Activation of PKR: an open and shut case?";
RL   Trends Biochem. Sci. 32:57-62(2007).
RN   [39]
RP   FUNCTION, INTERACTION WITH NCK1, AND ACTIVITY REGULATION.
RX   PubMed=18835251; DOI=10.1016/j.bbrc.2008.09.112;
RA   Cardin E., Larose L.;
RT   "Nck-1 interacts with PKR and modulates its activation by dsRNA.";
RL   Biochem. Biophys. Res. Commun. 377:231-235(2008).
RN   [40]
RP   INTERACTION WITH DUS2L, AND ACTIVITY REGULATION.
RX   PubMed=18096616; DOI=10.1093/nar/gkm1129;
RA   Mittelstadt M., Frump A., Khuu T., Fowlkes V., Handy I., Patel C.V.,
RA   Patel R.C.;
RT   "Interaction of human tRNA-dihydrouridine synthase-2 with interferon-
RT   induced protein kinase PKR.";
RL   Nucleic Acids Res. 36:998-1008(2008).
RN   [41]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83 AND SER-456, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [42]
RP   MUTAGENESIS OF ASP-486, AND INTERACTION WITH VACCINIA VIRUS PROTEIN K3
RP   (MICROBIAL INFECTION).
RX   PubMed=18971339; DOI=10.1073/pnas.0805524105;
RA   Seo E.J., Liu F., Kawagishi-Kobayashi M., Ung T.L., Cao C., Dar A.C.,
RA   Sicheri F., Dever T.E.;
RT   "Protein kinase PKR mutants resistant to the poxvirus pseudosubstrate K3L
RT   protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:16894-16899(2008).
RN   [43]
RP   FUNCTION.
RX   PubMed=19507191; DOI=10.1002/jcp.21848;
RA   Blalock W.L., Grimaldi C., Fala F., Follo M., Horn S., Basecke J.,
RA   Martinelli G., Cocco L., Martelli A.M.;
RT   "PKR activity is required for acute leukemic cell maintenance and growth: a
RT   role for PKR-mediated phosphatase activity to regulate GSK-3
RT   phosphorylation.";
RL   J. Cell. Physiol. 221:232-241(2009).
RN   [44]
RP   FUNCTION, AND INTERACTION WITH DHX9.
RX   PubMed=19229320; DOI=10.1371/journal.ppat.1000311;
RA   Sadler A.J., Latchoumanin O., Hawkes D., Mak J., Williams B.R.;
RT   "An antiviral response directed by PKR phosphorylation of the RNA helicase
RT   A.";
RL   PLoS Pathog. 5:E1000311-E1000311(2009).
RN   [45]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [46]
RP   FUNCTION IN HCV RESTRICTION.
RX   PubMed=19189853; DOI=10.1016/j.virusres.2009.01.007;
RA   Kang J.I., Kwon S.N., Park S.H., Kim Y.K., Choi S.Y., Kim J.P., Ahn B.Y.;
RT   "PKR protein kinase is activated by hepatitis C virus and inhibits viral
RT   replication through translational control.";
RL   Virus Res. 142:51-56(2009).
RN   [47]
RP   FUNCTION.
RX   PubMed=20171114; DOI=10.1016/j.cyto.2010.01.008;
RA   Lin S.S., Lee D.C., Law A.H., Fang J.W., Chua D.T., Lau A.S.;
RT   "A role for protein kinase PKR in the mediation of Epstein-Barr virus
RT   latent membrane protein-1-induced IL-6 and IL-10 expression.";
RL   Cytokine 50:210-219(2010).
RN   [48]
RP   FUNCTION AS CDK1 KINASE UPON DNA DAMAGE, AND FUNCTION AS TYROSINE-PROTEIN
RP   KINASE.
RX   PubMed=20395957; DOI=10.1038/embor.2010.45;
RA   Yoon C.-H., Miah M.A., Kim K.P., Bae Y.-S.;
RT   "New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers
RT   Cdc2 polyubiquitination and G2 arrest under genotoxic stresses.";
RL   EMBO Rep. 11:393-399(2010).
RN   [49]
RP   FUNCTION.
RX   PubMed=21123651; DOI=10.1101/gad.1965010;
RA   Harashima A., Guettouche T., Barber G.N.;
RT   "Phosphorylation of the NFAR proteins by the dsRNA-dependent protein kinase
RT   PKR constitutes a novel mechanism of translational regulation and cellular
RT   defense.";
RL   Genes Dev. 24:2640-2653(2010).
RN   [50]
RP   INTERACTION WITH HRSV NUCLEOPROTEIN (MICROBIAL INFECTION).
RX   PubMed=20519500; DOI=10.1074/jbc.m109.077321;
RA   Groskreutz D.J., Babor E.C., Monick M.M., Varga S.M., Hunninghake G.W.;
RT   "Respiratory syncytial virus limits alpha subunit of eukaryotic translation
RT   initiation factor 2 (eIF2alpha) phosphorylation to maintain translation and
RT   viral replication.";
RL   J. Biol. Chem. 285:24023-24031(2010).
RN   [51]
RP   FUNCTION IN HCV RESTRICTION.
RX   PubMed=19840259; DOI=10.1111/j.1478-3231.2009.02144.x;
RA   Chang J.H., Kato N., Muroyama R., Taniguchi H., Guleng B., Dharel N.,
RA   Shao R.X., Tateishi K., Jazag A., Kawabe T., Omata M.;
RT   "Double-stranded RNA-activated protein kinase inhibits hepatitis C virus
RT   replication but may be not essential in interferon treatment.";
RL   Liver Int. 30:311-318(2010).
RN   [52]
RP   FUNCTION, AND PHOSPHORYLATION AT THR-451.
RX   PubMed=20685959; DOI=10.1091/mbc.e10-06-0481;
RA   Yang X., Nath A., Opperman M.J., Chan C.;
RT   "The double-stranded RNA-dependent protein kinase differentially regulates
RT   insulin receptor substrates 1 and 2 in HepG2 cells.";
RL   Mol. Biol. Cell 21:3449-3458(2010).
RN   [53]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [54]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [55]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
RX   PubMed=21029237; DOI=10.1111/j.1750-3639.2010.00437.x;
RA   Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F., Hugon J.;
RT   "Modulation of tau phosphorylation by the kinase PKR: implications in
RT   Alzheimer's disease.";
RL   Brain Pathol. 21:189-200(2011).
RN   [56]
RP   REVIEW.
RX   PubMed=21924887; DOI=10.1016/j.coi.2011.08.009;
RA   Pfaller C.K., Li Z., George C.X., Samuel C.E.;
RT   "Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old
RT   players as modulators of the interferon response.";
RL   Curr. Opin. Immunol. 23:573-582(2011).
RN   [57]
RP   REVIEW.
RX   PubMed=21166592; DOI=10.1089/jir.2010.0099;
RA   Pindel A., Sadler A.;
RT   "The role of protein kinase R in the interferon response.";
RL   J. Interferon Cytokine Res. 31:59-70(2011).
RN   [58]
RP   FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY, AND
RP   PHOSPHORYLATION.
RX   PubMed=21072047; DOI=10.1038/leu.2010.264;
RA   Blalock W.L., Bavelloni A., Piazzi M., Tagliavini F., Faenza I.,
RA   Martelli A.M., Follo M.Y., Cocco L.;
RT   "Multiple forms of PKR present in the nuclei of acute leukemia cells
RT   represent an active kinase that is responsive to stress.";
RL   Leukemia 25:236-245(2011).
RN   [59]
RP   FUNCTION IN HBV RESTRICTION.
RX   PubMed=21710204; DOI=10.1007/s10059-011-1059-6;
RA   Park I.H., Baek K.W., Cho E.Y., Ahn B.Y.;
RT   "PKR-dependent mechanisms of interferon-? for inhibiting hepatitis B virus
RT   replication.";
RL   Mol. Cells 32:167-172(2011).
RN   [60]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=22214662; DOI=10.4161/cc.11.2.18999;
RA   Bennett R.L., Pan Y., Christian J., Hui T., May W.S. Jr.;
RT   "The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and
RT   activation, leading to G(1) arrest.";
RL   Cell Cycle 11:407-417(2012).
RN   [61]
RP   REVIEW.
RX   PubMed=22633454; DOI=10.1016/j.immuni.2012.05.010;
RA   Lacy-Hulbert A., Stuart L.M.;
RT   "Penetration resistance: PKR's other talent.";
RL   Immunity 36:695-696(2012).
RN   [62]
RP   FUNCTION.
RX   PubMed=22948139; DOI=10.1074/jbc.m112.390039;
RA   McAllister C.S., Taghavi N., Samuel C.E.;
RT   "Protein kinase PKR amplification of interferon beta induction occurs
RT   through initiation factor eIF-2alpha-mediated translational control.";
RL   J. Biol. Chem. 287:36384-36392(2012).
RN   [63]
RP   FUNCTION, AND INTERACTION WITH STAT3.
RX   PubMed=23084476; DOI=10.1016/j.molcel.2012.09.013;
RA   Shen S., Niso-Santano M., Adjemian S., Takehara T., Malik S.A., Minoux H.,
RA   Souquere S., Marino G., Lachkar S., Senovilla L., Galluzzi L., Kepp O.,
RA   Pierron G., Maiuri M.C., Hikita H., Kroemer R., Kroemer G.;
RT   "Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity.";
RL   Mol. Cell 48:667-680(2012).
RN   [64]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA   Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA   Giglione C.;
RT   "Comparative large-scale characterisation of plant vs. mammal proteins
RT   reveals similar and idiosyncratic N-alpha acetylation features.";
RL   Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN   [65]
RP   FUNCTION, INTERACTION WITH NLRP1; NLRP3; NLRC4 AND AIM2, AND
RP   AUTOPHOSPHORYLATION.
RX   PubMed=22801494; DOI=10.1038/nature11290;
RA   Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbaeck P.,
RA   Valdes-Ferrer S.I., Olofsson P.S., Kalb T., Roth J., Zou Y.,
RA   Erlandsson-Harris H., Yang H., Ting J.P., Wang H., Andersson U.,
RA   Antoine D.J., Chavan S.S., Hotamisligil G.S., Tracey K.J.;
RT   "Novel role of PKR in inflammasome activation and HMGB1 release.";
RL   Nature 488:670-674(2012).
RN   [66]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [67]
RP   REVIEW.
RX   PubMed=23092889; DOI=10.1126/scisignal.2003511;
RA   Kang R., Tang D.;
RT   "PKR-dependent inflammatory signals.";
RL   Sci. Signal. 5:PE47-PE47(2012).
RN   [68]
RP   FUNCTION.
RX   PubMed=22381929; DOI=10.1016/j.virol.2012.01.029;
RA   Taghavi N., Samuel C.E.;
RT   "Protein kinase PKR catalytic activity is required for the PKR-dependent
RT   activation of mitogen-activated protein kinases and amplification of
RT   interferon beta induction following virus infection.";
RL   Virology 427:208-216(2012).
RN   [69]
RP   REVIEW.
RX   PubMed=23202496; DOI=10.3390/v4112598;
RA   Dabo S., Meurs E.F.;
RT   "dsRNA-dependent protein kinase PKR and its role in stress, signaling and
RT   HCV infection.";
RL   Viruses 4:2598-2635(2012).
RN   [70]
RP   TISSUE SPECIFICITY.
RX   PubMed=23403623; DOI=10.1182/blood-2012-09-456400;
RA   Liu X., Bennett R.L., Cheng X., Byrne M., Reinhard M.K., May W.S. Jr.;
RT   "PKR regulates proliferation, differentiation and survival of murine
RT   hematopoietic stem/progenitor cells.";
RL   Blood 121:3364-3374(2013).
RN   [71]
RP   REVIEW.
RX   PubMed=23354059; DOI=10.1007/s00018-012-1252-6;
RA   Donnelly N., Gorman A.M., Gupta S., Samali A.;
RT   "The eIF2alpha kinases: their structures and functions.";
RL   Cell. Mol. Life Sci. 70:3493-3511(2013).
RN   [72]
RP   FUNCTION, ISGYLATION AT LYS-69 AND LYS-159, AND ACTIVITY REGULATION.
RX   PubMed=23229543; DOI=10.1074/jbc.m112.401851;
RA   Okumura F., Okumura A.J., Uematsu K., Hatakeyama S., Zhang D.E., Kamura T.;
RT   "Activation of double-stranded RNA-activated protein kinase (PKR) by
RT   interferon-stimulated gene 15 (ISG15) modification down-regulates protein
RT   translation.";
RL   J. Biol. Chem. 288:2839-2847(2013).
RN   [73]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-542, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [74]
RP   INTERACTION WITH TOSCANA VIRUS PROTEIN NSS (MICROBIAL INFECTION), AND
RP   ACTIVITY REGULATION.
RX   PubMed=23325696; DOI=10.1128/jvi.02506-12;
RA   Kalveram B., Ikegami T.;
RT   "Toscana virus NSs protein promotes degradation of double-stranded RNA-
RT   dependent protein kinase.";
RL   J. Virol. 87:3710-3718(2013).
RN   [75]
RP   FUNCTION IN MV RESTRICTION.
RX   PubMed=23115276; DOI=10.1128/jvi.02270-12;
RA   Okonski K.M., Samuel C.E.;
RT   "Stress granule formation induced by measles virus is protein kinase PKR
RT   dependent and impaired by RNA adenosine deaminase ADAR1.";
RL   J. Virol. 87:756-766(2013).
RN   [76]
RP   FUNCTION.
RX   PubMed=23372823; DOI=10.1371/journal.pone.0055108;
RA   Li Y., Xie J., Wu S., Xia J., Zhang P., Liu C., Zhang P., Huang X.;
RT   "Protein kinase regulated by dsRNA downregulates the interferon production
RT   in dengue virus- and dsrna-stimulated human lung epithelial cells.";
RL   PLoS ONE 8:E55108-E55108(2013).
RN   [77]
RP   FUNCTION IN HCV RESTRICTION.
RX   PubMed=23399035; DOI=10.1016/j.virol.2013.01.015;
RA   Zhang L., Alter H.J., Wang H., Jia S., Wang E., Marincola F.M., Shih J.W.,
RA   Wang R.Y.;
RT   "The modulation of hepatitis C virus 1a replication by PKR is dependent on
RT   NF-kB mediated interferon beta response in Huh7.5.1 cells.";
RL   Virology 438:28-36(2013).
RN   [78]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [79]
RP   INTERACTION WITH VACCINIA VIRUS PROTEIN E3 (MICROBIAL INFECTION).
RX   PubMed=25740987; DOI=10.1128/jvi.03288-14;
RA   Dueck K.J., Hu Y.S., Chen P., Deschambault Y., Lee J., Varga J., Cao J.;
RT   "Mutational analysis of vaccinia virus E3 protein: the biological functions
RT   do not correlate with its biochemical capacity to bind double-stranded
RT   RNA.";
RL   J. Virol. 89:5382-5394(2015).
RN   [80]
RP   INTERACTION WITH MBIP AND MOCS2B, SUBCELLULAR LOCATION, AND
RP   PHOSPHORYLATION.
RX   PubMed=26705305; DOI=10.1093/jmcb/mjv070;
RA   Suganuma T., Swanson S.K., Florens L., Washburn M.P., Workman J.L.;
RT   "Moco biosynthesis and the ATAC acetyltransferase engage translation
RT   initiation by inhibiting latent PKR activity.";
RL   J. Mol. Cell Biol. 8:44-50(2016).
RN   [81]
RP   MUTAGENESIS OF PHE-489; THR-496; ILE-502; LYS-510 AND GLN-516,
RP   CHARACTERIZATION OF VARIANT VAL-506, AND INTERACTION WITH HCMV TRS1
RP   (MICROBIAL INFECTION).
RX   PubMed=27780231; DOI=10.1371/journal.ppat.1005966;
RA   Carpentier K.S., Esparo N.M., Child S.J., Geballe A.P.;
RT   "A Single Amino Acid Dictates Protein Kinase R Susceptibility to Unrelated
RT   Viral Antagonists.";
RL   PLoS Pathog. 12:e1005966-e1005966(2016).
RN   [82]
RP   INTERACTION WITH HUMAN HERPES VIRUS 8 PROTEIN KTA/ORF57 (MICROBIAL
RP   INFECTION).
RX   PubMed=29084250; DOI=10.1371/journal.ppat.1006677;
RA   Sharma N.R., Majerciak V., Kruhlak M.J., Zheng Z.M.;
RT   "KSHV inhibits stress granule formation by viral ORF57 blocking PKR
RT   activation.";
RL   PLoS Pathog. 13:e1006677-e1006677(2017).
RN   [83] {ECO:0007744|PDB:1QU6}
RP   STRUCTURE BY NMR OF 1-170, AND DOMAIN.
RX   PubMed=9736623; DOI=10.1093/emboj/17.18.5458;
RA   Nanduri S., Carpick B.W., Yang Y., Williams B.R.G., Qin J.;
RT   "Structure of the double-stranded RNA-binding domain of the protein kinase
RT   PKR reveals the molecular basis of its dsRNA-mediated activation.";
RL   EMBO J. 17:5458-5465(1998).
RN   [84] {ECO:0007744|PDB:2A19, ECO:0007744|PDB:2A1A}
RP   X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 258-550 IN COMPLEX WITH
RP   EIF2S1/EIF-2ALPHA, PHOSPHORYLATION AT THR-446, DOMAIN, SUBUNIT, COFACTOR,
RP   AND INTERACTION WITH EIF2S1/EIF-2ALPHA.
RX   PubMed=16179258; DOI=10.1016/j.cell.2005.06.044;
RA   Dar A.C., Dever T.E., Sicheri F.;
RT   "Higher-order substrate recognition of eIF2alpha by the RNA-dependent
RT   protein kinase PKR.";
RL   Cell 122:887-900(2005).
RN   [85] {ECO:0007744|PDB:6D3K, ECO:0007744|PDB:6D3L}
RP   X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 229-551, AND SUBUNIT.
RX   PubMed=31246429; DOI=10.1021/acs.biochem.9b00161;
RA   Mayo C.B., Erlandsen H., Mouser D.J., Feinstein A.G., Robinson V.L.,
RA   May E.R., Cole J.L.;
RT   "Structural Basis of Protein Kinase R Autophosphorylation.";
RL   Biochemistry 58:2967-2977(2019).
RN   [86]
RP   INVOLVEMENT IN LEUDEN, FUNCTION, VARIANTS LEUDEN LEU-11; SER-32; PHE-97;
RP   SER-109; VAL-109; PHE-133; SER-325 AND CYS-461, CHARACTERIZATION OF
RP   VARIANTS LEUDEN LEU-11; PHE-133 AND CYS-461, AND VARIANT GLN-114.
RX   PubMed=32197074; DOI=10.1016/j.ajhg.2020.02.016;
RG   Undiagnosed Diseases Network;
RA   Mao D., Reuter C.M., Ruzhnikov M.R.Z., Beck A.E., Farrow E.G., Emrick L.T.,
RA   Rosenfeld J.A., Mackenzie K.M., Robak L., Wheeler M.T., Burrage L.C.,
RA   Jain M., Liu P., Calame D., Kuery S., Sillesen M., Schmitz-Abe K.,
RA   Tonduti D., Spaccini L., Iascone M., Genetti C.A., Koenig M.K., Graf M.,
RA   Tran A., Alejandro M., Lee B.H., Thiffault I., Agrawal P.B.,
RA   Bernstein J.A., Bellen H.J., Chao H.T.;
RT   "De novo EIF2AK1 and EIF2AK2 variants are associated with developmental
RT   delay, leukoencephalopathy, and neurologic decompensation.";
RL   Am. J. Hum. Genet. 106:570-583(2020).
RN   [87]
RP   VARIANTS [LARGE SCALE ANALYSIS] GLU-428; VAL-439 AND VAL-506.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
RN   [88]
RP   VARIANTS DYT33 THR-32; ARG-130 AND ALA-138, CHARACTERIZATION OF VARIANTS
RP   DYT33 THR-32 AND ARG-130, AND INVOLVEMENT IN DYT33.
RX   PubMed=33236446; DOI=10.1002/ana.25973;
RA   Kuipers D.J.S., Mandemakers W., Lu C.S., Olgiati S., Breedveld G.J.,
RA   Fevga C., Tadic V., Carecchio M., Osterman B., Sagi-Dain L., Wu-Chou Y.H.,
RA   Chen C.C., Chang H.C., Wu S.L., Yeh T.H., Weng Y.H., Elia A.E.,
RA   Panteghini C., Marotta N., Pauly M.G., Kuehn A.A., Volkmann J., Lace B.,
RA   Meijer I.A., Kandaswamy K., Quadri M., Garavaglia B., Lohmann K., Bauer P.,
RA   Mencacci N.E., Lubbe S.J., Klein C., Bertoli-Avella A.M., Bonifati V.;
RT   "EIF2AK2 Missense Variants Associated with Early Onset Generalized
RT   Dystonia.";
RL   Ann. Neurol. 89:485-497(2021).
RN   [89]
RP   VARIANT DYT33 ARG-130, AND INVOLVEMENT IN DYT33.
RX   PubMed=33866603; DOI=10.1002/ana.26081;
RA   Musacchio T., Zech M., Reich M.M., Winkelmann J., Volkmann J.;
RT   "A Recurrent EIF2AK2 Missense Variant Causes Autosomal-Dominant Isolated
RT   Dystonia.";
RL   Ann. Neurol. 89:1257-1258(2021).
RN   [90]
RP   VARIANT DYT33 ARG-130.
RX   PubMed=35146068; DOI=10.1002/mdc3.13371;
RA   Magrinelli F., Moualek D., Tazir M., Pacha L.A., Verghese A., Bhatia K.P.,
RA   Maroofian R., Houlden H.;
RT   "Heterozygous EIF2AK2 Variant Causes Adolescence-Onset Generalized Dystonia
RT   Partially Responsive to DBS.";
RL   Mov. Disord. Clin. Pract. 9:268-271(2022).
CC   -!- FUNCTION: IFN-induced dsRNA-dependent serine/threonine-protein kinase
CC       that phosphorylates the alpha subunit of eukaryotic translation
CC       initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the
CC       innate immune response to viral infection (PubMed:18835251,
CC       PubMed:19189853, PubMed:19507191, PubMed:21072047, PubMed:21123651,
CC       PubMed:22381929, PubMed:22948139, PubMed:23229543). Inhibits viral
CC       replication via the integrated stress response (ISR): EIF2S1/eIF-2-
CC       alpha phosphorylation in response to viral infection converts
CC       EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting
CC       to a shutdown of cellular and viral protein synthesis, while
CC       concomitantly initiating the preferential translation of ISR-specific
CC       mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853,
CC       PubMed:21123651, PubMed:22948139, PubMed:23229543). Exerts its
CC       antiviral activity on a wide range of DNA and RNA viruses including
CC       hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV)
CC       and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853,
CC       PubMed:19840259, PubMed:20171114, PubMed:21710204, PubMed:23115276,
CC       PubMed:23399035). Also involved in the regulation of signal
CC       transduction, apoptosis, cell proliferation and differentiation:
CC       phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9,
CC       ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380,
CC       PubMed:19229320, PubMed:22214662). In addition to serine/threonine-
CC       protein kinase activity, also has tyrosine-protein kinase activity and
CC       phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its
CC       ubiquitination and proteasomal degradation (PubMed:20395957). Either as
CC       an adapter protein and/or via its kinase activity, can regulate various
CC       signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling
CC       pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3)
CC       involved in the expression of genes encoding pro-inflammatory cytokines
CC       and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823). Activates
CC       the NF-kappa-B pathway via interaction with IKBKB and TRAF family of
CC       proteins and activates the p38 MAP kinase pathway via interaction with
CC       MAP2K6 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as
CC       both a positive and negative regulator of the insulin signaling pathway
CC       (ISP) (PubMed:20685959). Negatively regulates ISP by inducing the
CC       inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at
CC       'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A
CC       which activates FOXO1, which in turn up-regulates the expression of
CC       insulin receptor substrate 2 (IRS2) (PubMed:20685959). Can regulate
CC       NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2
CC       and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the
CC       regulation of the cytoskeleton by binding to gelsolin (GSN),
CC       sequestering the protein in an inactive conformation away from actin
CC       (By similarity). {ECO:0000250|UniProtKB:Q03963,
CC       ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380,
CC       ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216,
CC       ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853,
CC       ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191,
CC       ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114,
CC       ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959,
CC       ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651,
CC       ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662,
CC       ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494,
CC       ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476,
CC       ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543,
CC       ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035,
CC       ECO:0000269|PubMed:32197074}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC         COMP:20101, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC         ChEBI:CHEBI:61978, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU10027};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:16179258, ECO:0000303|PubMed:31246429};
CC   -!- ACTIVITY REGULATION: Initially produced in an inactive form and is
CC       activated by binding to viral dsRNA, which causes dimerization and
CC       autophosphorylation in the activation loop and stimulation of function.
CC       ISGylation can activate it in the absence of viral infection. Can also
CC       be activated by heparin, pro-inflammatory stimuli, growth factors,
CC       cytokines, oxidative stress and the cellular protein PRKRA. Activity is
CC       markedly stimulated by manganese ions. Activation is blocked by the
CC       viral components HIV-1 Tat protein and large amounts of HIV-1 trans-
CC       activation response (TAR) RNA element as well as by the cellular
CC       proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana
CC       virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its
CC       proteasomal degradation. Inhibited by vaccinia virus protein E3,
CC       probably via dsRNA sequestering. {ECO:0000269|PubMed:12882984,
CC       ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251,
CC       ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23325696}.
CC   -!- SUBUNIT: Homodimer (PubMed:16179258, PubMed:31246429). Interacts with
CC       STRBP (By similarity). Interacts with DNAJC3. Forms a complex with
CC       FANCA, FANCC, FANCG and HSP70. Interacts with ADAR/ADAR1. Interacts
CC       with IRS1 (By similarity). The inactive form interacts with NCK1 and
CC       GSN. Interacts (via the kinase catalytic domain) with STAT3 (via SH2
CC       domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus).
CC       Interacts with MAP2K6, IKBKB/IKKB, NPM1, TARBP2, NLRP1, NLRP3, NLRC4
CC       and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain).
CC       Interacts with DHX9 (via N-terminus) and this interaction is dependent
CC       upon activation of the kinase. Interacts with EIF2S1/EIF-2ALPHA; this
CC       interaction induces a conformational change in EIF2S1 and its
CC       phosphorylation by EIF2AK2 (PubMed:16179258). Interacts with MBIP; the
CC       interaction is direct and leads to inhibition of EIF2AK2 self-
CC       activating autophosphorylation (PubMed:26705305). Interacts with the
CC       molybdopterin synthase complex subunit MOCS2B; the interaction is
CC       direct and enhances the interaction between EIF2AK2 and MBIP
CC       (PubMed:26705305). {ECO:0000250|UniProtKB:Q03963,
CC       ECO:0000269|PubMed:10390359, ECO:0000269|PubMed:10848580,
CC       ECO:0000269|PubMed:11438532, ECO:0000269|PubMed:12882984,
CC       ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216,
CC       ECO:0000269|PubMed:15299030, ECO:0000269|PubMed:16179258,
CC       ECO:0000269|PubMed:17079286, ECO:0000269|PubMed:18096616,
CC       ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19229320,
CC       ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:23084476,
CC       ECO:0000269|PubMed:25740987, ECO:0000269|PubMed:26705305,
CC       ECO:0000269|PubMed:31246429, ECO:0000269|PubMed:8576172,
CC       ECO:0000269|PubMed:9079663, ECO:0000269|PubMed:9143277,
CC       ECO:0000269|PubMed:9781815}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus
CC       (HCMV) TRS1; this interaction retains EIF2AK2 to the nucleus and
CC       prevents its activation. {ECO:0000269|PubMed:16987971,
CC       ECO:0000269|PubMed:27780231}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with vaccinia virus protein K3
CC       (K3L); this interaction inhibits EIF2AK2.
CC       {ECO:0000269|PubMed:18971339}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with human herpes simplex
CC       virus 1 (HHV-1) protein US11 in an RNA-dependent manner.
CC       {ECO:0000269|PubMed:11836380}.
CC   -!- SUBUNIT: (Microbial infection) The inactive form interacts with Toscana
CC       virus (TOS) NSS. {ECO:0000269|PubMed:23325696}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8 protein v-
CC       IRF2; this interaction inhibits EIF2AK2 activation.
CC       {ECO:0000269|PubMed:11160738}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with vaccinia protein E3.
CC       {ECO:0000269|PubMed:25740987}.
CC   -!- SUBUNIT: (Microbial infection) Interacts (via N-terminus) with
CC       Hepatitis C virus (HCV) mature core protein (via N-terminus); this
CC       interaction induces the autophosphorylation of EIF2AK2.
CC       {ECO:0000269|PubMed:17267064}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with Hepatitis C virus (HCV)
CC       non-structural protein 5A (NS5A); this interaction leads to disruption
CC       of EIF2AK2 dimerization by NS5A. {ECO:0000269|PubMed:16951545,
CC       ECO:0000269|PubMed:17451199, ECO:0000269|PubMed:9143277,
CC       ECO:0000269|PubMed:9710605}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with Hepatitis C virus (HCV)
CC       envelope glycoprotein E2; this interaction inhibits EIF2AK2 and blocks
CC       its inhibitory effect on protein synthesis and cell growth.
CC       {ECO:0000269|PubMed:9143277}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with human respiratory
CC       syncytial virus (HRSV) nucleoprotein; this interaction inhibits EIF2AK2
CC       phosphorylation of EIF2S1 and blocks EIF2AK2-mediated translation
CC       shutoff. {ECO:0000269|PubMed:20519500}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with human herpesvirus 8
CC       protein MTA/ORF57; this interaction inhibits stress granule formation.
CC       {ECO:0000269|PubMed:29084250}.
CC   -!- INTERACTION:
CC       P19525; P78563-4: ADARB1; NbExp=3; IntAct=EBI-640775, EBI-12002366;
CC       P19525; P06493: CDK1; NbExp=4; IntAct=EBI-640775, EBI-444308;
CC       P19525; Q7L2E3: DHX30; NbExp=4; IntAct=EBI-640775, EBI-1211456;
CC       P19525; Q96C10: DHX58; NbExp=2; IntAct=EBI-640775, EBI-744193;
CC       P19525; Q08211: DHX9; NbExp=4; IntAct=EBI-640775, EBI-352022;
CC       P19525; Q9UPY3: DICER1; NbExp=2; IntAct=EBI-640775, EBI-395506;
CC       P19525; Q6P2E9: EDC4; NbExp=2; IntAct=EBI-640775, EBI-1006038;
CC       P19525; P19525: EIF2AK2; NbExp=2; IntAct=EBI-640775, EBI-640775;
CC       P19525; P05198: EIF2S1; NbExp=5; IntAct=EBI-640775, EBI-1056162;
CC       P19525; P56537: EIF6; NbExp=2; IntAct=EBI-640775, EBI-372243;
CC       P19525; Q8IY81: FTSJ3; NbExp=3; IntAct=EBI-640775, EBI-744088;
CC       P19525; Q9HCE1: MOV10; NbExp=3; IntAct=EBI-640775, EBI-1055820;
CC       P19525; Q96P20: NLRP3; NbExp=6; IntAct=EBI-640775, EBI-6253230;
CC       P19525; P06748: NPM1; NbExp=4; IntAct=EBI-640775, EBI-78579;
CC       P19525; O75569: PRKRA; NbExp=6; IntAct=EBI-640775, EBI-713955;
CC       P19525; O75569-1: PRKRA; NbExp=3; IntAct=EBI-640775, EBI-15588172;
CC       P19525; Q9NUL3: STAU2; NbExp=3; IntAct=EBI-640775, EBI-722938;
CC       P19525; Q15633: TARBP2; NbExp=2; IntAct=EBI-640775, EBI-978581;
CC       P19525; Q9H0E2: TOLLIP; NbExp=2; IntAct=EBI-640775, EBI-74615;
CC       P19525; Q9UL40: ZNF346; NbExp=4; IntAct=EBI-640775, EBI-2462313;
CC       P19525; Q27968: DNAJC3; Xeno; NbExp=5; IntAct=EBI-640775, EBI-640793;
CC       P19525; P0DTC9: N; Xeno; NbExp=8; IntAct=EBI-640775, EBI-25475856;
CC       P19525; P20639: OPG041; Xeno; NbExp=3; IntAct=EBI-640775, EBI-8674942;
CC       P19525; P04487: US11; Xeno; NbExp=3; IntAct=EBI-640775, EBI-6150681;
CC       P19525; Q2HR71: vIRF-2; Xeno; NbExp=2; IntAct=EBI-640775, EBI-8876177;
CC       P19525; PRO_0000278746 [O92972]; Xeno; NbExp=2; IntAct=EBI-640775, EBI-6918883;
CC       P19525; PRO_0000037570 [P27958]; Xeno; NbExp=4; IntAct=EBI-640775, EBI-6904269;
CC       P19525; PRO_0000037576 [P27958]; Xeno; NbExp=5; IntAct=EBI-640775, EBI-8753518;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15121867,
CC       ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:22214662,
CC       ECO:0000269|PubMed:26705305}. Nucleus {ECO:0000269|PubMed:21029237,
CC       ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:26705305}. Cytoplasm,
CC       perinuclear region {ECO:0000269|PubMed:15121867}. Note=Nuclear
CC       localization is elevated in acute leukemia, myelodysplastic syndrome
CC       (MDS), melanoma, breast, colon, prostate and lung cancer patient
CC       samples or cell lines as well as neurocytes from advanced Creutzfeldt-
CC       Jakob disease patients. {ECO:0000269|PubMed:21072047}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P19525-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P19525-2; Sequence=VSP_046177;
CC   -!- TISSUE SPECIFICITY: Highly expressed in thymus, spleen and bone marrow
CC       compared to non-hematopoietic tissues such as small intestine, liver,
CC       or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer
CC       disease (AD) brain. Elevated levels seen in breast and colon
CC       carcinomas, and which correlates with tumor progression and
CC       invasiveness or risk of progression. {ECO:0000269|PubMed:21029237,
CC       ECO:0000269|PubMed:23403623}.
CC   -!- INDUCTION: By type I interferons. {ECO:0000269|PubMed:1695551}.
CC   -!- DOMAIN: Contains 2 dsRNA-binding domain (DRBM) (PubMed:9736623). The N-
CC       terminus contains the catalytic domain dimerization. The C-terminus
CC       binds EIF2S1/EIF2-alpha (PubMed:16179258).
CC       {ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:9736623}.
CC   -!- PTM: Autophosphorylated on several Ser, Thr and Tyr residues.
CC       Autophosphorylation of Thr-451 is dependent on Thr-446 and is
CC       stimulated by dsRNA binding and dimerization. Autophosphorylation
CC       apparently leads to the activation of the kinase. Tyrosine
CC       autophosphorylation is essential for efficient dsRNA-binding,
CC       dimerization, and kinase activation. Autophosphorylation is inhibited
CC       by the concerted action of ATAC complex subunit MBIP and molybdopterin
CC       synthase complex subunit MOCS2B (PubMed:26705305).
CC       {ECO:0000269|PubMed:11152499, ECO:0000269|PubMed:11337501,
CC       ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:16373505,
CC       ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21029237,
CC       ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:26705305}.
CC   -!- DISEASE: Leukoencephalopathy, developmental delay, and episodic
CC       neurologic regression syndrome (LEUDEN) [MIM:618877]: An autosomal
CC       dominant disorder characterized by global developmental delay apparent
CC       in early childhood, cognitive impairment, ataxia, poor or absent speech
CC       with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor,
CC       and abnormal involuntary movements. Affected individuals also exhibit
CC       neurological regression in the setting of febrile illness or infection.
CC       Many patients have seizures. Brain imaging shows diffuse white matter
CC       abnormalities with poor myelination. {ECO:0000269|PubMed:32197074}.
CC       Note=The disease may be caused by variants affecting the gene
CC       represented in this entry.
CC   -!- DISEASE: Dystonia 33 (DYT33) [MIM:619687]: A form of dystonia, a
CC       disorder defined by the presence of sustained involuntary muscle
CC       contraction, often leading to abnormal postures. DYT33 is a slowly
CC       progressive form characterized by onset of focal or generalized
CC       dystonia in the first decades of life. Disease manifestations are
CC       variable. Some patients show ambulation difficulties, dysarthria, or
CC       dysphagia. Some affected individuals may manifest motor delay, lower
CC       limb spasticity, and mild developmental delay with intellectual
CC       disability. DYT33 penetrance is incomplete. Inheritance can be
CC       autosomal dominant or recessive. {ECO:0000269|PubMed:33236446,
CC       ECO:0000269|PubMed:33866603, ECO:0000269|PubMed:35146068}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC       kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/41866/EIF2AK2";
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DR   EMBL; M35663; AAA36409.1; -; mRNA.
DR   EMBL; M85294; AAA18253.1; -; mRNA.
DR   EMBL; U50648; AAC50768.1; -; Genomic_DNA.
DR   EMBL; U50634; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50635; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50636; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50637; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50638; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50639; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50640; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50641; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50642; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50643; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50644; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50645; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50646; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; U50647; AAC50768.1; JOINED; Genomic_DNA.
DR   EMBL; AF167472; AAF13156.1; -; Genomic_DNA.
DR   EMBL; AF167460; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AF167462; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AF167463; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AF167464; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AF167465; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AF167466; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AF167468; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AF167470; AAF13156.1; JOINED; Genomic_DNA.
DR   EMBL; AY302136; AAP57628.1; -; mRNA.
DR   EMBL; AK290655; BAF83344.1; -; mRNA.
DR   EMBL; AK313818; BAG36554.1; -; mRNA.
DR   EMBL; AY228338; AAO38055.1; -; Genomic_DNA.
DR   EMBL; AC007899; AAY24317.1; -; Genomic_DNA.
DR   EMBL; CH471053; EAX00407.1; -; Genomic_DNA.
DR   EMBL; CH471053; EAX00408.1; -; Genomic_DNA.
DR   EMBL; CH471053; EAX00409.1; -; Genomic_DNA.
DR   EMBL; BC093676; AAH93676.1; -; mRNA.
DR   EMBL; BC101475; AAI01476.1; -; mRNA.
DR   CCDS; CCDS1786.1; -. [P19525-1]
DR   CCDS; CCDS46259.1; -. [P19525-2]
DR   PIR; JC5225; JC5225.
DR   RefSeq; NP_001129123.1; NM_001135651.3. [P19525-1]
DR   RefSeq; NP_001129124.1; NM_001135652.2. [P19525-2]
DR   RefSeq; NP_002750.1; NM_002759.4. [P19525-1]
DR   RefSeq; XP_011531289.1; XM_011532987.3. [P19525-1]
DR   RefSeq; XP_054198993.1; XM_054343018.1. [P19525-1]
DR   PDB; 1QU6; NMR; -; A=1-170.
DR   PDB; 2A19; X-ray; 2.50 A; B/C=258-550.
DR   PDB; 2A1A; X-ray; 2.80 A; B=258-550.
DR   PDB; 3UIU; X-ray; 2.90 A; A/B=254-551.
DR   PDB; 6D3K; X-ray; 2.60 A; A/B/C=229-551.
DR   PDB; 6D3L; X-ray; 3.10 A; A=229-551.
DR   PDB; 7OBK; X-ray; 1.80 A; B=541-551.
DR   PDB; 7OBL; X-ray; 1.80 A; B=541-551.
DR   PDB; 8BI7; X-ray; 1.40 A; B=541-551.
DR   PDB; 8I9J; EM; 6.39 A; A=1-170.
DR   PDB; 8IZN; EM; 6.67 A; A=1-170.
DR   PDBsum; 1QU6; -.
DR   PDBsum; 2A19; -.
DR   PDBsum; 2A1A; -.
DR   PDBsum; 3UIU; -.
DR   PDBsum; 6D3K; -.
DR   PDBsum; 6D3L; -.
DR   PDBsum; 7OBK; -.
DR   PDBsum; 7OBL; -.
DR   PDBsum; 8BI7; -.
DR   PDBsum; 8I9J; -.
DR   PDBsum; 8IZN; -.
DR   AlphaFoldDB; P19525; -.
DR   BMRB; P19525; -.
DR   EMDB; EMD-35274; -.
DR   EMDB; EMD-35866; -.
DR   SMR; P19525; -.
DR   BioGRID; 111596; 395.
DR   DIP; DIP-2657N; -.
DR   FunCoup; P19525; 998.
DR   IntAct; P19525; 176.
DR   MINT; P19525; -.
DR   STRING; 9606.ENSP00000233057; -.
DR   BindingDB; P19525; -.
DR   ChEMBL; CHEMBL5785; -.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugBank; DB07995; H-89.
DR   DrugBank; DB00328; Indomethacin.
DR   DrugCentral; P19525; -.
DR   GuidetoPHARMACOLOGY; 2016; -.
DR   GlyGen; P19525; 2 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (1 site).
DR   iPTMnet; P19525; -.
DR   PhosphoSitePlus; P19525; -.
DR   SwissPalm; P19525; -.
DR   BioMuta; EIF2AK2; -.
DR   DMDM; 125527; -.
DR   jPOST; P19525; -.
DR   MassIVE; P19525; -.
DR   PaxDb; 9606-ENSP00000233057; -.
DR   PeptideAtlas; P19525; -.
DR   ProteomicsDB; 19391; -.
DR   ProteomicsDB; 53670; -. [P19525-1]
DR   Pumba; P19525; -.
DR   TopDownProteomics; P19525-1; -. [P19525-1]
DR   Antibodypedia; 3548; 1196 antibodies from 44 providers.
DR   DNASU; 5610; -.
DR   Ensembl; ENST00000233057.9; ENSP00000233057.4; ENSG00000055332.20. [P19525-1]
DR   Ensembl; ENST00000395127.6; ENSP00000378559.2; ENSG00000055332.20. [P19525-1]
DR   Ensembl; ENST00000405334.5; ENSP00000385014.1; ENSG00000055332.20. [P19525-2]
DR   Ensembl; ENST00000647926.1; ENSP00000497534.1; ENSG00000055332.20. [P19525-1]
DR   Ensembl; ENST00000679507.1; ENSP00000506024.1; ENSG00000055332.20. [P19525-1]
DR   Ensembl; ENST00000681463.1; ENSP00000505138.1; ENSG00000055332.20. [P19525-1]
DR   Ensembl; ENST00000681507.1; ENSP00000505772.1; ENSG00000055332.20. [P19525-1]
DR   GeneID; 5610; -.
DR   KEGG; hsa:5610; -.
DR   MANE-Select; ENST00000233057.9; ENSP00000233057.4; NM_001135651.3; NP_001129123.1.
DR   UCSC; uc010fab.3; human. [P19525-1]
DR   AGR; HGNC:9437; -.
DR   ClinPGx; PA33779; -.
DR   CTD; 5610; -.
DR   DisGeNET; 5610; -.
DR   GeneCards; EIF2AK2; -.
DR   HGNC; HGNC:9437; EIF2AK2.
DR   HPA; ENSG00000055332; Low tissue specificity.
DR   MalaCards; EIF2AK2; -.
DR   MIM; 176871; gene.
DR   MIM; 618877; phenotype.
DR   MIM; 619687; phenotype.
DR   OpenTargets; ENSG00000055332; -.
DR   Orphanet; 256; Early-onset generalized limb-onset dystonia.
DR   VEuPathDB; HostDB:ENSG00000055332; -.
DR   eggNOG; KOG1033; Eukaryota.
DR   GeneTree; ENSGT00940000160736; -.
DR   HOGENOM; CLU_023682_1_0_1; -.
DR   InParanoid; P19525; -.
DR   OMA; KIACEMM; -.
DR   OrthoDB; 341578at2759; -.
DR   PAN-GO; P19525; 2 GO annotations based on evolutionary models.
DR   PhylomeDB; P19525; -.
DR   PathwayCommons; P19525; -.
DR   Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR   Reactome; R-HSA-169131; Inhibition of PKR.
DR   Reactome; R-HSA-4755510; SUMOylation of immune response proteins.
DR   Reactome; R-HSA-909733; Interferon alpha/beta signaling.
DR   Reactome; R-HSA-9833109; Evasion by RSV of host interferon responses.
DR   Reactome; R-HSA-9833482; PKR-mediated signaling.
DR   SignaLink; P19525; -.
DR   SIGNOR; P19525; -.
DR   Agora; ENSG00000055332; -.
DR   BioGRID-ORCS; 5610; 13 hits in 1193 CRISPR screens.
DR   CD-CODE; 91857CE7; Nucleolus.
DR   CD-CODE; DEE660B4; Stress granule.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; EIF2AK2; human.
DR   EvolutionaryTrace; P19525; -.
DR   GeneWiki; Protein_kinase_R; -.
DR   GenomeRNAi; 5610; -.
DR   Pharos; P19525; Tchem.
DR   PRO; PR:P19525; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; P19525; protein.
DR   Bgee; ENSG00000055332; Expressed in endometrium epithelium and 211 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005840; C:ribosome; TAS:AgBase.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0003725; F:double-stranded RNA binding; IDA:MGI.
DR   GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IMP:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0016301; F:kinase activity; IDA:UniProt.
DR   GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR   GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR   GO; GO:0019888; F:protein phosphatase regulator activity; TAS:ProtInc.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProt.
DR   GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR   GO; GO:0140374; P:antiviral innate immune response; IDA:UniProt.
DR   GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB.
DR   GO; GO:0051607; P:defense response to virus; IEP:ARUK-UCL.
DR   GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
DR   GO; GO:0033689; P:negative regulation of osteoblast proliferation; IMP:UniProtKB.
DR   GO; GO:0017148; P:negative regulation of translation; IDA:UniProtKB.
DR   GO; GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB.
DR   GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
DR   GO; GO:0001819; P:positive regulation of cytokine production; ISS:UniProtKB.
DR   GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:UniProtKB.
DR   GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR   GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; ISS:UniProtKB.
DR   GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; ISS:UniProtKB.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; ISS:UniProtKB.
DR   GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB.
DR   GO; GO:1902033; P:regulation of hematopoietic stem cell proliferation; ISS:UniProtKB.
DR   GO; GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
DR   GO; GO:0006446; P:regulation of translational initiation; IBA:GO_Central.
DR   GO; GO:0035455; P:response to interferon-alpha; IDA:UniProtKB.
DR   GO; GO:0009615; P:response to virus; IMP:UniProtKB.
DR   GO; GO:0006412; P:translation; IEA:Ensembl.
DR   CDD; cd19903; DSRM_EIF2AK2_rpt1; 1.
DR   CDD; cd19904; DSRM_EIF2AK2_rpt2; 1.
DR   CDD; cd14047; STKc_EIF2AK2_PKR; 1.
DR   DisProt; DP03944; -.
DR   FunFam; 3.30.160.20:FF:000045; Eukaryotic translation initiation factor 2-alpha kinase 2; 1.
DR   FunFam; 3.30.160.20:FF:000062; Eukaryotic translation initiation factor 2-alpha kinase 2; 1.
DR   FunFam; 3.30.200.20:FF:000536; Eukaryotic translation initiation factor 2-alpha kinase 2; 1.
DR   FunFam; 1.10.510.10:FF:000251; eukaryotic translation initiation factor 2-alpha kinase 3; 1.
DR   Gene3D; 3.30.160.20; -; 2.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   IDEAL; IID00443; -.
DR   InterPro; IPR050339; CC_SR_Kinase.
DR   InterPro; IPR014720; dsRBD_dom.
DR   InterPro; IPR044452; EIF2AK2_DSRM_1.
DR   InterPro; IPR044453; EIF2AK2_DSRM_2.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR11042; EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE EIF2-ALPHA KINASE -RELATED; 1.
DR   PANTHER; PTHR11042:SF163; INTERFERON-INDUCED, DOUBLE-STRANDED RNA-ACTIVATED PROTEIN KINASE; 1.
DR   Pfam; PF00035; dsrm; 2.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00358; DSRM; 2.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF54768; dsRNA-binding domain-like; 2.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS50137; DS_RBD; 2.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Antiviral defense;
KW   ATP-binding; Cytoplasm; Direct protein sequencing; Disease variant;
KW   Dystonia; Host-virus interaction; Immunity; Innate immunity;
KW   Isopeptide bond; Kinase; Magnesium; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Proteomics identification; Reference proteome; Repeat;
KW   RNA-binding; Serine/threonine-protein kinase; Transcription;
KW   Transcription regulation; Transferase; Tyrosine-protein kinase;
KW   Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|Ref.13, ECO:0007744|PubMed:22223895,
FT                   ECO:0007744|PubMed:22814378"
FT   CHAIN           2..551
FT                   /note="Interferon-induced, double-stranded RNA-activated
FT                   protein kinase"
FT                   /id="PRO_0000085945"
FT   DOMAIN          9..77
FT                   /note="DRBM 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00266,
FT                   ECO:0000269|PubMed:9736623"
FT   DOMAIN          100..167
FT                   /note="DRBM 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00266,
FT                   ECO:0000269|PubMed:9736623"
FT   DOMAIN          267..538
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REPEAT          331..343
FT                   /note="1"
FT   REPEAT          345..357
FT                   /note="2"
FT   REGION          2..180
FT                   /note="(Microbial infection) Interaction with HCV NS5A"
FT                   /evidence="ECO:0000269|PubMed:17267064"
FT   REGION          202..222
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          266..551
FT                   /note="Interaction with TRAF5"
FT                   /evidence="ECO:0000269|PubMed:15121867"
FT   REGION          266..362
FT                   /note="Dimerization"
FT                   /evidence="ECO:0000269|PubMed:16179258"
FT   REGION          331..357
FT                   /note="2 X 13 AA approximate repeats"
FT   REGION          379..496
FT                   /note="Interaction with EIF2S1/EIF-2ALPHA"
FT                   /evidence="ECO:0000269|PubMed:16179258"
FT   COMPBIAS        202..215
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        414
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         273..281
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         296
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   BINDING         432
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000305|PubMed:16179258,
FT                   ECO:0000305|PubMed:31246429"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0000269|Ref.13, ECO:0007744|PubMed:22223895,
FT                   ECO:0007744|PubMed:22814378"
FT   MOD_RES         83
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:11152499,
FT                   ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332,
FT                   ECO:0007744|PubMed:20068231"
FT   MOD_RES         88
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000305|PubMed:11152499"
FT   MOD_RES         89
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000305|PubMed:11152499"
FT   MOD_RES         90
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000305|PubMed:11152499"
FT   MOD_RES         101
FT                   /note="Phosphotyrosine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16373505"
FT   MOD_RES         162
FT                   /note="Phosphotyrosine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16373505"
FT   MOD_RES         242
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000305|PubMed:11152499"
FT   MOD_RES         255
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000305|PubMed:11152499"
FT   MOD_RES         258
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000305|PubMed:11152499"
FT   MOD_RES         293
FT                   /note="Phosphotyrosine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16373505"
FT   MOD_RES         446
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:11337501,
FT                   ECO:0000269|PubMed:16179258"
FT   MOD_RES         451
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:11337501,
FT                   ECO:0000269|PubMed:20685959"
FT   MOD_RES         456
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         542
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   CROSSLNK        69
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ISG15)"
FT                   /evidence="ECO:0000269|PubMed:23229543"
FT   CROSSLNK        159
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ISG15)"
FT                   /evidence="ECO:0000269|PubMed:23229543"
FT   VAR_SEQ         263..303
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.7"
FT                   /id="VSP_046177"
FT   VARIANT         11
FT                   /note="M -> L (in LEUDEN; uncertain significance; reduced
FT                   phosphorylation of eukaryotic translation initiation factor
FT                   2-alpha in patient cells)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084260"
FT   VARIANT         32
FT                   /note="N -> S (in LEUDEN; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084261"
FT   VARIANT         32
FT                   /note="N -> T (in DYT33; uncertain significance; gain-of-
FT                   function variant resulting in increased levels of
FT                   phosphorylated EIF2AK2 and EIF2A in patient cells compared
FT                   to controls)"
FT                   /evidence="ECO:0000269|PubMed:33236446"
FT                   /id="VAR_086715"
FT   VARIANT         97
FT                   /note="S -> F (in LEUDEN; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084262"
FT   VARIANT         109
FT                   /note="A -> S (in LEUDEN; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084263"
FT   VARIANT         109
FT                   /note="A -> V (in LEUDEN; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084264"
FT   VARIANT         114
FT                   /note="L -> Q (found in a patient with dysmorphic facies,
FT                   syndactyly, congenital microcephaly and global
FT                   developmental delay; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084265"
FT   VARIANT         130
FT                   /note="G -> R (in DYT33; gain-of-function variant resulting
FT                   in increased levels of phosphorylated EIF2AK2 and EIF2A in
FT                   patient cells compared to controls)"
FT                   /evidence="ECO:0000269|PubMed:33236446,
FT                   ECO:0000269|PubMed:33866603, ECO:0000269|PubMed:35146068"
FT                   /id="VAR_086716"
FT   VARIANT         133
FT                   /note="Y -> F (in LEUDEN; uncertain significance; reduced
FT                   phosphorylation of eukaryotic translation initiation factor
FT                   2-alpha in patient cells)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084266"
FT   VARIANT         138
FT                   /note="G -> A (in DYT33; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:33236446"
FT                   /id="VAR_086717"
FT   VARIANT         325
FT                   /note="G -> S (in LEUDEN; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084267"
FT   VARIANT         428
FT                   /note="V -> E (in dbSNP:rs56219559)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040474"
FT   VARIANT         439
FT                   /note="L -> V (in a lung adenocarcinoma sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040475"
FT   VARIANT         461
FT                   /note="S -> C (in LEUDEN; uncertain significance; reduced
FT                   phosphorylation of eukaryotic translation initiation factor
FT                   2-alpha in patient cells)"
FT                   /evidence="ECO:0000269|PubMed:32197074"
FT                   /id="VAR_084268"
FT   VARIANT         506
FT                   /note="I -> V (no effect on PKR inhibition by HCMV protein
FT                   TRS1; dbSNP:rs34821155)"
FT                   /evidence="ECO:0000269|PubMed:17344846,
FT                   ECO:0000269|PubMed:27780231"
FT                   /id="VAR_040476"
FT   MUTAGEN         59..60
FT                   /note="SK->AA: In FL-PKR-2AI; moderate loss of activity but
FT                   no effect on dsRNA binding."
FT                   /evidence="ECO:0000269|PubMed:11337501"
FT   MUTAGEN         60
FT                   /note="K->A: Impairs dsRNA binding but not dimerization or
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:11337501"
FT   MUTAGEN         67
FT                   /note="A->E: Significant loss of activity; loss of dsRNA
FT                   binding and dimerization."
FT                   /evidence="ECO:0000269|PubMed:11337501"
FT   MUTAGEN         83
FT                   /note="S->A: No effect on enzymatic activity; when
FT                   associated with A-88; A-89 and A-90."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         88
FT                   /note="T->A: No effect on enzymatic activity; when
FT                   associated with A-83; A-89 and A-90."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         89
FT                   /note="T->A: No effect on enzymatic activity; when
FT                   associated with A-83; A-88 and A-90."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         90
FT                   /note="T->A: No effect on enzymatic activity; when
FT                   associated with A-83; A-88 and A-89."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         149..150
FT                   /note="TK->AA: In FL-PKR-2AII; no effect on activity."
FT                   /evidence="ECO:0000269|PubMed:11337501"
FT   MUTAGEN         242
FT                   /note="S->A: Moderate loss of activity; when associated
FT                   with A-255 and A-258."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         244..296
FT                   /note="Missing: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:11337501"
FT   MUTAGEN         255
FT                   /note="T->A: Moderate loss of activity; when associated
FT                   with A-242 and A-255."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         258
FT                   /note="T->A: Moderate loss of activity."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         296
FT                   /note="K->R: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:11152499"
FT   MUTAGEN         446
FT                   /note="T->A: Significant loss of activity and impairs
FT                   autophosphorylation of T-451."
FT                   /evidence="ECO:0000269|PubMed:11337501"
FT   MUTAGEN         451
FT                   /note="T->A: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:11337501"
FT   MUTAGEN         486
FT                   /note="D->V: 15-fold decrease in K3L binding affinity and
FT                   thus resistance of mutated PKR to K3L inhibition."
FT                   /evidence="ECO:0000269|PubMed:18971339"
FT   MUTAGEN         489
FT                   /note="F->S: Loss of PKR inhibition by HCMV protein TRS1."
FT                   /evidence="ECO:0000269|PubMed:27780231"
FT   MUTAGEN         496
FT                   /note="T->K: No effect on PKR inhibition by HCMV protein
FT                   TRS1."
FT                   /evidence="ECO:0000269|PubMed:27780231"
FT   MUTAGEN         502
FT                   /note="I->T: No effect on PKR inhibition by HCMV protein
FT                   TRS1."
FT                   /evidence="ECO:0000269|PubMed:27780231"
FT   MUTAGEN         510
FT                   /note="K->R: No effect on PKR inhibition by HCMV protein
FT                   TRS1."
FT                   /evidence="ECO:0000269|PubMed:27780231"
FT   MUTAGEN         516
FT                   /note="Q->E: No effect on PKR inhibition by HCMV protein
FT                   TRS1."
FT                   /evidence="ECO:0000269|PubMed:27780231"
FT   CONFLICT        102
FT                   /note="I -> M (in Ref. 7; AAP57628)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        224
FT                   /note="S -> R (in Ref. 7; AAP57628)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        512
FT                   /note="K -> E (in Ref. 6; AAF13156)"
FT                   /evidence="ECO:0000305"
FT   STRAND          5..7
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   HELIX           10..21
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   STRAND          26..32
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   TURN            35..37
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   STRAND          41..50
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   STRAND          54..56
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   HELIX           61..76
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   HELIX           102..111
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   STRAND          115..123
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   STRAND          125..138
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   STRAND          144..149
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   HELIX           150..167
FT                   /evidence="ECO:0007829|PDB:1QU6"
FT   HELIX           261..266
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          267..274
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          276..278
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          281..286
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   TURN            287..289
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          292..299
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           303..305
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           306..314
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          323..332
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          358..366
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           374..380
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           381..383
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           388..407
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          410..412
FT                   /evidence="ECO:0007829|PDB:2A1A"
FT   HELIX           417..419
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          420..424
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          427..430
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           433..435
FT                   /evidence="ECO:0007829|PDB:6D3L"
FT   STRAND          437..440
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           457..461
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           468..482
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           488..499
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   STRAND          505..507
FT                   /evidence="ECO:0007829|PDB:3UIU"
FT   HELIX           509..518
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           523..525
FT                   /evidence="ECO:0007829|PDB:2A19"
FT   HELIX           529..539
FT                   /evidence="ECO:0007829|PDB:2A19"
SQ   SEQUENCE   551 AA;  62094 MW;  815AD83ACAB45DA3 CRC64;
     MAGDLSAGFF MEELNTYRQK QGVVLKYQEL PNSGPPHDRR FTFQVIIDGR EFPEGEGRSK
     KEAKNAAAKL AVEILNKEKK AVSPLLLTTT NSSEGLSMGN YIGLINRIAQ KKRLTVNYEQ
     CASGVHGPEG FHYKCKMGQK EYSIGTGSTK QEAKQLAAKL AYLQILSEET SVKSDYLSSG
     SFATTCESQS NSLVTSTLAS ESSSEGDFSA DTSEINSNSD SLNSSSLLMN GLRNNQRKAK
     RSLAPRFDLP DMKETKYTVD KRFGMDFKEI ELIGSGGFGQ VFKAKHRIDG KTYVIKRVKY
     NNEKAEREVK ALAKLDHVNI VHYNGCWDGF DYDPETSDDS LESSDYDPEN SKNSSRSKTK
     CLFIQMEFCD KGTLEQWIEK RRGEKLDKVL ALELFEQITK GVDYIHSKKL IHRDLKPSNI
     FLVDTKQVKI GDFGLVTSLK NDGKRTRSKG TLRYMSPEQI SSQDYGKEVD LYALGLILAE
     LLHVCDTAFE TSKFFTDLRD GIISDIFDKK EKTLLQKLLS KKPEDRPNTS EILRTLTVWK
     KSPEKNERHT C
//
ID   G3P_HUMAN               Reviewed;         335 AA.
AC   P04406; E7EUT4; P00354; Q53X65;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   28-JAN-2026, entry version 279.
DE   RecName: Full=Glyceraldehyde-3-phosphate dehydrogenase {ECO:0000303|PubMed:6096136};
DE            Short=GAPDH {ECO:0000303|PubMed:2987855};
DE            EC=1.2.1.12 {ECO:0000269|PubMed:3170585};
DE   AltName: Full=Peptidyl-cysteine S-nitrosylase GAPDH {ECO:0000305};
DE            EC=2.6.99.- {ECO:0000250|UniProtKB:P04797};
GN   Name=GAPDH {ECO:0000303|PubMed:2987855, ECO:0000312|HGNC:HGNC:4141};
GN   Synonyms=GAPD {ECO:0000303|PubMed:6096136};
GN   ORFNames=CDABP0047, OK/SW-cl.12;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=6096136; DOI=10.1002/j.1460-2075.1984.tb02185.x;
RA   Hanauer A., Mandel J.-L.;
RT   "The glyceraldehyde 3 phosphate dehydrogenase gene family: structure of a
RT   human cDNA and of an X chromosome linked pseudogene; amazing complexity of
RT   the gene family in mouse.";
RL   EMBO J. 3:2627-2633(1984).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=6096821; DOI=10.1093/nar/12.23.9179;
RA   Arcari P., Martinelli R., Salvatore F.;
RT   "The complete sequence of a full length cDNA for human liver
RT   glyceraldehyde-3-phosphate dehydrogenase: evidence for multiple mRNA
RT   species.";
RL   Nucleic Acids Res. 12:9179-9189(1984).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   PubMed=2987855; DOI=10.1093/nar/13.7.2485;
RA   Tso J.Y., Sun X.-H., Kao T.-H., Reece K.S., Wu R.;
RT   "Isolation and characterization of rat and human glyceraldehyde-3-phosphate
RT   dehydrogenase cDNAs: genomic complexity and molecular evolution of the
RT   gene.";
RL   Nucleic Acids Res. 13:2485-2502(1985).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Lung;
RX   PubMed=3664468;
RA   Tokunaga K., Nakamura Y., Sakata K., Fujimori K., Ohkubo M., Sawada K.,
RA   Sakiyama S.;
RT   "Enhanced expression of a glyceraldehyde-3-phosphate dehydrogenase gene in
RT   human lung cancers.";
RL   Cancer Res. 47:5616-5619(1987).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3027061; DOI=10.1016/s0021-9258(19)75833-5;
RA   Allen R.W., Trach K.A., Hoch J.A.;
RT   "Identification of the 37-kDa protein displaying a variable interaction
RT   with the erythroid cell membrane as glyceraldehyde-3-phosphate
RT   dehydrogenase.";
RL   J. Biol. Chem. 262:649-653(1987).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=3170585; DOI=10.1016/s0021-9258(19)37593-3;
RA   Ercolani L., Florence B., Denaro M., Alexander M.;
RT   "Isolation and complete sequence of a functional human glyceraldehyde-3-
RT   phosphate dehydrogenase gene.";
RL   J. Biol. Chem. 263:15335-15341(1988).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Placenta;
RX   PubMed=1924305; DOI=10.1073/pnas.88.19.8460;
RA   Meyer-Siegler K., Mauro D.J., Seal G., Wurzer J., Deriel J.K.,
RA   Sirover M.A.;
RT   "A human nuclear uracil DNA glycosylase is the 37-kDa subunit of
RT   glyceraldehyde-3-phosphate dehydrogenase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 88:8460-8464(1991).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Astrocytoma;
RX   PubMed=10944468; DOI=10.1006/bbrc.2000.3282;
RA   Ye Z., Connor J.R.;
RT   "cDNA cloning by amplification of circularized first strand cDNAs reveals
RT   non-IRE-regulated iron-responsive mRNAs.";
RL   Biochem. Biophys. Res. Commun. 275:223-227(2000).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Leukemia;
RA   Zhou J., Yu W., Tang H., Mei G., Tsang Y.T.M., Bouck J., Gibbs R.A.,
RA   Margolin J.F.;
RT   "Pediatric leukemia cDNA sequencing project.";
RL   Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Colon adenocarcinoma;
RA   Shichijo S., Itoh K.;
RT   "Identification of immuno-peptidmics that are recognized by tumor-reactive
RT   CTL generated from TIL of colon cancer patients.";
RL   Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [12]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLY-22.
RG   NIEHS SNPs program;
RL   Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN   [14]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16541075; DOI=10.1038/nature04569;
RA   Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA   Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA   Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA   Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA   Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA   Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA   Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA   Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA   Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA   Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA   Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA   Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA   Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA   Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA   Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA   Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA   Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA   David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA   D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA   Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA   Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA   Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA   LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA   Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA   Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA   Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA   Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA   Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA   Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA   Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA   Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA   Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA   Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA   Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA   Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA   Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA   Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA   Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA   Gibbs R.A.;
RT   "The finished DNA sequence of human chromosome 12.";
RL   Nature 440:346-351(2006).
RN   [15]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [16]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Eye, Kidney, Lung, Lymph, and Placenta;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [17]
RP   PRELIMINARY PROTEIN SEQUENCE OF 2-335.
RC   TISSUE=Muscle;
RX   PubMed=7030790; DOI=10.1016/0014-5793(81)80587-x;
RA   Nowak K., Wolny M., Banas T.;
RT   "The complete amino acid sequence of human muscle glyceraldehyde 3-
RT   phosphate dehydrogenase.";
RL   FEBS Lett. 134:143-146(1981).
RN   [18]
RP   PROTEIN SEQUENCE OF 2-13.
RC   TISSUE=Platelet;
RX   PubMed=12665801; DOI=10.1038/nbt810;
RA   Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R.,
RA   Vandekerckhove J.;
RT   "Exploring proteomes and analyzing protein processing by mass spectrometric
RT   identification of sorted N-terminal peptides.";
RL   Nat. Biotechnol. 21:566-569(2003).
RN   [19]
RP   PROTEIN SEQUENCE OF 2-13; 62-84; 118-139; 198-215; 220-227; 235-248 AND
RP   310-335, CLEAVAGE OF INITIATOR METHIONINE, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RC   TISSUE=Prostatic carcinoma;
RA   Bienvenut W.V., Gao M., Leug H.;
RL   Submitted (JUL-2009) to UniProtKB.
RN   [20]
RP   PROTEIN SEQUENCE OF 67-80; 87-107; 119-139; 146-186; 201-215; 235-248 AND
RP   310-334, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA   Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL   Submitted (DEC-2008) to UniProtKB.
RN   [21]
RP   PROTEIN SEQUENCE OF 220-226 AND 242-246.
RC   TISSUE=Heart;
RX   PubMed=7498159; DOI=10.1002/elps.11501601192;
RA   Kovalyov L.I., Shishkin S.S., Efimochkin A.S., Kovalyova M.A.,
RA   Ershova E.S., Egorov T.A., Musalyamov A.K.;
RT   "The major protein expression profile and two-dimensional protein database
RT   of human heart.";
RL   Electrophoresis 16:1160-1169(1995).
RN   [22]
RP   PARTIAL PROTEIN SEQUENCE.
RC   TISSUE=Muscle;
RX   PubMed=1193541;
RA   Nowak K., Kuczek M., Ostropolska L., Malarska A., Wolny M., Branowski T.;
RT   "The covalent structure of glyceraldehyde-phosphate dehydrogenase from
RT   human muscles. Isolation and amino acid sequences of peptides from tryptic
RT   digest.";
RL   Hoppe-Seyler's Z. Physiol. Chem. 356:1181-1183(1975).
RN   [23]
RP   FUNCTION, AND INTERACTION WITH PRKCI.
RX   PubMed=11724794; DOI=10.1074/jbc.m109744200;
RA   Tisdale E.J.;
RT   "Glyceraldehyde-3-phosphate dehydrogenase is phosphorylated by protein
RT   kinase Ciota /lambda and plays a role in microtubule dynamics in the early
RT   secretory pathway.";
RL   J. Biol. Chem. 277:3334-3341(2002).
RN   [24]
RP   SUBCELLULAR LOCATION.
RX   PubMed=12829261; DOI=10.1016/s0304-4165(03)00117-x;
RA   Mazzola J.L., Sirover M.A.;
RT   "Subcellular localization of human glyceraldehyde-3-phosphate dehydrogenase
RT   is independent of its glycolytic function.";
RL   Biochim. Biophys. Acta 1622:50-56(2003).
RN   [25]
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RC   TISSUE=Lymphoblast;
RX   PubMed=14654843; DOI=10.1038/nature02166;
RA   Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., Mann M.;
RT   "Proteomic characterization of the human centrosome by protein correlation
RT   profiling.";
RL   Nature 426:570-574(2003).
RN   [26]
RP   IDENTIFICATION IN THE GAIT COMPLEX.
RX   PubMed=15479637; DOI=10.1016/j.cell.2004.09.030;
RA   Sampath P., Mazumder B., Seshadri V., Gerber C.A., Chavatte L., Kinter M.,
RA   Ting S.M., Dignam J.D., Kim S., Driscoll D.M., Fox P.L.;
RT   "Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific
RT   silencing of translation.";
RL   Cell 119:195-208(2004).
RN   [27]
RP   INTERACTION WITH WARS1.
RX   PubMed=15628863; DOI=10.1021/bi048313k;
RA   Wakasugi K., Nakano T., Morishima I.;
RT   "Oxidative stress-responsive intracellular regulation specific for the
RT   angiostatic form of human tryptophanyl-tRNA synthetase.";
RL   Biochemistry 44:225-232(2005).
RN   [28]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-42, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=15592455; DOI=10.1038/nbt1046;
RA   Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA   Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT   "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL   Nat. Biotechnol. 23:94-101(2005).
RN   [29]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA   Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT   networks.";
RL   Cell 127:635-648(2006).
RN   [30]
RP   INTERACTION WITH USP25.
RX   PubMed=16501887; DOI=10.1007/s00018-005-5533-1;
RA   Bosch-Comas A., Lindsten K., Gonzalez-Duarte R., Masucci M.G., Marfany G.;
RT   "The ubiquitin-specific protease USP25 interacts with three sarcomeric
RT   proteins.";
RL   Cell. Mol. Life Sci. 63:723-734(2006).
RN   [31]
RP   ISGYLATION.
RX   PubMed=16815975; DOI=10.1073/pnas.0600397103;
RA   Wong J.J., Pung Y.F., Sze N.S., Chin K.C.;
RT   "HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I
RT   IFN-induced ISGylation of protein targets.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:10735-10740(2006).
RN   [32]
RP   PHOSPHORYLATION AT THR-75; SER-122; SER-148; THR-229; THR-237 AND SER-312,
RP   DEAMIDATION AT ASN-9; ASN-64; ASN-70; ASN-149; ASN-155; ASN-225 AND
RP   ASN-316, AND METHYLATION AT LYS-5; LYS-66; LYS-194; LYS-215; LYS-227;
RP   LYS-260; LYS-263 AND LYS-334.
RX   PubMed=18183946; DOI=10.1021/pr700657y;
RA   Seo J., Jeong J., Kim Y.M., Hwang N., Paek E., Lee K.-J.;
RT   "Strategy for comprehensive identification of post-translational
RT   modifications in cellular proteins, including low abundant modifications:
RT   application to glyceraldehyde-3-phosphate dehydrogenase.";
RL   J. Proteome Res. 7:587-602(2008).
RN   [33]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83; SER-151 AND THR-184, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [34]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [35]
RP   INTERACTION WITH FKBP6.
RX   PubMed=19001379; DOI=10.1074/jbc.m709779200;
RA   Jarczowski F., Jahreis G., Erdmann F., Schierhorn A., Fischer G.,
RA   Edlich F.;
RT   "FKBP36 is an inherent multifunctional glyceraldehyde-3-phosphate
RT   dehydrogenase inhibitor.";
RL   J. Biol. Chem. 284:766-773(2009).
RN   [36]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-184; THR-211 AND SER-312, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [37]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-61; LYS-194; LYS-219; LYS-227 AND
RP   LYS-254, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19608861; DOI=10.1126/science.1175371;
RA   Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA   Olsen J.V., Mann M.;
RT   "Lysine acetylation targets protein complexes and co-regulates major
RT   cellular functions.";
RL   Science 325:834-840(2009).
RN   [38]
RP   INTERACTION WITH EIF1AD.
RX   PubMed=20644585; DOI=10.1134/s1068162010030027;
RA   Rakitina T.V., Bogatova O.V., Smirnova E.V., Pozdeev V.I., Kostanian I.A.,
RA   Lipkin V.M.;
RT   "Haponin (eIF1AD) interacts with glyceraldehyde 3-phosphate dehydrogenase
RT   in the CHO-K1 cell line.";
RL   Bioorg. Khim. 36:312-318(2010).
RN   [39]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-75; SER-83 AND THR-184, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [40]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [41]
RP   MALONYLATION AT LYS-194 AND LYS-215.
RX   PubMed=21908771; DOI=10.1074/mcp.m111.012658;
RA   Peng C., Lu Z., Xie Z., Cheng Z., Chen Y., Tan M., Luo H., Zhang Y., He W.,
RA   Yang K., Zwaans B.M., Tishkoff D., Ho L., Lombard D., He T.C., Dai J.,
RA   Verdin E., Ye Y., Zhao Y.;
RT   "The first identification of lysine malonylation substrates and its
RT   regulatory enzyme.";
RL   Mol. Cell. Proteomics 10:M111.012658.01-M111.012658.12(2011).
RN   [42]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA   Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA   Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT   "System-wide temporal characterization of the proteome and phosphoproteome
RT   of human embryonic stem cell differentiation.";
RL   Sci. Signal. 4:RS3-RS3(2011).
RN   [43]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22905912; DOI=10.1021/pr300539b;
RA   Rosenow A., Noben J.P., Jocken J., Kallendrusch S., Fischer-Posovszky P.,
RA   Mariman E.C., Renes J.;
RT   "Resveratrol-induced changes of the human adipocyte secretion profile.";
RL   J. Proteome Res. 11:4733-4743(2012).
RN   [44]
RP   INTERACTION WITH RPL13A, AND S-NITROSYLATION AT CYS-247.
RX   PubMed=22771119; DOI=10.1016/j.molcel.2012.06.006;
RA   Jia J., Arif A., Willard B., Smith J.D., Stuehr D.J., Hazen S.L., Fox P.L.;
RT   "Protection of extraribosomal RPL13a by GAPDH and dysregulation by S-
RT   nitrosylation.";
RL   Mol. Cell 47:656-663(2012).
RN   [45]
RP   FUNCTION, AND RECONSTITUTION OF THE GAIT COMPLEX.
RX   PubMed=23071094; DOI=10.1128/mcb.01168-12;
RA   Arif A., Chatterjee P., Moodt R.A., Fox P.L.;
RT   "Heterotrimeric GAIT complex drives transcript-selective translation
RT   inhibition in murine macrophages.";
RL   Mol. Cell. Biol. 32:5046-5055(2012).
RN   [46]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [47]
RP   FUNCTION, GLYCOSYLATION (MICROBIAL INFECTION), INTERACTION WITH TRAF2, AND
RP   MUTAGENESIS OF CYS-152; THR-211; THR-229; SER-241; THR-246 AND THR-277.
RX   PubMed=23332158; DOI=10.1016/j.chom.2012.11.010;
RA   Gao X., Wang X., Pham T.H., Feuerbacher L.A., Lubos M.L., Huang M.,
RA   Olsen R., Mushegian A., Slawson C., Hardwidge P.R.;
RT   "NleB, a bacterial effector with glycosyltransferase activity, targets
RT   GAPDH function to inhibit NF-kappaB activation.";
RL   Cell Host Microbe 13:87-99(2013).
RN   [48]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83; SER-151; THR-153; THR-229
RP   AND SER-333, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [49]
RP   S-NITROSYLATION AT CYS-247, MUTAGENESIS OF LEU-245 AND GLU-250, AND DOMAIN.
RX   PubMed=25417112; DOI=10.1016/j.cell.2014.09.032;
RA   Jia J., Arif A., Terenzi F., Willard B., Plow E.F., Hazen S.L., Fox P.L.;
RT   "Target-selective protein S-nitrosylation by sequence motif recognition.";
RL   Cell 159:623-634(2014).
RN   [50]
RP   MECHANISM OF FREE RADICAL-INDUCED AGGREGATION, ACTIVE SITE, OXIDATION AT
RP   MET-46, AND MUTAGENESIS OF MET-46; MET-105; CYS-152; CYS-156; TRP-196;
RP   CYS-247 AND TYR-320.
RX   PubMed=25086035; DOI=10.1074/jbc.m114.570275;
RA   Samson A.L., Knaupp A.S., Kass I., Kleifeld O., Marijanovic E.M.,
RA   Hughes V.A., Lupton C.J., Buckle A.M., Bottomley S.P., Medcalf R.L.;
RT   "Oxidation of an exposed methionine instigates the aggregation of
RT   glyceraldehyde-3-phosphate dehydrogenase.";
RL   J. Biol. Chem. 289:26922-26936(2014).
RN   [51]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-177; THR-182; THR-184 AND
RP   SER-241, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [52]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [53]
RP   FUNCTION, GLYCOSYLATION (MICROBIAL INFECTION), INTERACTION WITH TRAF2, AND
RP   MUTAGENESIS OF CYS-152.
RX   PubMed=27387501; DOI=10.1074/jbc.m116.738278;
RA   Gao X., Pham T.H., Feuerbacher L.A., Chen K., Hays M.P., Singh G.,
RA   Rueter C., Hurtado-Guerrero R., Hardwidge P.R.;
RT   "Citrobacter rodentium NleB protein inhibits tumor necrosis factor (TNF)
RT   receptor-associated factor 3 (TRAF3) ubiquitination to reduce host type I
RT   interferon production.";
RL   J. Biol. Chem. 291:18232-18238(2016).
RN   [54]
RP   GLYCOSYLATION AT ARG-197 AND ARG-200 (MICROBIAL INFECTION).
RX   PubMed=28522607; DOI=10.1074/jbc.m117.790675;
RA   El Qaidi S., Chen K., Halim A., Siukstaite L., Rueter C.,
RA   Hurtado-Guerrero R., Clausen H., Hardwidge P.R.;
RT   "NleB/SseK effectors from Citrobacter rodentium, Escherichia coli, and
RT   Salmonella enterica display distinct differences in host substrate
RT   specificity.";
RL   J. Biol. Chem. 292:11423-11430(2017).
RN   [55]
RP   SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-186, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=28112733; DOI=10.1038/nsmb.3366;
RA   Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA   Nielsen M.L.;
RT   "Site-specific mapping of the human SUMO proteome reveals co-modification
RT   with phosphorylation.";
RL   Nat. Struct. Mol. Biol. 24:325-336(2017).
RN   [56]
RP   X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS).
RX   PubMed=957435; DOI=10.1016/0022-2836(76)90013-9;
RA   Mercer W.D., Winn S.I., Watson H.C.;
RT   "Twinning in crystals of human skeletal muscle D-glyceraldehyde-3-phosphate
RT   dehydrogenase.";
RL   J. Mol. Biol. 104:277-283(1976).
RN   [57]
RP   X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEX WITH NAD, AND SUBUNIT.
RX   PubMed=16239728; DOI=10.1107/s0907444905026740;
RA   Ismail S.A., Park H.W.;
RT   "Structural analysis of human liver glyceraldehyde-3-phosphate
RT   dehydrogenase.";
RL   Acta Crystallogr. D 61:1508-1513(2005).
RN   [58]
RP   X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) IN COMPLEX WITH NAD, AND SUBUNIT.
RX   PubMed=16510976; DOI=10.1107/s0907444905042289;
RA   Jenkins J.L., Tanner J.J.;
RT   "High-resolution structure of human D-glyceraldehyde-3-phosphate
RT   dehydrogenase.";
RL   Acta Crystallogr. D 62:290-301(2006).
CC   -!- FUNCTION: Catalyzes the conversion of D-glyceraldehyde 3-phosphate
CC       (G3P) into 3-phospho-D-glyceroyl phosphate in glycolysis and the
CC       reverse reaction in gluconeogenesis (PubMed:11724794, PubMed:3170585).
CC       Also shows nitrosylase activity, thereby playing a role in nuclear
CC       functions (PubMed:11724794, PubMed:3170585). Modulates the organization
CC       and assembly of the cytoskeleton (By similarity). Facilitates the CHP1-
CC       dependent microtubule and membrane associations through its ability to
CC       stimulate the binding of CHP1 to microtubules (By similarity).
CC       Component of the GAIT (gamma interferon-activated inhibitor of
CC       translation) complex which mediates interferon-gamma-induced
CC       transcript-selective translation inhibition in inflammation processes
CC       (PubMed:23071094). Upon interferon-gamma treatment assembles into the
CC       GAIT complex which binds to stem loop-containing GAIT elements in the
CC       3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and
CC       suppresses their translation (PubMed:23071094). Also plays a role in
CC       innate immunity by promoting TNF-induced NF-kappa-B activation and type
CC       I interferon production, via interaction with TRAF2 and TRAF3,
CC       respectively (PubMed:23332158, PubMed:27387501). Participates in
CC       nuclear events including transcription, RNA transport, DNA replication
CC       and apoptosis (By similarity). Nuclear functions are probably due to
CC       the nitrosylase activity that mediates cysteine S-nitrosylation of
CC       nuclear target proteins such as SIRT1, HDAC2 and PRKDC (By similarity).
CC       {ECO:0000250|UniProtKB:P04797, ECO:0000269|PubMed:11724794,
CC       ECO:0000269|PubMed:23071094, ECO:0000269|PubMed:23332158,
CC       ECO:0000269|PubMed:27387501, ECO:0000269|PubMed:3170585}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=D-glyceraldehyde 3-phosphate + phosphate + NAD(+) = (2R)-3-
CC         phospho-glyceroyl phosphate + NADH + H(+); Xref=Rhea:RHEA:10300,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, ChEBI:CHEBI:57540,
CC         ChEBI:CHEBI:57604, ChEBI:CHEBI:57945, ChEBI:CHEBI:59776; EC=1.2.1.12;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU10009,
CC         ECO:0000269|PubMed:3170585};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10301;
CC         Evidence={ECO:0000305};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10302;
CC         Evidence={ECO:0000305};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=S-nitroso-L-cysteinyl-[GAPDH] + L-cysteinyl-[protein] = L-
CC         cysteinyl-[GAPDH] + S-nitroso-L-cysteinyl-[protein];
CC         Xref=Rhea:RHEA:66684, Rhea:RHEA-COMP:10131, Rhea:RHEA-COMP:17089,
CC         Rhea:RHEA-COMP:17090, Rhea:RHEA-COMP:17091, ChEBI:CHEBI:29950,
CC         ChEBI:CHEBI:149494; Evidence={ECO:0000250|UniProtKB:P04797};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66685;
CC         Evidence={ECO:0000250|UniProtKB:P04797};
CC   -!- ACTIVITY REGULATION: Glyceraldehyde-3-phosphate dehydrogenase activity
CC       is inhibited by fumarate, via the formation of S-(2-succinyl)cysteine
CC       residues. {ECO:0000250|UniProtKB:P04797}.
CC   -!- PATHWAY: Carbohydrate degradation; glycolysis; pyruvate from D-
CC       glyceraldehyde 3-phosphate: step 1/5.
CC   -!- SUBUNIT: Homotetramer (PubMed:16239728, PubMed:16510976). Interacts
CC       with TPPP; the interaction is direct (By similarity). Interacts (when
CC       S-nitrosylated) with SIAH1; leading to nuclear translocation (By
CC       similarity). Interacts with RILPL1/GOSPEL, leading to prevent the
CC       interaction between GAPDH and SIAH1 and prevent nuclear translocation
CC       (By similarity). Interacts with CHP1; the interaction increases the
CC       binding of CHP1 with microtubules (By similarity). Associates with
CC       microtubules (By similarity). Interacts with EIF1AD, USP25, PRKCI and
CC       WARS1 (PubMed:11724794, PubMed:15628863, PubMed:16501887,
CC       PubMed:20644585). Interacts with phosphorylated RPL13A; inhibited by
CC       oxidatively-modified low-densitity lipoprotein (LDL(ox))
CC       (PubMed:22771119). Component of the GAIT complex (PubMed:15479637).
CC       Interacts with FKBP6; leading to inhibit GAPDH catalytic activity
CC       (PubMed:19001379). Interacts with TRAF2, promoting TRAF2 ubiquitination
CC       (PubMed:23332158). Interacts with TRAF3, promoting TRAF3 ubiquitination
CC       (PubMed:27387501). {ECO:0000250|UniProtKB:P04797,
CC       ECO:0000250|UniProtKB:P10096, ECO:0000269|PubMed:11724794,
CC       ECO:0000269|PubMed:15479637, ECO:0000269|PubMed:15628863,
CC       ECO:0000269|PubMed:16239728, ECO:0000269|PubMed:16501887,
CC       ECO:0000269|PubMed:16510976, ECO:0000269|PubMed:19001379,
CC       ECO:0000269|PubMed:20644585, ECO:0000269|PubMed:22771119,
CC       ECO:0000269|PubMed:23332158, ECO:0000269|PubMed:27387501}.
CC   -!- INTERACTION:
CC       P04406; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-354056, EBI-10173507;
CC       P04406; Q9UIJ7: AK3; NbExp=3; IntAct=EBI-354056, EBI-3916527;
CC       P04406; P05067: APP; NbExp=3; IntAct=EBI-354056, EBI-77613;
CC       P04406; Q9UQM7: CAMK2A; NbExp=3; IntAct=EBI-354056, EBI-1383687;
CC       P04406; Q14194: CRMP1; NbExp=3; IntAct=EBI-354056, EBI-473101;
CC       P04406; P35222: CTNNB1; NbExp=3; IntAct=EBI-354056, EBI-491549;
CC       P04406; Q9BPW9-4: DHRS9; NbExp=3; IntAct=EBI-354056, EBI-19157435;
CC       P04406; P00533: EGFR; NbExp=7; IntAct=EBI-354056, EBI-297353;
CC       P04406; O00471: EXOC5; NbExp=3; IntAct=EBI-354056, EBI-949824;
CC       P04406; O75344: FKBP6; NbExp=3; IntAct=EBI-354056, EBI-744771;
CC       P04406; P06241: FYN; NbExp=3; IntAct=EBI-354056, EBI-515315;
CC       P04406; P04406: GAPDH; NbExp=2; IntAct=EBI-354056, EBI-354056;
CC       P04406; O14556: GAPDHS; NbExp=3; IntAct=EBI-354056, EBI-1057431;
CC       P04406; Q8NEA9: GMCL2; NbExp=3; IntAct=EBI-354056, EBI-745707;
CC       P04406; P42858: HTT; NbExp=7; IntAct=EBI-354056, EBI-466029;
CC       P04406; Q92993-2: KAT5; NbExp=3; IntAct=EBI-354056, EBI-20795332;
CC       P04406; P42695: NCAPD3; NbExp=2; IntAct=EBI-354056, EBI-722805;
CC       P04406; P35228: NOS2; NbExp=8; IntAct=EBI-354056, EBI-6662224;
CC       P04406; P12004: PCNA; NbExp=3; IntAct=EBI-354056, EBI-358311;
CC       P04406; P00558: PGK1; NbExp=2; IntAct=EBI-354056, EBI-709599;
CC       P04406; P48147: PREP; NbExp=5; IntAct=EBI-354056, EBI-1049962;
CC       P04406; P17612: PRKACA; NbExp=3; IntAct=EBI-354056, EBI-476586;
CC       P04406; Q8WUY3: PRUNE2; NbExp=3; IntAct=EBI-354056, EBI-743880;
CC       P04406; Q9UHX1-2: PUF60; NbExp=3; IntAct=EBI-354056, EBI-11529177;
CC       P04406; P15927: RPA2; NbExp=2; IntAct=EBI-354056, EBI-621404;
CC       P04406; P05109: S100A8; NbExp=6; IntAct=EBI-354056, EBI-355281;
CC       P04406; Q96GZ6: SLC41A3; NbExp=3; IntAct=EBI-354056, EBI-7225508;
CC       P04406; P00441: SOD1; NbExp=3; IntAct=EBI-354056, EBI-990792;
CC       P04406; Q9BSI4: TINF2; NbExp=2; IntAct=EBI-354056, EBI-717399;
CC       P04406; P10599: TXN; NbExp=4; IntAct=EBI-354056, EBI-594644;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:12829261}.
CC       Nucleus {ECO:0000250|UniProtKB:P04797}. Cytoplasm, perinuclear region
CC       {ECO:0000269|PubMed:12829261}. Membrane {ECO:0000269|PubMed:12829261}.
CC       Cytoplasm, cytoskeleton {ECO:0000250|UniProtKB:P04797}.
CC       Note=Translocates to the nucleus following S-nitrosylation and
CC       interaction with SIAH1, which contains a nuclear localization signal
CC       (By similarity). Postnuclear and Perinuclear regions (PubMed:12829261).
CC       {ECO:0000250|UniProtKB:P04797, ECO:0000269|PubMed:12829261}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P04406-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P04406-2; Sequence=VSP_047289;
CC   -!- DOMAIN: The [IL]-x-C-x-x-[DE] motif is a proposed target motif for
CC       cysteine S-nitrosylation mediated by the iNOS-S100A8/A9
CC       transnitrosylase complex. {ECO:0000305|PubMed:25417112}.
CC   -!- PTM: S-nitrosylation of Cys-152 leads to interaction with SIAH1,
CC       followed by translocation to the nucleus (By similarity). S-
CC       nitrosylation of Cys-247 is induced by interferon-gamma and LDL(ox)
CC       implicating the iNOS-S100A8/9 transnitrosylase complex and seems to
CC       prevent interaction with phosphorylated RPL13A and to interfere with
CC       GAIT complex activity (PubMed:22771119, PubMed:25417112).
CC       {ECO:0000250|UniProtKB:P04797, ECO:0000269|PubMed:22771119,
CC       ECO:0000269|PubMed:25417112}.
CC   -!- PTM: ISGylated. {ECO:0000305|PubMed:16815975}.
CC   -!- PTM: Sulfhydration at Cys-152 increases catalytic activity.
CC       {ECO:0000250|UniProtKB:P16858}.
CC   -!- PTM: Oxidative stress can promote the formation of high molecular
CC       weight disulfide-linked GAPDH aggregates, through a process called
CC       nucleocytoplasmic coagulation. Such aggregates can be observed in vivo
CC       in the affected tissues of patients with Alzheimer disease or alcoholic
CC       liver cirrhosis, or in cell cultures during necrosis. Oxidation at Met-
CC       46 may play a pivotal role in the formation of these insoluble
CC       structures. This modification has been detected in vitro following
CC       treatment with free radical donor (+/-)-(E)-4-ethyl-2-[(E)-
CC       hydroxyimino]-5-nitro-3-hexenamide. It has been proposed to destabilize
CC       nearby residues, increasing the likelihood of secondary oxidative
CC       damages, including oxidation of Tyr-45 and Met-105. This cascade of
CC       oxidations may augment GAPDH misfolding, leading to intermolecular
CC       disulfide cross-linking and aggregation. {ECO:0000305|PubMed:25086035}.
CC   -!- PTM: Succination of Cys-152 and Cys-247 by the Krebs cycle intermediate
CC       fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits
CC       glyceraldehyde-3-phosphate dehydrogenase activity. Fumarate
CC       concentration as well as succination of cysteine residues in GAPDH is
CC       significantly increased in muscle of diabetic mammals. It was proposed
CC       that the S-(2-succinyl)cysteine chemical modification may be a useful
CC       biomarker of mitochondrial and oxidative stress in diabetes and that
CC       succination of GAPDH and other thiol proteins by fumarate may
CC       contribute to the metabolic changes underlying the development of
CC       diabetes complications. {ECO:0000250|UniProtKB:P04797}.
CC   -!- PTM: (Microbial infection) Glycosylated by C.rodentium protein NleB,
CC       enteropathogenic E.coli protein NleB1 and S.typhimurium protein Ssek1:
CC       arginine GlcNAcylation prevents the interaction with TRAF2 and TRAF3
CC       (PubMed:23332158, PubMed:27387501, PubMed:28522607). This leads to
CC       reduced ubiquitination of TRAF2 and TRAF3, and subsequent inhibition of
CC       NF-kappa-B signaling and type I interferon production, respectively
CC       (PubMed:23332158, PubMed:27387501). {ECO:0000269|PubMed:23332158,
CC       ECO:0000269|PubMed:27387501, ECO:0000269|PubMed:28522607}.
CC   -!- SIMILARITY: Belongs to the glyceraldehyde-3-phosphate dehydrogenase
CC       family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Glyceraldehyde 3-phosphate
CC       dehydrogenase entry;
CC       URL="https://en.wikipedia.org/wiki/Glyceraldehyde_3-phosphate_dehydrogenase";
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DR   EMBL; X01677; CAA25833.1; -; mRNA.
DR   EMBL; M17851; AAA86283.1; -; mRNA.
DR   EMBL; M33197; AAA52518.1; -; mRNA.
DR   EMBL; J02642; AAA52496.1; -; mRNA.
DR   EMBL; J04038; AAA53191.1; -; Genomic_DNA.
DR   EMBL; X53778; CAA37794.1; -; mRNA.
DR   EMBL; AF261085; AAF99678.1; -; mRNA.
DR   EMBL; AY007133; AAG01996.1; -; mRNA.
DR   EMBL; AB062273; BAB93466.1; -; mRNA.
DR   EMBL; BT006893; AAP35539.1; -; mRNA.
DR   EMBL; AY340484; AAP88932.1; -; Genomic_DNA.
DR   EMBL; CR407671; CAG28599.1; -; mRNA.
DR   EMBL; AC006064; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471116; EAW88787.1; -; Genomic_DNA.
DR   EMBL; BC001601; AAH01601.1; -; mRNA.
DR   EMBL; BC004109; AAH04109.1; -; mRNA.
DR   EMBL; BC009081; AAH09081.1; -; mRNA.
DR   EMBL; BC013310; AAH13310.1; -; mRNA.
DR   EMBL; BC023632; AAH23632.1; -; mRNA.
DR   EMBL; BC025925; AAH25925.1; -; mRNA.
DR   EMBL; BC026907; AAH26907.1; -; mRNA.
DR   EMBL; BC029618; AAH29618.1; -; mRNA.
DR   EMBL; BC083511; AAH83511.1; -; mRNA.
DR   CCDS; CCDS58201.1; -. [P04406-2]
DR   CCDS; CCDS8549.1; -. [P04406-1]
DR   PIR; A31988; DEHUG3.
DR   RefSeq; NP_001243728.1; NM_001256799.3. [P04406-2]
DR   RefSeq; NP_001276674.1; NM_001289745.3. [P04406-1]
DR   RefSeq; NP_001276675.1; NM_001289746.2. [P04406-1]
DR   RefSeq; NP_002037.2; NM_002046.5. [P04406-1]
DR   PDB; 1U8F; X-ray; 1.75 A; O/P/Q/R=1-335.
DR   PDB; 1ZNQ; X-ray; 2.50 A; O/P/Q/R=1-335.
DR   PDB; 3GPD; X-ray; 3.50 A; G/R=2-335.
DR   PDB; 4WNC; X-ray; 1.99 A; A/B/C/D/E/F/G/O=1-335.
DR   PDB; 4WNI; X-ray; 2.30 A; A/B/C/O=1-335.
DR   PDB; 6ADE; X-ray; 3.15 A; A/B/C=1-335.
DR   PDB; 6IQ6; X-ray; 2.29 A; A/B/C/D/E/F/G/H=1-335.
DR   PDB; 6M61; X-ray; 1.82 A; O/P/Q/R=1-335.
DR   PDB; 6YND; X-ray; 1.52 A; A/B/C/D/E/F/G/H=1-335.
DR   PDB; 6YNE; X-ray; 1.85 A; A/B/C/D=1-335.
DR   PDB; 6YNF; X-ray; 2.39 A; A/B/C/D/E/F/G/H=2-335.
DR   PDB; 6YNH; X-ray; 2.62 A; B/D/F/G=1-335.
DR   PDB; 8DNS; EM; 3.22 A; O/P/Q/R=1-335.
DR   PDB; 8G12; EM; 2.17 A; A/B/C/D=2-335.
DR   PDB; 8G13; EM; 2.30 A; A/B/C/D=2-335.
DR   PDB; 8G14; EM; 2.30 A; A/B/C/D=2-335.
DR   PDB; 8G15; EM; 2.07 A; A/B/C/D=2-335.
DR   PDB; 8G16; EM; 2.07 A; A/B/C/D=2-335.
DR   PDB; 8G17; EM; 1.98 A; A/B/C/D=2-335.
DR   PDB; 8P5F; X-ray; 1.82 A; AAA/DDD/EEE/GGG=1-335.
DR   PDB; 9L3E; X-ray; 1.77 A; O/P/Q/R=1-335.
DR   PDBsum; 1U8F; -.
DR   PDBsum; 1ZNQ; -.
DR   PDBsum; 3GPD; -.
DR   PDBsum; 4WNC; -.
DR   PDBsum; 4WNI; -.
DR   PDBsum; 6ADE; -.
DR   PDBsum; 6IQ6; -.
DR   PDBsum; 6M61; -.
DR   PDBsum; 6YND; -.
DR   PDBsum; 6YNE; -.
DR   PDBsum; 6YNF; -.
DR   PDBsum; 6YNH; -.
DR   PDBsum; 8DNS; -.
DR   PDBsum; 8G12; -.
DR   PDBsum; 8G13; -.
DR   PDBsum; 8G14; -.
DR   PDBsum; 8G15; -.
DR   PDBsum; 8G16; -.
DR   PDBsum; 8G17; -.
DR   PDBsum; 8P5F; -.
DR   PDBsum; 9L3E; -.
DR   AlphaFoldDB; P04406; -.
DR   EMDB; EMD-27579; -.
DR   EMDB; EMD-29659; -.
DR   EMDB; EMD-29660; -.
DR   EMDB; EMD-29661; -.
DR   EMDB; EMD-29662; -.
DR   EMDB; EMD-29663; -.
DR   EMDB; EMD-29664; -.
DR   EMDB; EMD-32162; -.
DR   SMR; P04406; -.
DR   BioGRID; 108868; 748.
DR   ComplexPortal; CPX-2476; GAIT complex.
DR   CORUM; P04406; -.
DR   DIP; DIP-32521N; -.
DR   FunCoup; P04406; 1599.
DR   IntAct; P04406; 269.
DR   MINT; P04406; -.
DR   STRING; 9606.ENSP00000380070; -.
DR   BindingDB; P04406; -.
DR   ChEMBL; CHEMBL2284; -.
DR   DrugBank; DB07347; 4-(2-Aminoethyl)Benzenesulfonyl Fluoride.
DR   DrugBank; DB02059; Adenosine-5-Diphosphoribose.
DR   DrugBank; DB11638; Artenimol.
DR   DrugBank; DB09130; Copper.
DR   DrugBank; DB00157; NADH.
DR   DrugBank; DB12879; Omigapil.
DR   DrugBank; DB03893; Thionicotinamide-Adenine-Dinucleotide.
DR   DrugBank; DB09092; Xanthinol.
DR   DrugCentral; P04406; -.
DR   MoonDB; P04406; Curated.
DR   MoonProt; P04406; -.
DR   GlyConnect; 1941; 7 N-Linked glycans (2 sites).
DR   GlyCosmos; P04406; 6 sites, 9 glycans.
DR   GlyGen; P04406; 4 sites, 18 N-linked glycans (2 sites), 2 O-linked glycans (2 sites).
DR   iPTMnet; P04406; -.
DR   MetOSite; P04406; -.
DR   PhosphoSitePlus; P04406; -.
DR   SwissPalm; P04406; -.
DR   BioMuta; GAPDH; -.
DR   DMDM; 120649; -.
DR   OGP; P04406; -.
DR   REPRODUCTION-2DPAGE; IPI00219018; -.
DR   REPRODUCTION-2DPAGE; P04406; -.
DR   CPTAC; CPTAC-2733; -.
DR   CPTAC; CPTAC-5855; -.
DR   CPTAC; CPTAC-5880; -.
DR   CPTAC; CPTAC-5942; -.
DR   jPOST; P04406; -.
DR   MassIVE; P04406; -.
DR   PaxDb; 9606-ENSP00000229239; -.
DR   PeptideAtlas; P04406; -.
DR   PRIDE; P04406; -.
DR   ProteomicsDB; 18491; -.
DR   ProteomicsDB; 51703; -. [P04406-1]
DR   Pumba; P04406; -.
DR   TopDownProteomics; P04406-1; -. [P04406-1]
DR   ABCD; P04406; 1 sequenced antibody.
DR   Antibodypedia; 3923; 2690 antibodies from 59 providers.
DR   CPTC; P04406; 1 antibody.
DR   DNASU; 2597; -.
DR   Ensembl; ENST00000229239.10; ENSP00000229239.5; ENSG00000111640.16. [P04406-1]
DR   Ensembl; ENST00000396858.5; ENSP00000380067.1; ENSG00000111640.16. [P04406-2]
DR   Ensembl; ENST00000396859.5; ENSP00000380068.1; ENSG00000111640.16. [P04406-1]
DR   Ensembl; ENST00000396861.5; ENSP00000380070.1; ENSG00000111640.16. [P04406-1]
DR   Ensembl; ENST00000619601.1; ENSP00000478864.1; ENSG00000111640.16. [P04406-2]
DR   GeneID; 2597; -.
DR   KEGG; hsa:2597; -.
DR   MANE-Select; ENST00000229239.10; ENSP00000229239.5; NM_002046.7; NP_002037.2.
DR   UCSC; uc031qfw.3; human. [P04406-1]
DR   AGR; HGNC:4141; -.
DR   ClinPGx; PA28554; -.
DR   CTD; 2597; -.
DR   DisGeNET; 2597; -.
DR   GeneCards; GAPDH; -.
DR   HGNC; HGNC:4141; GAPDH.
DR   HPA; ENSG00000111640; Group enriched (skeletal muscle, tongue).
DR   MalaCards; GAPDH; -.
DR   MIM; 138400; gene.
DR   OpenTargets; ENSG00000111640; -.
DR   VEuPathDB; HostDB:ENSG00000111640; -.
DR   eggNOG; KOG0657; Eukaryota.
DR   GeneTree; ENSGT00940000153298; -.
DR   HOGENOM; CLU_030140_0_3_1; -.
DR   InParanoid; P04406; -.
DR   OMA; YGYTCNM; -.
DR   OrthoDB; 9528699at2759; -.
DR   PAN-GO; P04406; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P04406; -.
DR   BioCyc; MetaCyc:HS03433-MONOMER; -.
DR   BRENDA; 1.2.1.12; 2681.
DR   PathwayCommons; P04406; -.
DR   Reactome; R-HSA-70171; Glycolysis.
DR   Reactome; R-HSA-70263; Gluconeogenesis.
DR   SABIO-RK; P04406; -.
DR   SignaLink; P04406; -.
DR   SIGNOR; P04406; -.
DR   UniPathway; UPA00109; UER00184.
DR   Agora; ENSG00000111640; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 2597; 626 hits in 1149 CRISPR screens.
DR   CD-CODE; 232F8A39; P-body.
DR   CD-CODE; 91857CE7; Nucleolus.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; GAPDH; human.
DR   EvolutionaryTrace; P04406; -.
DR   GeneWiki; Glyceraldehyde_3-phosphate_dehydrogenase; -.
DR   GenomeRNAi; 2597; -.
DR   Pharos; P04406; Tchem.
DR   PRO; PR:P04406; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; P04406; protein.
DR   Bgee; ENSG00000111640; Expressed in frontal pole and 218 other cell types or tissues.
DR   ExpressionAtlas; P04406; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0097452; C:GAIT complex; IDA:UniProtKB.
DR   GO; GO:0005811; C:lipid droplet; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0015630; C:microtubule cytoskeleton; ISS:UniProtKB.
DR   GO; GO:0031965; C:nuclear membrane; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:CACAO.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:1990904; C:ribonucleoprotein complex; IDA:UniProtKB.
DR   GO; GO:0031982; C:vesicle; HDA:UniProtKB.
DR   GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR   GO; GO:0097718; F:disordered domain specific binding; IPI:CAFA.
DR   GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; ISS:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0008017; F:microtubule binding; ISS:UniProtKB.
DR   GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR   GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR   GO; GO:0035605; F:peptidyl-cysteine S-nitrosylase activity; ISS:UniProtKB.
DR   GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IDA:UniProtKB.
DR   GO; GO:0061621; P:canonical glycolysis; IDA:UniProt.
DR   GO; GO:0071346; P:cellular response to type II interferon; IDA:UniProtKB.
DR   GO; GO:0050832; P:defense response to fungus; IDA:UniProtKB.
DR   GO; GO:0006096; P:glycolytic process; IBA:GO_Central.
DR   GO; GO:0051873; P:killing by host of symbiont cells; IDA:UniProtKB.
DR   GO; GO:0031640; P:killing of cells of another organism; IDA:UniProtKB.
DR   GO; GO:0000226; P:microtubule cytoskeleton organization; ISS:UniProtKB.
DR   GO; GO:0010951; P:negative regulation of endopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0017148; P:negative regulation of translation; IDA:UniProtKB.
DR   GO; GO:0051402; P:neuron apoptotic process; ISS:UniProtKB.
DR   GO; GO:0035606; P:peptidyl-cysteine S-trans-nitrosylation; ISS:UniProtKB.
DR   GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:UniProtKB.
DR   GO; GO:0001819; P:positive regulation of cytokine production; IDA:UniProtKB.
DR   GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProtKB.
DR   GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR   CDD; cd18126; GAPDH_I_C; 1.
DR   CDD; cd05214; GAPDH_I_N; 1.
DR   FunFam; 3.30.360.10:FF:000001; Glyceraldehyde-3-phosphate dehydrogenase; 1.
DR   FunFam; 3.40.50.720:FF:001161; Glyceraldehyde-3-phosphate dehydrogenase; 1.
DR   Gene3D; 3.30.360.10; Dihydrodipicolinate Reductase, domain 2; 1.
DR   Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR   InterPro; IPR020831; GlycerAld/Erythrose_P_DH.
DR   InterPro; IPR020830; GlycerAld_3-P_DH_AS.
DR   InterPro; IPR020829; GlycerAld_3-P_DH_cat.
DR   InterPro; IPR020828; GlycerAld_3-P_DH_NAD(P)-bd.
DR   InterPro; IPR006424; Glyceraldehyde-3-P_DH_1.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   NCBIfam; TIGR01534; GAPDH-I; 1.
DR   PANTHER; PTHR10836; GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE; 1.
DR   PANTHER; PTHR10836:SF111; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; 1.
DR   Pfam; PF02800; Gp_dh_C; 1.
DR   Pfam; PF00044; Gp_dh_N; 1.
DR   PIRSF; PIRSF000149; GAP_DH; 1.
DR   PRINTS; PR00078; G3PDHDRGNASE.
DR   SMART; SM00846; Gp_dh_N; 1.
DR   SUPFAM; SSF55347; Glyceraldehyde-3-phosphate dehydrogenase-like, C-terminal domain; 1.
DR   SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR   PROSITE; PS00071; GAPDH; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; ADP-ribosylation; Alternative splicing;
KW   Apoptosis; Cytoplasm; Cytoskeleton; Direct protein sequencing; Glycolysis;
KW   Glycoprotein; Immunity; Innate immunity; Isopeptide bond; Membrane;
KW   Methylation; NAD; Nucleus; Oxidation; Oxidoreductase; Phosphoprotein;
KW   Proteomics identification; Reference proteome; S-nitrosylation;
KW   Transferase; Translation regulation; Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:12665801, ECO:0000269|Ref.19"
FT   CHAIN           2..335
FT                   /note="Glyceraldehyde-3-phosphate dehydrogenase"
FT                   /id="PRO_0000145486"
FT   REGION          2..148
FT                   /note="Interaction with WARS1"
FT                   /evidence="ECO:0000269|PubMed:15628863"
FT   MOTIF           245..250
FT                   /note="[IL]-x-C-x-x-[DE] motif"
FT                   /evidence="ECO:0000305|PubMed:25417112"
FT   ACT_SITE        152
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   BINDING         13..14
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         35
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         80
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         122
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         151..153
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         182
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         211..212
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         234
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         316
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   SITE            179
FT                   /note="Activates thiol group during catalysis"
FT                   /evidence="ECO:0000305|PubMed:16239728,
FT                   ECO:0000305|PubMed:16510976"
FT   MOD_RES         5
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         9
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         42
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0007744|PubMed:15592455"
FT   MOD_RES         46
FT                   /note="Methionine sulfoxide; in vitro"
FT                   /evidence="ECO:0000305|PubMed:25086035"
FT   MOD_RES         61
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         64
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         66
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         70
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         75
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:18183946,
FT                   ECO:0007744|PubMed:20068231"
FT   MOD_RES         83
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17081983,
FT                   ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT   MOD_RES         122
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         148
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         149
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         151
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         152
FT                   /note="ADP-ribosylcysteine; by autocatalysis; in
FT                   irreversibly inhibited form"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         152
FT                   /note="Cysteine persulfide"
FT                   /evidence="ECO:0000250|UniProtKB:P16858"
FT   MOD_RES         152
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         152
FT                   /note="S-nitrosocysteine; in reversibly inhibited form"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         153
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         155
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         177
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         182
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         184
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:24275569"
FT   MOD_RES         194
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         194
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         194
FT                   /note="N6-malonyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:21908771"
FT   MOD_RES         211
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         215
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         215
FT                   /note="N6-malonyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:21908771"
FT   MOD_RES         219
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         225
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         227
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         227
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         229
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:18183946,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         237
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         241
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         247
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         247
FT                   /note="S-nitrosocysteine"
FT                   /evidence="ECO:0000269|PubMed:22771119,
FT                   ECO:0000269|PubMed:25417112"
FT   MOD_RES         254
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         260
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         263
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         312
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:18183946,
FT                   ECO:0007744|PubMed:19690332"
FT   MOD_RES         316
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         333
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         334
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   CARBOHYD        197
FT                   /note="(Microbial infection) N-beta-linked (GlcNAc)
FT                   arginine"
FT                   /evidence="ECO:0000269|PubMed:28522607"
FT   CARBOHYD        200
FT                   /note="(Microbial infection) N-beta-linked (GlcNAc)
FT                   arginine"
FT                   /evidence="ECO:0000269|PubMed:28522607"
FT   CROSSLNK        186
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2)"
FT                   /evidence="ECO:0007744|PubMed:28112733"
FT   VAR_SEQ         1..42
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_047289"
FT   VARIANT         22
FT                   /note="A -> G (in dbSNP:rs45541435)"
FT                   /evidence="ECO:0000269|Ref.12"
FT                   /id="VAR_018889"
FT   VARIANT         251
FT                   /note="K -> N (in dbSNP:rs1062429)"
FT                   /id="VAR_049218"
FT   MUTAGEN         46
FT                   /note="M->L: Drastic reduction of the extent and
FT                   significant prolongation of the lag phase of free radical-
FT                   induced aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         105
FT                   /note="M->L: Increased resistance to free radical-induced
FT                   aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         152
FT                   /note="C->S: Markedly reduced glycolytic activity; when
FT                   associated with S-156 and S-247. Forms free radical-induced
FT                   aggregates, but to a lesser extent than wild-type protein;
FT                   when associated with S-156 and S-247. Abolished interaction
FT                   with TRAF2 and TRAF3."
FT                   /evidence="ECO:0000269|PubMed:23332158,
FT                   ECO:0000269|PubMed:25086035, ECO:0000269|PubMed:27387501"
FT   MUTAGEN         156
FT                   /note="C->S: Markedly reduced glycolytic activity; when
FT                   associated with S-152 and S-247. Forms free radical-induced
FT                   aggregates, but to a lesser extent than wild-type protein;
FT                   when associated with S-156 and S-247."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         196
FT                   /note="W->F: Increased free radical-induced aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         211
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         229
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         241
FT                   /note="S->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         245
FT                   /note="L->M: Inhibits S-nitrosylation of Cys-247; when
FT                   associated with M-250."
FT                   /evidence="ECO:0000269|PubMed:25417112"
FT   MUTAGEN         246
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         247
FT                   /note="C->S: Markedly reduced glycolytic activity; when
FT                   associated with S-152 and S-156. Forms free radical-induced
FT                   aggregates, but to a lesser extent than wild-type protein;
FT                   when associated with S-156 and S-247."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         250
FT                   /note="E->M: Inhibits S-nitrosylation of Cys-247; when
FT                   associated with M-245."
FT                   /evidence="ECO:0000269|PubMed:25417112"
FT   MUTAGEN         277
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         320
FT                   /note="Y->F: No effect on free radical-induced
FT                   aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   CONFLICT        225
FT                   /note="N -> D (in Ref. 2; CAA25833)"
FT                   /evidence="ECO:0000305"
FT   STRAND          5..9
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           13..25
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          27..34
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          36..38
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           40..48
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            51..53
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          60..63
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          66..69
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          72..77
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           82..84
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           88..90
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          94..97
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          99..101
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           105..108
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           110..113
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          117..123
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          126..128
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            133..135
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           137..139
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          146..148
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           152..168
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          170..179
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          185..189
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           196..199
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            202..204
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          207..210
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           213..220
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           222..224
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          227..234
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          241..251
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           255..267
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            268..273
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          274..277
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           283..286
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          292..296
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            297..299
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          301..304
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          307..314
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           318..333
FT                   /evidence="ECO:0007829|PDB:6YND"
SQ   SEQUENCE   335 AA;  36053 MW;  C9C135E8AE3E8744 CRC64;
     MGKVKVGVNG FGRIGRLVTR AAFNSGKVDI VAINDPFIDL NYMVYMFQYD STHGKFHGTV
     KAENGKLVIN GNPITIFQER DPSKIKWGDA GAEYVVESTG VFTTMEKAGA HLQGGAKRVI
     ISAPSADAPM FVMGVNHEKY DNSLKIISNA SCTTNCLAPL AKVIHDNFGI VEGLMTTVHA
     ITATQKTVDG PSGKLWRDGR GALQNIIPAS TGAAKAVGKV IPELNGKLTG MAFRVPTANV
     SVVDLTCRLE KPAKYDDIKK VVKQASEGPL KGILGYTEHQ VVSSDFNSDT HSSTFDAGAG
     IALNDHFVKL ISWYDNEFGY SNRVVDLMAH MASKE
//
ID   GSK3A_HUMAN             Reviewed;         483 AA.
AC   P49840; O14959;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-2000, sequence version 2.
DT   28-JAN-2026, entry version 227.
DE   RecName: Full=Glycogen synthase kinase-3 alpha;
DE            Short=GSK-3 alpha;
DE            EC=2.7.11.26;
DE   AltName: Full=Serine/threonine-protein kinase GSK3A;
DE            EC=2.7.11.1 {ECO:0000269|PubMed:22539723, ECO:0000269|PubMed:25897075};
GN   Name=GSK3A;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Foreskin;
RA   He X., Saint-Jeannet J.P., Woodgett J.R., Varmus H.E., Dawid I.B.;
RT   "Glycogen synthase kinase 3 and dorsoventral patterning in Xenopus
RT   embryos.";
RL   Submitted (MAR-1995) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Brain;
RA   Hoshino T., Kondo K., Ishiguro K., Takashima A., Imahori K.;
RT   "Isolation of cDNA clones for human glycogen synthase kinase 3alpha.";
RL   Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA   Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA   Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA   Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA   Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA   Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA   Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA   Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA   Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA   McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA   Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA   Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA   She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA   Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA   Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Eye, and Pancreas;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   FUNCTION, AND ASSOCIATION WITH DIABETES MELLITUS.
RX   PubMed=10868943; DOI=10.2337/diabetes.49.2.263;
RA   Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L.,
RA   Henry R.R.;
RT   "Potential role of glycogen synthase kinase-3 in skeletal muscle insulin
RT   resistance of type 2 diabetes.";
RL   Diabetes 49:263-271(2000).
RN   [6]
RP   ASSOCIATION WITH ALZHEIMER DISEASE, AND FUNCTION.
RX   PubMed=12761548; DOI=10.1038/nature01640;
RA   Phiel C.J., Wilson C.A., Lee V.M., Klein P.S.;
RT   "GSK-3alpha regulates production of Alzheimer's disease amyloid-beta
RT   peptides.";
RL   Nature 423:435-439(2003).
RN   [7]
RP   FUNCTION IN WNT SIGNALING, AND INTERACTION WITH AXIN1 AND
RP   CTNNB1/BETA-CATENIN.
RX   PubMed=17229088; DOI=10.1111/j.1460-9568.2006.05243.x;
RA   Asuni A.A., Hooper C., Reynolds C.H., Lovestone S., Anderton B.H.,
RA   Killick R.;
RT   "GSK3alpha exhibits beta-catenin and tau directed kinase activities that
RT   are modulated by Wnt.";
RL   Eur. J. Neurosci. 24:3387-3392(2006).
RN   [8]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=11749387; DOI=10.1021/cr000110o;
RA   Ali A., Hoeflich K.P., Woodgett J.R.;
RT   "Glycogen synthase kinase-3: properties, functions, and regulation.";
RL   Chem. Rev. 101:2527-2540(2001).
RN   [9]
RP   REVIEW ON FUNCTION.
RX   PubMed=17478001; DOI=10.1016/j.diabres.2007.01.033;
RA   Lee J., Kim M.S.;
RT   "The role of GSK3 in glucose homeostasis and the development of insulin
RT   resistance.";
RL   Diabetes Res. Clin. Pract. 77:S49-S57(2007).
RN   [10]
RP   INTERACTION WITH DDX3X AND TNFRSF10B.
RX   PubMed=18846110; DOI=10.1038/cdd.2008.124;
RA   Sun M., Song L., Li Y., Zhou T., Jope R.S.;
RT   "Identification of an antiapoptotic protein complex at death receptors.";
RL   Cell Death Differ. 15:1887-1900(2008).
RN   [11]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-72, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [13]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [14]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=19366350; DOI=10.1111/j.1476-5381.2008.00085.x;
RA   Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A.;
RT   "Glycogen synthase kinase 3: more than a namesake.";
RL   Br. J. Pharmacol. 156:885-898(2009).
RN   [15]
RP   INTERACTION WITH CTNND2.
RX   PubMed=19706605; DOI=10.1074/jbc.m109.002659;
RA   Oh M., Kim H., Yang I., Park J.H., Cong W.T., Baek M.C., Bareiss S., Ki H.,
RA   Lu Q., No J., Kwon I., Choi J.K., Kim K.;
RT   "GSK-3 phosphorylates delta-catenin and negatively regulates its stability
RT   via ubiquitination/proteosome-mediated proteolysis.";
RL   J. Biol. Chem. 284:28579-28589(2009).
RN   [16]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE
RP   ANALYSIS] AT SER-2; SER-77 AND SER-97, CLEAVAGE OF INITIATOR METHIONINE
RP   [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE
RP   SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [17]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [18]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [19]
RP   CATALYTIC ACTIVITY.
RX   PubMed=22539723; DOI=10.1126/science.1217032;
RA   Lin S.Y., Li T.Y., Liu Q., Zhang C., Li X., Chen Y., Zhang S.M., Lian G.,
RA   Liu Q., Ruan K., Wang Z., Zhang C.S., Chien K.Y., Wu J., Li Q., Han J.,
RA   Lin S.C.;
RT   "GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to
RT   autophagy.";
RL   Science 336:477-481(2012).
RN   [20]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [21]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [22]
RP   INTERACTION WITH MYCOBACTERIUM TUBERCULOSIS PTPA, AND DEPHOSPHORYLATION
RP   (MICROBIAL INFECTION).
RX   PubMed=25187516; DOI=10.1074/jbc.m114.582502;
RA   Poirier V., Bach H., Av-Gay Y.;
RT   "Mycobacterium tuberculosis promotes anti-apoptotic activity of the
RT   macrophage by PtpA protein-dependent dephosphorylation of host GSK3alpha.";
RL   J. Biol. Chem. 289:29376-29385(2014).
RN   [23]
RP   FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH RICTOR.
RX   PubMed=25897075; DOI=10.1074/jbc.m114.633057;
RA   Koo J., Wu X., Mao Z., Khuri F.R., Sun S.Y.;
RT   "Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-
RT   mediated Ubiquitination and Proteasomal Degradation.";
RL   J. Biol. Chem. 290:14120-14129(2015).
RN   [24]
RP   FUNCTION.
RX   PubMed=30704899; DOI=10.1016/j.molcel.2018.12.017;
RA   Cheng X., Ma X., Zhu Q., Song D., Ding X., Li L., Jiang X., Wang X.,
RA   Tian R., Su H., Shen Z., Chen S., Liu T., Gong W., Liu W., Sun Q.;
RT   "Pacer is a mediator of mTORC1 and GSK3-TIP60 signaling in regulation of
RT   autophagosome maturation and lipid metabolism.";
RL   Mol. Cell 73:1-15(2019).
RN   [25]
RP   INTERACTION WITH LMBR1L.
RX   PubMed=31073040; DOI=10.1126/science.aau0812;
RA   Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J.,
RA   Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M.,
RA   Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y.,
RA   Beutler B.;
RT   "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling.";
RL   Science 364:0-0(2019).
RN   [26]
RP   VARIANT [LARGE SCALE ANALYSIS] PHE-461.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
CC   -!- FUNCTION: Constitutively active protein kinase that acts as a negative
CC       regulator in the hormonal control of glucose homeostasis, Wnt signaling
CC       and regulation of transcription factors and microtubules, by
CC       phosphorylating and inactivating glycogen synthase (GYS1 or GYS2),
CC       CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001,
CC       PubMed:19366350). Requires primed phosphorylation of the majority of
CC       its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350).
CC       Contributes to insulin regulation of glycogen synthesis by
CC       phosphorylating and inhibiting GYS1 activity and hence glycogen
CC       synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350).
CC       Regulates glycogen metabolism in liver, but not in muscle (By
CC       similarity). May also mediate the development of insulin resistance by
CC       regulating activation of transcription factors (PubMed:10868943,
CC       PubMed:17478001). In Wnt signaling, regulates the level and
CC       transcriptional activity of nuclear CTNNB1/beta-catenin
CC       (PubMed:17229088). Facilitates amyloid precursor protein (APP)
CC       processing and the generation of APP-derived amyloid plaques found in
CC       Alzheimer disease (PubMed:12761548). May be involved in the regulation
CC       of replication in pancreatic beta-cells (By similarity). Is necessary
CC       for the establishment of neuronal polarity and axon outgrowth (By
CC       similarity). Through phosphorylation of the anti-apoptotic protein
CC       MCL1, may control cell apoptosis in response to growth factors
CC       deprivation (By similarity). Acts as a regulator of autophagy by
CC       mediating phosphorylation of KAT5/TIP60 under starvation conditions
CC       which activates KAT5/TIP60 acetyltransferase activity and promotes
CC       acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer
CC       (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling
CC       pathway via death domain receptors. Promotes the formation of an anti-
CC       apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors,
CC       including TNFRSF10B. The anti-apoptotic function is most effective with
CC       weak apoptotic signals and can be overcome by stronger stimulation (By
CC       similarity). Phosphorylates mTORC2 complex component RICTOR at 'Thr-
CC       1695' which facilitates FBXW7-mediated ubiquitination and subsequent
CC       degradation of RICTOR (PubMed:25897075). {ECO:0000250|UniProtKB:P18265,
CC       ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q2NL51,
CC       ECO:0000269|PubMed:10868943, ECO:0000269|PubMed:12761548,
CC       ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:25897075,
CC       ECO:0000269|PubMed:30704899, ECO:0000303|PubMed:11749387,
CC       ECO:0000303|PubMed:17478001, ECO:0000303|PubMed:19366350}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein]
CC         + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC         COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau
CC         protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC         Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.26;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:22539723};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:25897075};
CC   -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-279. In
CC       response to insulin, inhibited by phosphorylation at Ser-21 by
CC       PKB/AKT1; phosphorylation at this site causes a conformational change,
CC       preventing access of substrates to the active site. Inhibited by
CC       lithium. {ECO:0000269|PubMed:11749387, ECO:0000269|PubMed:19366350}.
CC   -!- SUBUNIT: Monomer. Interacts with ARRB2 (By similarity). Interacts with
CC       AXIN1 and CTNNB1/beta-catenin (PubMed:17229088). Interacts with CTNND2
CC       (PubMed:19706605). Interacts with LMBR1L (PubMed:31073040). Interacts
CC       with DDX3X (PubMed:18846110). Interacts with TNFRSF10B
CC       (PubMed:18846110). Interacts with RICTOR; the interaction results in
CC       phosphorylation of RICTOR at 'Thr-1695' by GSK3A which facilitates
CC       FBXW7-mediated ubiquitination and subsequent degradation of RICTOR
CC       (PubMed:25897075). {ECO:0000250|UniProtKB:Q2NL51,
CC       ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:18846110,
CC       ECO:0000269|PubMed:19706605, ECO:0000269|PubMed:25897075,
CC       ECO:0000305|PubMed:31073040}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with M.tuberculosis PtpA.
CC       {ECO:0000269|PubMed:25187516}.
CC   -!- INTERACTION:
CC       P49840; PRO_0000000093 [P05067]: APP; NbExp=3; IntAct=EBI-1044067, EBI-2431589;
CC       P49840; O15169: AXIN1; NbExp=6; IntAct=EBI-1044067, EBI-710484;
CC       P49840; Q9Y2T1: AXIN2; NbExp=4; IntAct=EBI-1044067, EBI-4400025;
CC       P49840; P15056: BRAF; NbExp=6; IntAct=EBI-1044067, EBI-365980;
CC       P49840; O75398: DEAF1; NbExp=3; IntAct=EBI-1044067, EBI-718185;
CC       P49840; Q6P3S6: FBXO42; NbExp=3; IntAct=EBI-1044067, EBI-2506081;
CC       P49840; Q92837: FRAT1; NbExp=5; IntAct=EBI-1044067, EBI-3934879;
CC       P49840; Q9P0R6: GSKIP; NbExp=6; IntAct=EBI-1044067, EBI-1052580;
CC       P49840; P08238: HSP90AB1; NbExp=3; IntAct=EBI-1044067, EBI-352572;
CC       P49840; P42858: HTT; NbExp=6; IntAct=EBI-1044067, EBI-466029;
CC       P49840; O75581: LRP6; NbExp=3; IntAct=EBI-1044067, EBI-910915;
CC       P49840; P10636-8: MAPT; NbExp=2; IntAct=EBI-1044067, EBI-366233;
CC       P49840; Q14596: NBR1; NbExp=7; IntAct=EBI-1044067, EBI-742698;
CC       P49840; P62258: YWHAE; NbExp=3; IntAct=EBI-1044067, EBI-356498;
CC       P49840; P61981: YWHAG; NbExp=5; IntAct=EBI-1044067, EBI-359832;
CC       P49840; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-1044067, EBI-524753;
CC   -!- PTM: Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling,
CC       the activated PKB/AKT1 protein kinase phosphorylates and deactivates
CC       GSK3A, resulting in the dephosphorylation and activation of GYS1.
CC       Activated by phosphorylation at Tyr-279.
CC   -!- PTM: (Microbial infection) Dephosphorylated at Tyr-279 by
CC       M.tuberculosis PtpA, which leads to prevention of apoptosis during
CC       early stages of microbial infection. {ECO:0000269|PubMed:25187516}.
CC   -!- MISCELLANEOUS: Higher expression and activity of GSK3A are found in the
CC       skeletal muscle (vastus lateralis) of patients with type 2 diabetes
CC       (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors
CC       have been identified and characterized in preclinical models for
CC       treatments of type 2 diabetes (PubMed:19366350).
CC       {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. GSK-3 subfamily. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
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DR   EMBL; L40027; AAA62432.1; -; mRNA.
DR   EMBL; D63424; BAA23608.1; -; mRNA.
DR   EMBL; AC006486; AAD11986.1; -; Genomic_DNA.
DR   EMBL; BC027984; AAH27984.1; -; mRNA.
DR   EMBL; BC051865; AAH51865.1; -; mRNA.
DR   CCDS; CCDS12599.1; -.
DR   RefSeq; NP_063937.2; NM_019884.2.
DR   PDB; 7SXF; X-ray; 1.94 A; A=101-444.
DR   PDB; 7SXG; X-ray; 2.40 A; A=103-445.
DR   PDBsum; 7SXF; -.
DR   PDBsum; 7SXG; -.
DR   AlphaFoldDB; P49840; -.
DR   SMR; P49840; -.
DR   BioGRID; 109186; 479.
DR   ComplexPortal; CPX-107; Beta-catenin destruction core complex, APC-AXIN1-GSK3A variant.
DR   ComplexPortal; CPX-441; Beta-catenin destruction core complex, APC-AXIN2-GSK3A variant.
DR   ComplexPortal; CPX-442; Beta-catenin destruction core complex, APC2-AXIN1-GSK3A variant.
DR   ComplexPortal; CPX-443; Beta-catenin destruction core complex, APC2-AXIN2-GSK3A variant.
DR   ELM; P49840; -.
DR   FunCoup; P49840; 1731.
DR   IntAct; P49840; 171.
DR   MINT; P49840; -.
DR   STRING; 9606.ENSP00000222330; -.
DR   BindingDB; P49840; -.
DR   ChEMBL; CHEMBL2850; -.
DR   DrugBank; DB01950; AR-AO-14418.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugBank; DB16607; Lithium chloride.
DR   DrugBank; DB11913; LY-2090314.
DR   DrugBank; DB00313; Valproic acid.
DR   DrugCentral; P49840; -.
DR   GuidetoPHARMACOLOGY; 2029; -.
DR   GlyCosmos; P49840; 1 site, 1 glycan.
DR   GlyGen; P49840; 3 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; P49840; -.
DR   PhosphoSitePlus; P49840; -.
DR   SwissPalm; P49840; -.
DR   BioMuta; GSK3A; -.
DR   DMDM; 12644292; -.
DR   CPTAC; CPTAC-3040; -.
DR   jPOST; P49840; -.
DR   MassIVE; P49840; -.
DR   PaxDb; 9606-ENSP00000222330; -.
DR   PeptideAtlas; P49840; -.
DR   ProteomicsDB; 56150; -.
DR   Pumba; P49840; -.
DR   Antibodypedia; 3833; 1208 antibodies from 49 providers.
DR   DNASU; 2931; -.
DR   Ensembl; ENST00000222330.8; ENSP00000222330.3; ENSG00000105723.13.
DR   Ensembl; ENST00000453535.1; ENSP00000412663.1; ENSG00000105723.13.
DR   GeneID; 2931; -.
DR   KEGG; hsa:2931; -.
DR   MANE-Select; ENST00000222330.8; ENSP00000222330.3; NM_019884.3; NP_063937.2.
DR   UCSC; uc002otb.2; human.
DR   AGR; HGNC:4616; -.
DR   ClinPGx; PA29008; -.
DR   CTD; 2931; -.
DR   DisGeNET; 2931; -.
DR   GeneCards; GSK3A; -.
DR   HGNC; HGNC:4616; GSK3A.
DR   HPA; ENSG00000105723; Low tissue specificity.
DR   MIM; 606784; gene.
DR   OpenTargets; ENSG00000105723; -.
DR   VEuPathDB; HostDB:ENSG00000105723; -.
DR   eggNOG; KOG0658; Eukaryota.
DR   GeneTree; ENSGT00520000055635; -.
DR   InParanoid; P49840; -.
DR   OMA; CLHAFFD; -.
DR   OrthoDB; 272141at2759; -.
DR   PAN-GO; P49840; 10 GO annotations based on evolutionary models.
DR   PhylomeDB; P49840; -.
DR   BRENDA; 2.7.11.26; 2681.
DR   PathwayCommons; P49840; -.
DR   Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
DR   Reactome; R-HSA-381038; XBP1(S) activates chaperone genes.
DR   Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR   Reactome; R-HSA-9635465; Suppression of apoptosis.
DR   Reactome; R-HSA-9683610; Maturation of nucleoprotein.
DR   Reactome; R-HSA-9694631; Maturation of nucleoprotein.
DR   SignaLink; P49840; -.
DR   SIGNOR; P49840; -.
DR   Agora; ENSG00000105723; -.
DR   BioGRID-ORCS; 2931; 21 hits in 1191 CRISPR screens.
DR   CD-CODE; 7FF4107C; Beta-Catenin Destruction Complex.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   ChiTaRS; GSK3A; human.
DR   GeneWiki; GSK3A; -.
DR   GenomeRNAi; 2931; -.
DR   Pharos; P49840; Tclin.
DR   PRO; PR:P49840; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; P49840; protein.
DR   Bgee; ENSG00000105723; Expressed in cortical plate and 213 other cell types or tissues.
DR   ExpressionAtlas; P49840; baseline and differential.
DR   GO; GO:0097440; C:apical dendrite; NAS:ARUK-UCL.
DR   GO; GO:0030424; C:axon; IBA:GO_Central.
DR   GO; GO:0030877; C:beta-catenin destruction complex; TAS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR   GO; GO:0043025; C:neuronal cell body; NAS:ARUK-UCL.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0098794; C:postsynapse; IEA:GOC.
DR   GO; GO:1990635; C:proximal dendrite; NAS:ARUK-UCL.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:BHF-UCL.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:Ensembl.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:ARUK-UCL.
DR   GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR   GO; GO:0050321; F:tau-protein kinase activity; TAS:UniProtKB.
DR   GO; GO:0141068; P:autosome genomic imprinting; IEA:Ensembl.
DR   GO; GO:0160213; P:beta-arrestin-dependent dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0003214; P:cardiac left ventricle morphogenesis; ISS:BHF-UCL.
DR   GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR   GO; GO:0016477; P:cell migration; IEA:Ensembl.
DR   GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IEA:Ensembl.
DR   GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
DR   GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR   GO; GO:0071285; P:cellular response to lithium ion; IEA:Ensembl.
DR   GO; GO:0060079; P:excitatory postsynaptic potential; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB.
DR   GO; GO:0005977; P:glycogen metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
DR   GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR   GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IBA:GO_Central.
DR   GO; GO:0061052; P:negative regulation of cell growth involved in cardiac muscle cell development; ISS:BHF-UCL.
DR   GO; GO:0046325; P:negative regulation of D-glucose import; IMP:BHF-UCL.
DR   GO; GO:2000466; P:negative regulation of glycogen (starch) synthase activity; TAS:UniProtKB.
DR   GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; TAS:UniProtKB.
DR   GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:BHF-UCL.
DR   GO; GO:0032007; P:negative regulation of TOR signaling; ISS:BHF-UCL.
DR   GO; GO:2000077; P:negative regulation of type B pancreatic cell development; TAS:UniProtKB.
DR   GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR   GO; GO:0071879; P:positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway; ISS:BHF-UCL.
DR   GO; GO:0106071; P:positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISS:BHF-UCL.
DR   GO; GO:1902004; P:positive regulation of amyloid-beta formation; IMP:ARUK-UCL.
DR   GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; ISS:ARUK-UCL.
DR   GO; GO:0045823; P:positive regulation of heart contraction; ISS:BHF-UCL.
DR   GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; ISS:UniProtKB.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:ARUK-UCL.
DR   GO; GO:0045732; P:positive regulation of protein catabolic process; NAS:BHF-UCL.
DR   GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0031398; P:positive regulation of protein ubiquitination; IMP:ARUK-UCL.
DR   GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; IEA:Ensembl.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IBA:GO_Central.
DR   GO; GO:1901524; P:regulation of mitophagy; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0010975; P:regulation of neuron projection development; IBA:GO_Central.
DR   GO; GO:0003073; P:regulation of systemic arterial blood pressure; ISS:BHF-UCL.
DR   GO; GO:0019082; P:viral protein processing; TAS:Reactome.
DR   GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR   CDD; cd14137; STKc_GSK3; 1.
DR   FunFam; 1.10.510.10:FF:000055; Glycogen synthase kinase-3 beta; 1.
DR   FunFam; 3.30.200.20:FF:000009; Glycogen synthase kinase-3 beta; 1.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR050591; GSK-3.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR039192; STKc_GSK3.
DR   PANTHER; PTHR24057; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1.
DR   PANTHER; PTHR24057:SF14; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alzheimer disease; ATP-binding;
KW   Carbohydrate metabolism; Diabetes mellitus; Glycogen metabolism; Kinase;
KW   Neurogenesis; Nucleotide-binding; Phosphoprotein;
KW   Proteomics identification; Reference proteome;
KW   Serine/threonine-protein kinase; Signal transduction inhibitor;
KW   Transferase; Wnt signaling pathway.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:19369195,
FT                   ECO:0007744|PubMed:19413330"
FT   CHAIN           2..483
FT                   /note="Glycogen synthase kinase-3 alpha"
FT                   /id="PRO_0000085978"
FT   DOMAIN          119..403
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..96
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          449..483
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..15
FT                   /note="Gly residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        25..82
FT                   /note="Gly residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        244
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         125..133
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         148
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         2
FT                   /note="N-acetylserine"
FT                   /evidence="ECO:0007744|PubMed:19369195,
FT                   ECO:0007744|PubMed:19413330"
FT   MOD_RES         2
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976,
FT                   ECO:0007744|PubMed:19369195"
FT   MOD_RES         21
FT                   /note="Phosphoserine; by PKB/AKT1"
FT                   /evidence="ECO:0000250|UniProtKB:Q2NL51"
FT   MOD_RES         72
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976"
FT   MOD_RES         77
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19369195"
FT   MOD_RES         97
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19369195"
FT   MOD_RES         279
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P18265"
FT   VARIANT         109
FT                   /note="Q -> E (in dbSNP:rs35978177)"
FT                   /id="VAR_051625"
FT   VARIANT         461
FT                   /note="L -> F (in dbSNP:rs35454502)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040539"
FT   CONFLICT        449
FT                   /note="A -> S (in Ref. 1; AAA62432)"
FT                   /evidence="ECO:0000305"
FT   STRAND          102..112
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          114..118
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          120..126
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          132..137
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          144..152
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           159..166
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          175..182
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          189..196
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          199..201
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           202..211
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           218..237
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           247..249
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          250..252
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   TURN            254..256
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          259..261
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           264..266
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           283..285
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           288..291
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           300..315
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           325..336
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           341..347
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           349..351
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           364..366
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           374..383
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           388..390
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           394..398
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           401..403
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           404..407
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   TURN            414..416
FT                   /evidence="ECO:0007829|PDB:7SXG"
FT   HELIX           429..431
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           434..436
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           437..440
FT                   /evidence="ECO:0007829|PDB:7SXF"
SQ   SEQUENCE   483 AA;  50981 MW;  F18C012C03B7D786 CRC64;
     MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK ASVGAMGGGV
     GASSSGGGPG GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV TTVVATLGQG PERSQEVAYT
     DIKVIGNGSF GVVYQARLAE TRELVAIKKV LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY
     SSGEKKDELY LNLVLEYVPE TVYRVARHFT KAKLTIPILY VKVYMYQLFR SLAYIHSQGV
     CHRDIKPQNL LVDPDTAVLK LCDFGSAKQL VRGEPNVSYI CSRYYRAPEL IFGATDYTSS
     IDVWSAGCVL AELLLGQPIF PGDSGVDQLV EIIKVLGTPT REQIREMNPN YTEFKFPQIK
     AHPWTKVFKS RTPPEAIALC SSLLEYTPSS RLSPLEACAH SFFDELRCLG TQLPNNRPLP
     PLFNFSAGEL SIQPSLNAIL IPPHLRSPAG TTTLTPSSQA LTETPTSSDW QSTDATPTLT
     NSS
//
ID   GSK3B_HUMAN             Reviewed;         420 AA.
AC   P49841; D3DN89; Q9BWH3; Q9UL47;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   02-MAY-2002, sequence version 2.
DT   28-JAN-2026, entry version 273.
DE   RecName: Full=Glycogen synthase kinase-3 beta {ECO:0000305};
DE            Short=GSK-3 beta;
DE            EC=2.7.11.26 {ECO:0000269|PubMed:14690523};
DE   AltName: Full=Serine/threonine-protein kinase GSK3B;
DE            EC=2.7.11.1 {ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942, ECO:0000269|PubMed:21343617, ECO:0000269|PubMed:22539723, ECO:0000269|PubMed:25827072, ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:29059170};
GN   Name=GSK3B {ECO:0000312|HGNC:HGNC:4617};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND MUTAGENESIS OF SER-9.
RX   PubMed=7980435; DOI=10.1042/bj3030701;
RA   Stambolic V., Woodgett J.R.;
RT   "Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells
RT   via serine 9 phosphorylation.";
RL   Biochem. J. 303:701-704(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Eye, and Placenta;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-28.
RX   PubMed=10486203; DOI=10.1006/geno.1999.5875;
RA   Lau K.F., Miller C.C.J., Anderton B.H., Shaw P.C.;
RT   "Molecular cloning and characterization of the human glycogen synthase
RT   kinase-3beta promoter.";
RL   Genomics 60:121-128(1999).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 185-202.
RX   PubMed=10523816; DOI=10.1038/sj.mp.4000538;
RA   Rhoads A.R., Karkera J.D., Detera-Wadleigh S.D.;
RT   "Radiation hybrid mapping of genes in the lithium-sensitive wnt signaling
RT   pathway.";
RL   Mol. Psychiatry 4:437-442(1999).
RN   [6]
RP   FUNCTION IN PHOSPHORYLATION OF JUN.
RX   PubMed=1846781; DOI=10.1016/0092-8674(91)90241-p;
RA   Boyle W.J., Smeal T., Defize L.H., Angel P., Woodgett J.R., Karin M.,
RA   Hunter T.;
RT   "Activation of protein kinase C decreases phosphorylation of c-Jun at sites
RT   that negatively regulate its DNA-binding activity.";
RL   Cell 64:573-584(1991).
RN   [7]
RP   FUNCTION IN PHOSPHORYLATION OF EIF2BE/EIF2B5.
RX   PubMed=8397507; DOI=10.1042/bj2940625;
RA   Welsh G.I., Proud C.G.;
RT   "Glycogen synthase kinase-3 is rapidly inactivated in response to insulin
RT   and phosphorylates eukaryotic initiation factor eIF-2B.";
RL   Biochem. J. 294:625-629(1993).
RN   [8]
RP   PHOSPHORYLATION AT SER-9.
RX   PubMed=8250835; DOI=10.1042/bj2960015;
RA   Sutherland C., Leighton I.A., Cohen P.;
RT   "Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new
RT   kinase connections in insulin and growth-factor signalling.";
RL   Biochem. J. 296:15-19(1993).
RN   [9]
RP   ACTIVITY REGULATION BY AKT1.
RX   PubMed=8524413; DOI=10.1038/378785a0;
RA   Cross D.A., Alessi D.R., Cohen P., Andjelkovich M., Hemmings B.A.;
RT   "Inhibition of glycogen synthase kinase-3 by insulin mediated by protein
RT   kinase B.";
RL   Nature 378:785-789(1995).
RN   [10]
RP   FUNCTION IN PHOSPHORYLATION OF NFATC1/NFATC.
RX   PubMed=9072970; DOI=10.1126/science.275.5308.1930;
RA   Beals C.R., Sheridan C.M., Turck C.W., Gardner P., Crabtree G.R.;
RT   "Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3.";
RL   Science 275:1930-1934(1997).
RN   [11]
RP   INTERACTION WITH DNM1L.
RC   TISSUE=Liver;
RX   PubMed=9731200; DOI=10.1006/bbrc.1998.9253;
RA   Hong Y.-R., Chen C.-H., Cheng D.-S., Howng S.-L., Chow C.-C.;
RT   "Human dynamin-like protein interacts with the glycogen synthase kinase
RT   3beta.";
RL   Biochem. Biophys. Res. Commun. 249:697-703(1998).
RN   [12]
RP   INTERACTION WITH MUC1, AND FUNCTION.
RX   PubMed=9819408; DOI=10.1128/mcb.18.12.7216;
RA   Li Y., Bharti A., Chen D., Gong J., Kufe D.;
RT   "Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-
RT   associated antigen and beta-catenin.";
RL   Mol. Cell. Biol. 18:7216-7224(1998).
RN   [13]
RP   CHARACTERIZATION.
RX   PubMed=9736715; DOI=10.1073/pnas.95.19.11211;
RA   Delcommenne M., Tan C., Gray V., Rue L., Woodgett J.R., Dedhar S.;
RT   "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase
RT   kinase 3 and protein kinase B/AKT by the integrin-linked kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:11211-11216(1998).
RN   [14]
RP   INTERACTION WITH NIN.
RX   PubMed=11004522; DOI=10.1016/s0167-4781(00)00127-5;
RA   Hong Y.-R., Chen C.-H., Chang J.-H., Wang S.-K., Sy W.-D., Chou C.-K.,
RA   Howng S.-L.;
RT   "Cloning and characterization of a novel human ninein protein that
RT   interacts with the glycogen synthase kinase 3beta.";
RL   Biochim. Biophys. Acta 1492:513-516(2000).
RN   [15]
RP   ASSOCIATION WITH DIABETES MELLITUS.
RX   PubMed=10868943; DOI=10.2337/diabetes.49.2.263;
RA   Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L.,
RA   Henry R.R.;
RT   "Potential role of glycogen synthase kinase-3 in skeletal muscle insulin
RT   resistance of type 2 diabetes.";
RL   Diabetes 49:263-271(2000).
RN   [16]
RP   FUNCTION, AND MUTAGENESIS OF ARG-96 AND LEU-128.
RX   PubMed=11430833; DOI=10.1016/s1097-2765(01)00253-2;
RA   Frame S., Cohen P., Biondi R.M.;
RT   "A common phosphate binding site explains the unique substrate specificity
RT   of GSK3 and its inactivation by phosphorylation.";
RL   Mol. Cell 7:1321-1327(2001).
RN   [17]
RP   PHOSPHORYLATION AT SER-9 BY SGK3, AND INTERACTION WITH SGK3.
RX   PubMed=12054501; DOI=10.1016/s0006-291x(02)00349-2;
RA   Dai F., Yu L., He H., Chen Y., Yu J., Yang Y., Xu Y., Ling W., Zhao S.;
RT   "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL)
RT   phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9
RT   through direct interaction.";
RL   Biochem. Biophys. Res. Commun. 293:1191-1196(2002).
RN   [18]
RP   FUNCTION IN PHOSPHORYLATION OF MAPT/TAU.
RX   PubMed=14690523; DOI=10.1111/j.1471-4159.2004.02155.x;
RA   Cho J.H., Johnson G.V.;
RT   "Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta
RT   (GSK3beta) plays a critical role in regulating tau's ability to bind and
RT   stabilize microtubules.";
RL   J. Neurochem. 88:349-358(2004).
RN   [19]
RP   FUNCTION, INTERACTION WITH SNAI1, AND SUBCELLULAR LOCATION.
RX   PubMed=15448698; DOI=10.1038/ncb1173;
RA   Zhou B.P., Deng J., Xia W., Xu J., Li Y.M., Gunduz M., Hung M.C.;
RT   "Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control
RT   of epithelial-mesenchymal transition.";
RL   Nat. Cell Biol. 6:931-940(2004).
RN   [20]
RP   INTERACTION WITH CABYR.
RX   PubMed=15752768; DOI=10.1016/j.bbrc.2005.02.089;
RA   Hsu H.-C., Lee Y.-L., Cheng T.-S., Howng S.-L., Chang L.-K., Lu P.-J.,
RA   Hong Y.-R.;
RT   "Characterization of two non-testis-specific CABYR variants that bind to
RT   GSK3beta with a proline-rich extensin-like domain.";
RL   Biochem. Biophys. Res. Commun. 329:1108-1117(2005).
RN   [21]
RP   FUNCTION, AND INTERACTION WITH SNAI1.
RX   PubMed=15647282; DOI=10.1074/jbc.m413878200;
RA   Yook J.I., Li X.Y., Ota I., Fearon E.R., Weiss S.J.;
RT   "Wnt-dependent regulation of the E-cadherin repressor snail.";
RL   J. Biol. Chem. 280:11740-11748(2005).
RN   [22]
RP   INTERACTION WITH GSKIP.
RX   PubMed=16981698; DOI=10.1021/bi061147r;
RA   Chou H.-Y., Howng S.-L., Cheng T.-S., Hsiao Y.-L., Lieu A.-S., Loh J.-K.,
RA   Hwang S.-L., Lin C.-C., Hsu C.-M., Wang C., Lee C.-I., Lu P.-J.,
RA   Chou C.-K., Huang C.-Y., Hong Y.-R.;
RT   "GSKIP is homologous to the axin GSK3beta interaction domain and functions
RT   as a negative regulator of GSK3beta.";
RL   Biochemistry 45:11379-11389(2006).
RN   [23]
RP   INTERACTION WITH PRUNE1.
RX   PubMed=16428445; DOI=10.1128/mcb.26.3.898-911.2006;
RA   Kobayashi T., Hino S., Oue N., Asahara T., Zollo M., Yasui W., Kikuchi A.;
RT   "Glycogen synthase kinase 3 and h-prune regulate cell migration by
RT   modulating focal adhesions.";
RL   Mol. Cell. Biol. 26:898-911(2006).
RN   [24]
RP   FUNCTION, AND PHOSPHORYLATION AT SER-9.
RX   PubMed=16484495; DOI=10.1126/science.1121613;
RA   Yin L., Wang J., Klein P.S., Lazar M.A.;
RT   "Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of
RT   the circadian clock.";
RL   Science 311:1002-1005(2006).
RN   [25]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-9 AND 85-LYS-LYS-86.
RX   PubMed=17050006; DOI=10.1016/j.bbamcr.2006.09.015;
RA   Garcia-Alvarez G., Ventura V., Ros O., Aligue R., Gil J., Tauler A.;
RT   "Glycogen synthase kinase-3beta binds to E2F1 and regulates its
RT   transcriptional activity.";
RL   Biochim. Biophys. Acta 1773:375-382(2007).
RN   [26]
RP   INTERACTION WITH AXIN1.
RX   PubMed=17318175; DOI=10.1038/sj.emboj.7601607;
RA   Luo W., Peterson A., Garcia B.A., Coombs G., Kofahl B., Heinrich R.,
RA   Shabanowitz J., Hunt D.F., Yost H.J., Virshup D.M.;
RT   "Protein phosphatase 1 regulates assembly and function of the beta-catenin
RT   degradation complex.";
RL   EMBO J. 26:1511-1521(2007).
RN   [27]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=17681942; DOI=10.1074/jbc.m703948200;
RA   Higgins M.J., Graves P.R., Graves L.M.;
RT   "Regulation of human cytidine triphosphate synthetase 1 by glycogen
RT   synthase kinase 3.";
RL   J. Biol. Chem. 282:29493-29503(2007).
RN   [28]
RP   FUNCTION, AND INTERACTION WITH BIRC2; DDX3X AND TNFRSF10B.
RX   PubMed=18846110; DOI=10.1038/cdd.2008.124;
RA   Sun M., Song L., Li Y., Zhou T., Jope R.S.;
RT   "Identification of an antiapoptotic protein complex at death receptors.";
RL   Cell Death Differ. 15:1887-1900(2008).
RN   [29]
RP   FUNCTION IN PHOSPHORYLATION OF SIK1.
RX   PubMed=18348280; DOI=10.1002/jcb.21737;
RA   Hashimoto Y.K., Satoh T., Okamoto M., Takemori H.;
RT   "Importance of autophosphorylation at Ser186 in the A-loop of salt
RT   inducible kinase 1 for its sustained kinase activity.";
RL   J. Cell. Biochem. 104:1724-1739(2008).
RN   [30]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-402, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [31]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-390, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [32]
RP   INTERACTION WITH MMP2.
RX   PubMed=19493954; DOI=10.1093/cvr/cvp175;
RA   Kandasamy A.D., Schulz R.;
RT   "Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2
RT   mediated proteolysis in cardiomyoblasts.";
RL   Cardiovasc. Res. 83:698-706(2009).
RN   [33]
RP   FUNCTION, AND INTERACTION WITH CLOCK-BMAL1.
RX   PubMed=19946213; DOI=10.4161/cc.8.24.10273;
RA   Spengler M.L., Kuropatwinski K.K., Schumer M., Antoch M.P.;
RT   "A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and
RT   degradation.";
RL   Cell Cycle 8:4138-4146(2009).
RN   [34]
RP   INTERACTION WITH CTNND2.
RX   PubMed=19706605; DOI=10.1074/jbc.m109.002659;
RA   Oh M., Kim H., Yang I., Park J.H., Cong W.T., Baek M.C., Bareiss S., Ki H.,
RA   Lu Q., No J., Kwon I., Choi J.K., Kim K.;
RT   "GSK-3 phosphorylates delta-catenin and negatively regulates its stability
RT   via ubiquitination/proteosome-mediated proteolysis.";
RL   J. Biol. Chem. 284:28579-28589(2009).
RN   [35]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [36]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [37]
RP   FUNCTION, AND ALTERNATIVE SPLICING.
RX   PubMed=20067585; DOI=10.1111/j.1471-4159.2010.06581.x;
RA   Castano Z., Gordon-Weeks P.R., Kypta R.M.;
RT   "The neuron-specific isoform of glycogen synthase kinase-3beta is required
RT   for axon growth.";
RL   J. Neurochem. 113:117-130(2010).
RN   [38]
RP   FUNCTION.
RX   PubMed=20932480; DOI=10.1016/j.molcel.2010.09.013;
RA   Heyd F., Lynch K.W.;
RT   "Phosphorylation-dependent regulation of PSF by GSK3 controls CD45
RT   alternative splicing.";
RL   Mol. Cell 40:126-137(2010).
RN   [39]
RP   INTERACTION WITH DAB2IP AND PPP2CA.
RX   PubMed=20080667; DOI=10.1073/pnas.0908133107;
RA   Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M., Kabbani W.,
RA   Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W., Hsieh J.T.;
RT   "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and
RT   prostate cancer metastasis.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010).
RN   [40]
RP   FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-9.
RX   PubMed=20937854; DOI=10.1073/pnas.1000975107;
RA   Zaoui K., Benseddik K., Daou P., Salaun D., Badache A.;
RT   "ErbB2 receptor controls microtubule capture by recruiting ACF7 to the
RT   plasma membrane of migrating cells.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010).
RN   [41]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=11749387; DOI=10.1021/cr000110o;
RA   Ali A., Hoeflich K.P., Woodgett J.R.;
RT   "Glycogen synthase kinase-3: properties, functions, and regulation.";
RL   Chem. Rev. 101:2527-2540(2001).
RN   [42]
RP   REVIEW ON FUNCTION.
RX   PubMed=17478001; DOI=10.1016/j.diabres.2007.01.033;
RA   Lee J., Kim M.S.;
RT   "The role of GSK3 in glucose homeostasis and the development of insulin
RT   resistance.";
RL   Diabetes Res. Clin. Pract. 77:S49-S57(2007).
RN   [43]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=19366350; DOI=10.1111/j.1476-5381.2008.00085.x;
RA   Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A.;
RT   "Glycogen synthase kinase 3: more than a namesake.";
RL   Br. J. Pharmacol. 156:885-898(2009).
RN   [44]
RP   INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2A AND GSKIP.
RX   PubMed=20007971; DOI=10.1074/jbc.m109.047944;
RA   Hundsrucker C., Skroblin P., Christian F., Zenn H.M., Popara V., Joshi M.,
RA   Eichhorst J., Wiesner B., Herberg F.W., Reif B., Rosenthal W.,
RA   Klussmann E.;
RT   "Glycogen synthase kinase 3beta interaction protein functions as an A-
RT   kinase anchoring protein.";
RL   J. Biol. Chem. 285:5507-5521(2010).
RN   [45]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [46]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [47]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
RX   PubMed=21029237; DOI=10.1111/j.1750-3639.2010.00437.x;
RA   Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F., Hugon J.;
RT   "Modulation of tau phosphorylation by the kinase PKR: implications in
RT   Alzheimer's disease.";
RL   Brain Pathol. 21:189-200(2011).
RN   [48]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=21343617; DOI=10.1126/scisignal.2001731;
RA   Chen C.H., Shaikenov T., Peterson T.R., Aimbetov R., Bissenbaev A.K.,
RA   Lee S.W., Wu J., Lin H.K., Sarbassov D.D.;
RT   "ER stress inhibits mTORC2 and Akt signaling through GSK-3beta-mediated
RT   phosphorylation of rictor.";
RL   Sci. Signal. 4:ra10-ra10(2011).
RN   [49]
RP   FUNCTION.
RX   PubMed=22514281; DOI=10.1074/jbc.m111.306373;
RA   Sun L., Lv F., Guo X., Gao G.;
RT   "Glycogen synthase kinase 3? (GSK3?) modulates antiviral activity of zinc-
RT   finger antiviral protein (ZAP).";
RL   J. Biol. Chem. 287:22882-22888(2012).
RN   [50]
RP   CATALYTIC ACTIVITY.
RX   PubMed=22539723; DOI=10.1126/science.1217032;
RA   Lin S.Y., Li T.Y., Liu Q., Zhang C., Li X., Chen Y., Zhang S.M., Lian G.,
RA   Liu Q., Ruan K., Wang Z., Zhang C.S., Chien K.Y., Wu J., Li Q., Han J.,
RA   Lin S.C.;
RT   "GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to
RT   autophagy.";
RL   Science 336:477-481(2012).
RN   [51]
RP   ADP-RIBOSYLATION BY PARP10.
RX   PubMed=23332125; DOI=10.1186/1478-811x-11-5;
RA   Feijs K.L., Kleine H., Braczynski A., Forst A.H., Herzog N., Verheugd P.,
RA   Linzen U., Kremmer E., Luscher B.;
RT   "ARTD10 substrate identification on protein microarrays: regulation of
RT   GSK3beta by mono-ADP-ribosylation.";
RL   Cell Commun. Signal. 11:5-5(2013).
RN   [52]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-390, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [53]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [54]
RP   FUNCTION, INTERACTION WITH NCYM, AND PHOSPHORYLATION AT SER-9.
RX   PubMed=24391509; DOI=10.1371/journal.pgen.1003996;
RA   Suenaga Y., Islam S.M., Alagu J., Kaneko Y., Kato M., Tanaka Y., Kawana H.,
RA   Hossain S., Matsumoto D., Yamamoto M., Shoji W., Itami M., Shibata T.,
RA   Nakamura Y., Ohira M., Haraguchi S., Takatori A., Nakagawara A.;
RT   "NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that
RT   inhibits GSK3beta resulting in the stabilization of MYCN in human
RT   neuroblastomas.";
RL   PLoS Genet. 10:E1003996-E1003996(2014).
RN   [55]
RP   PHOSPHORYLATION AT SER-9 AND TYR-216, INTERACTION WITH JPT1, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=25169422; DOI=10.1002/jcb.24956;
RA   Varisli L., Ozturk B.E., Akyuz G.K., Korkmaz K.S.;
RT   "HN1 negatively influences the beta-catenin/E-cadherin interaction, and
RT   contributes to migration in prostate cells.";
RL   J. Cell. Biochem. 116:170-178(2015).
RN   [56]
RP   INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2B AND GSKIP.
RX   PubMed=25920809; DOI=10.1016/j.bbamcr.2015.04.013;
RA   Loh J.K., Lin C.C., Yang M.C., Chou C.H., Chen W.S., Hong M.C., Cho C.L.,
RA   Hsu C.M., Cheng J.T., Chou A.K., Chang C.H., Tseng C.N., Wang C.H.,
RA   Lieu A.S., Howng S.L., Hong Y.R.;
RT   "GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis
RT   signaling in the regulation of mitochondrial elongation.";
RL   Biochim. Biophys. Acta 1853:1796-1807(2015).
RN   [57]
RP   FUNCTION, AND INTERACTION WITH RICTOR.
RX   PubMed=25897075; DOI=10.1074/jbc.m114.633057;
RA   Koo J., Wu X., Mao Z., Khuri F.R., Sun S.Y.;
RT   "Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-
RT   mediated Ubiquitination and Proteasomal Degradation.";
RL   J. Biol. Chem. 290:14120-14129(2015).
RN   [58]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=25733715; DOI=10.1083/jcb.201406020;
RA   Albrecht L.V., Zhang L., Shabanowitz J., Purevjav E., Towbin J.A.,
RA   Hunt D.F., Green K.J.;
RT   "GSK3- and PRMT-1-dependent modifications of desmoplakin control
RT   desmoplakin-cytoskeleton dynamics.";
RL   J. Cell Biol. 208:597-612(2015).
RN   [59]
RP   INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2A AND GSKIP.
RX   PubMed=27484798; DOI=10.1074/jbc.m116.738047;
RA   Dema A., Schroeter M.F., Perets E., Skroblin P., Moutty M.C., Deak V.A.,
RA   Birchmeier W., Klussmann E.;
RT   "The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3beta
RT   Interaction Protein (GSKIP) Regulates beta-Catenin through Its Interactions
RT   with Both Protein Kinase A (PKA) and GSK3beta.";
RL   J. Biol. Chem. 291:19618-19630(2016).
RN   [60]
RP   INTERACTION WITH AXIN1 AND GID8.
RX   PubMed=28829046; DOI=10.1038/cr.2017.107;
RA   Lu Y., Xie S., Zhang W., Zhang C., Gao C., Sun Q., Cai Y., Xu Z., Xiao M.,
RA   Xu Y., Huang X., Wu X., Liu W., Wang F., Kang Y., Zhou T.;
RT   "Twa1/Gid8 is a beta-catenin nuclear retention factor in Wnt signaling and
RT   colorectal tumorigenesis.";
RL   Cell Res. 27:1422-1440(2017).
RN   [61]
RP   FUNCTION, AND INTERACTION WITH BMAL1.
RX   PubMed=28903391; DOI=10.18632/oncotarget.18973;
RA   Lu Y., Zheng X., Hu W., Bian S., Zhang Z., Tao D., Liu Y., Ma Y.;
RT   "Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating
RT   the stability and activity of BMAL1 and CLOCK.";
RL   Oncotarget 8:54913-54924(2017).
RN   [62]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-9.
RX   PubMed=28992046; DOI=10.1093/jmcb/mjx034;
RA   Wang D., Zhao J., Li S., Wei J., Nan L., Mallampalli R.K.,
RA   Weathington N.M., Ma H., Zhao Y.;
RT   "Phosphorylated E2F1 is stabilized by nuclear USP11 to drive Peg10 gene
RT   expression and activate lung epithelial cells.";
RL   J. Mol. Cell Biol. 10:60-73(2018).
RN   [63]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=25827072; DOI=10.1016/j.canlet.2015.03.037;
RA   Jin Y., Shenoy A.K., Doernberg S., Chen H., Luo H., Shen H., Lin T.,
RA   Tarrash M., Cai Q., Hu X., Fiske R., Chen T., Wu L., Mohammed K.A.,
RA   Rottiers V., Lee S.S., Lu J.;
RT   "FBXO11 promotes ubiquitination of the Snail family of transcription
RT   factors in cancer progression and epidermal development.";
RL   Cancer Lett. 362:70-82(2015).
RN   [64]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=29059170; DOI=10.1038/onc.2017.370;
RA   Liu Y., Zhou H., Zhu R., Ding F., Li Y., Cao X., Liu Z.;
RT   "SPSB3 targets SNAIL for degradation in GSK-3beta phosphorylation-dependent
RT   manner and regulates metastasis.";
RL   Oncogene 37:768-776(2018).
RN   [65]
RP   FUNCTION.
RX   PubMed=30704899; DOI=10.1016/j.molcel.2018.12.017;
RA   Cheng X., Ma X., Zhu Q., Song D., Ding X., Li L., Jiang X., Wang X.,
RA   Tian R., Su H., Shen Z., Chen S., Liu T., Gong W., Liu W., Sun Q.;
RT   "Pacer is a mediator of mTORC1 and GSK3-TIP60 signaling in regulation of
RT   autophagosome maturation and lipid metabolism.";
RL   Mol. Cell 73:1-15(2019).
RN   [66]
RP   INTERACTION WITH LMBR1L.
RX   PubMed=31073040; DOI=10.1126/science.aau0812;
RA   Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J.,
RA   Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M.,
RA   Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y.,
RA   Beutler B.;
RT   "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling.";
RL   Science 364:0-0(2019).
RN   [67]
RP   INTERACTION WITH PKP3.
RX   PubMed=34058472; DOI=10.1016/j.bbrc.2021.05.043;
RA   Hong J.Y., Zapata J., Blackburn A., Baumert R., Bae S.M., Ji H., Nam H.J.,
RA   Miller R.K., McCrea P.D.;
RT   "A catenin of the plakophilin-subfamily, Pkp3, responds to canonical-Wnt
RT   pathway components and signals.";
RL   Biochem. Biophys. Res. Commun. 563:31-39(2021).
RN   [68]
RP   PHOSPHORYLATION AT SER-9, MUTAGENESIS OF CYS-14, SUBCELLULAR LOCATION, AND
RP   PALMITOYLATION AT CYS-14.
RX   PubMed=35606353; DOI=10.1038/s41389-022-00402-w;
RA   Zhao C., Yu H., Fan X., Niu W., Fan J., Sun S., Gong M., Zhao B., Fang Z.,
RA   Chen X.;
RT   "GSK3beta palmitoylation mediated by ZDHHC4 promotes tumorigenicity of
RT   glioblastoma stem cells in temozolomide-resistant glioblastoma through the
RT   EZH2-STAT3 axis.";
RL   Oncogenesis 11:28-28(2022).
RN   [69]
RP   PHOSPHORYLATION AT SER-9.
RX   PubMed=34764205; DOI=10.1158/0008-5472.can-21-1020;
RA   Ren X., Rong Z., Liu X., Gao J., Xu X., Zi Y., Mu Y., Guan Y., Cao Z.,
RA   Zhang Y., Zeng Z., Fan Q., Wang X., Pei Q., Wang X., Xin H., Li Z., Nie Y.,
RA   Qiu Z., Li N., Sun L., Deng Y.;
RT   "The Protein Kinase Activity of NME7 Activates Wnt/beta-Catenin Signaling
RT   to Promote One-Carbon Metabolism in Hepatocellular Carcinoma.";
RL   Cancer Res. 82:60-74(2022).
RN   [70]
RP   X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 35-386.
RX   PubMed=11440715; DOI=10.1016/s0092-8674(01)00374-9;
RA   Dajani R., Fraser E., Roe S.M., Young N., Good V., Dale T.C., Pearl L.H.;
RT   "Crystal structure of glycogen synthase kinase 3 beta: structural basis for
RT   phosphate-primed substrate specificity and autoinhibition.";
RL   Cell 105:721-732(2001).
RN   [71]
RP   X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 27-393 OF PHOSPHORYLATED GSK3B.
RX   PubMed=11738041; DOI=10.1016/s0969-2126(01)00679-7;
RA   Bax B., Carter P.S., Lewis C., Guy A.R., Bridges A., Tanner R., Pettman G.,
RA   Mannix C., Culbert A.A., Brown M.J.B., Smith D.G., Reith A.D.;
RT   "The structure of phosphorylated GSK-3beta complexed with a peptide,
RT   FRATtide, that inhibits beta-catenin phosphorylation.";
RL   Structure 9:1143-1152(2001).
RN   [72]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 35-384 IN COMPLEX WITH AXIN1,
RP   INTERACTION WITH AXIN1 AND FRAT1, FUNCTION, ACTIVITY REGULATION, AND
RP   PHOSPHORYLATION AT TYR-216.
RX   PubMed=12554650; DOI=10.1093/emboj/cdg068;
RA   Dajani R., Fraser E., Roe S.M., Yeo M., Good V.M., Thompson V., Dale T.C.,
RA   Pearl L.H.;
RT   "Structural basis for recruitment of glycogen synthase kinase 3beta to the
RT   axin-APC scaffold complex.";
RL   EMBO J. 22:494-501(2003).
CC   -!- FUNCTION: Constitutively active protein kinase that acts as a negative
CC       regulator in the hormonal control of glucose homeostasis, Wnt signaling
CC       and regulation of transcription factors and microtubules, by
CC       phosphorylating and inactivating glycogen synthase (GYS1 or GYS2),
CC       EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN,
CC       NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:11430833, PubMed:12554650,
CC       PubMed:14690523, PubMed:16484495, PubMed:1846781, PubMed:20937854,
CC       PubMed:9072970). Requires primed phosphorylation of the majority of its
CC       substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle,
CC       contributes to insulin regulation of glycogen synthesis by
CC       phosphorylating and inhibiting GYS1 activity and hence glycogen
CC       synthesis (PubMed:8397507). May also mediate the development of insulin
CC       resistance by regulating activation of transcription factors
CC       (PubMed:8397507). Regulates protein synthesis by controlling the
CC       activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as
CC       glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a
CC       multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and
CC       phosphorylates the N-terminus of CTNNB1 leading to its degradation
CC       mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN
CC       at sites proximal to its DNA-binding domain, thereby reducing its
CC       affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on
CC       conserved serine residues promoting NFATC1/NFATC nuclear export,
CC       shutting off NFATC1/NFATC gene regulation, and thereby opposing the
CC       action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on
CC       'Thr-548', decreasing significantly MAPT/TAU ability to bind and
CC       stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal
CC       component of neurofibrillary tangles in Alzheimer disease
CC       (PubMed:14690523). Plays an important role in ERBB2-dependent
CC       stabilization of microtubules at the cell cortex (PubMed:20937854).
CC       Phosphorylates MACF1, inhibiting its binding to microtubules which is
CC       critical for its role in bulge stem cell migration and skin wound
CC       repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the
CC       transcriptional level and is required for the NF-kappa-B-mediated anti-
CC       apoptotic response to TNF (TNF/TNFA) (By similarity). Negatively
CC       regulates replication in pancreatic beta-cells, resulting in apoptosis,
CC       loss of beta-cells and diabetes (By similarity). Through
CC       phosphorylation of the anti-apoptotic protein MCL1, may control cell
CC       apoptosis in response to growth factors deprivation (By similarity).
CC       Phosphorylates MUC1 in breast cancer cells, decreasing the interaction
CC       of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the
CC       establishment of neuronal polarity and axon outgrowth
CC       (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its
CC       activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to
CC       sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1
CC       which enhances its antiviral activity (PubMed:22514281). Phosphorylates
CC       SNAI1, leading to its ubiquitination and proteasomal degradation
CC       (PubMed:15448698, PubMed:15647282, PubMed:25827072, PubMed:29059170).
CC       Phosphorylates SFPQ at 'Thr-687' upon T-cell activation
CC       (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and
CC       stabilizes it by protecting it from proteasomal degradation. Regulates
CC       the circadian clock via phosphorylation of the major clock components
CC       including BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391).
CC       Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by
CC       the SCF(FBXO3) complex and proteasomal degradation (By similarity).
CC       Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal
CC       degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and
CC       'Ser-21' and primes it for ubiquitination and proteasomal degradation
CC       (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which
CC       positively regulates its activity. Phosphorylates MYCN in neuroblastoma
CC       cells which may promote its degradation (PubMed:24391509). Regulates
CC       the circadian rhythmicity of hippocampal long-term potentiation and
CC       BMAL1 and PER2 expression (By similarity). Acts as a regulator of
CC       autophagy by mediating phosphorylation of KAT5/TIP60 under starvation
CC       conditions, activating KAT5/TIP60 acetyltransferase activity and
CC       promoting acetylation of key autophagy regulators, such as ULK1 and
CC       RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic
CC       apoptotic signaling pathway via death domain receptors. Promotes the
CC       formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B,
CC       at death receptors, including TNFRSF10B. The anti-apoptotic function is
CC       most effective with weak apoptotic signals and can be overcome by
CC       stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting
CC       the interaction between E2F1 and USP11, stabilizing E2F1 and promoting
CC       its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2
CC       complex component RICTOR at 'Ser-1235' in response to endoplasmic
CC       stress, inhibiting mTORC2 (PubMed:21343617). Phosphorylates mTORC2
CC       complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated
CC       ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
CC       Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4)
CC       complex and FXR1 degradation by the proteasome (By similarity).
CC       Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its
CC       proteasomal degradation (By similarity). Phosphorylates and inhibits
CC       the CTP synthase and protein-asparagine deamidase activities of CTPS1
CC       (PubMed:17681942). Phosphorylates DSP at multiple sequential serine
CC       residues in the C-terminus tail, promoting its recruitment to
CC       developing desmosome cell-cell junctions (PubMed:25733715).
CC       {ECO:0000250|UniProtKB:P18266, ECO:0000250|UniProtKB:Q9WV60,
CC       ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650,
CC       ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698,
CC       ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495,
CC       ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942,
CC       ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781,
CC       ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19946213,
CC       ECO:0000269|PubMed:20067585, ECO:0000269|PubMed:20932480,
CC       ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21343617,
CC       ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509,
CC       ECO:0000269|PubMed:25733715, ECO:0000269|PubMed:25827072,
CC       ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:28903391,
CC       ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:29059170,
CC       ECO:0000269|PubMed:30704899, ECO:0000269|PubMed:8397507,
CC       ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein]
CC         + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC         COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC         Evidence={ECO:0000269|PubMed:14690523};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau
CC         protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC         Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.26; Evidence={ECO:0000269|PubMed:14690523};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942,
CC         ECO:0000269|PubMed:21343617, ECO:0000269|PubMed:22539723,
CC         ECO:0000269|PubMed:25827072, ECO:0000269|PubMed:28992046,
CC         ECO:0000269|PubMed:29059170};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:17050006};
CC   -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-216. In
CC       response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1
CC       and RPS6KA3; phosphorylation at this site causes a conformational
CC       change, preventing access of substrates to the active site. Inhibited
CC       by IL22 treatment which also triggers phosphorylation at Ser-9,
CC       promoting inactivation (By similarity). Inhibited by lithium.
CC       {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11749387,
CC       ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:19366350,
CC       ECO:0000269|PubMed:8524413}.
CC   -!- SUBUNIT: Monomer. Interacts with ARRB2, DISC1 and ZBED3 (By
CC       similarity). Interacts with CABYR, MMP2, MUC1, NIN and PRUNE1.
CC       Interacts with AXIN1; the interaction mediates hyperphosphorylation of
CC       CTNNB1 leading to its ubiquitination and destruction. Interacts with
CC       and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal
CC       domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and
CC       GSK3B (By similarity). Interacts with SGK3. Interacts with DAB2IP (via
CC       C2 domain); the interaction stimulates GSK3B kinase activation.
CC       Interacts (via C2 domain) with PPP2CA. Interacts with the CLOCK-BMAL1
CC       heterodimer (PubMed:19946213). Interacts with the BMAL1
CC       (PubMed:28903391). Interacts with CTNND2 (PubMed:19706605). Interacts
CC       with NCYM (PubMed:24391509). The complex composed, at least, of APC,
CC       CTNNB1 and GSK3B interacts with JPT1; the interaction requires the
CC       inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422).
CC       Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through
CC       GSKIP interaction; facilitates PKA-induced phosphorylation and
CC       regulates GSK3B activity (PubMed:20007971, PubMed:25920809,
CC       PubMed:27484798). Interacts with GSKIP (PubMed:16981698). Interacts
CC       with GID8 (PubMed:28829046). Interacts with PIWIL2 (By similarity).
CC       Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X
CC       (PubMed:18846110). Interacts with BIRC2 (PubMed:18846110). Interacts
CC       with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity
CC       (PubMed:18846110). Interacts with RICTOR; the interaction results in
CC       phosphorylation of RICTOR at 'Thr-1695' by GSK3B which facilitates
CC       FBXW7-mediated ubiquitination and subsequent degradation of RICTOR
CC       (PubMed:25897075). Found in a complex with SLC39A6, SLC39A10 and with
CC       GSK3B that controls NCAM1 phosphorylation (By similarity). Interacts
CC       with PKP3 (via ARM repeats); the interaction may be involved in PKP3
CC       protein degradation (PubMed:34058472). {ECO:0000250|UniProtKB:P18266,
CC       ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11004522,
CC       ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12554650,
CC       ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282,
CC       ECO:0000269|PubMed:15752768, ECO:0000269|PubMed:16428445,
CC       ECO:0000269|PubMed:16981698, ECO:0000269|PubMed:17318175,
CC       ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19493954,
CC       ECO:0000269|PubMed:19706605, ECO:0000269|PubMed:19946213,
CC       ECO:0000269|PubMed:20007971, ECO:0000269|PubMed:20080667,
CC       ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25169422,
CC       ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:25920809,
CC       ECO:0000269|PubMed:27484798, ECO:0000269|PubMed:28829046,
CC       ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:31073040,
CC       ECO:0000269|PubMed:34058472, ECO:0000269|PubMed:9731200,
CC       ECO:0000269|PubMed:9819408}.
CC   -!- INTERACTION:
CC       P49841; P31749: AKT1; NbExp=5; IntAct=EBI-373586, EBI-296087;
CC       P49841; P31751: AKT2; NbExp=2; IntAct=EBI-373586, EBI-296058;
CC       P49841; PRO_0000000093 [P05067]: APP; NbExp=2; IntAct=EBI-373586, EBI-2431589;
CC       P49841; O15169: AXIN1; NbExp=52; IntAct=EBI-373586, EBI-710484;
CC       P49841; Q9Y2T1: AXIN2; NbExp=6; IntAct=EBI-373586, EBI-4400025;
CC       P49841; Q96G01: BICD1; NbExp=7; IntAct=EBI-373586, EBI-1104509;
CC       P49841; O75952-3: CABYR; NbExp=3; IntAct=EBI-373586, EBI-10900795;
CC       P49841; O75952-5: CABYR; NbExp=3; IntAct=EBI-373586, EBI-10898671;
CC       P49841; P35222: CTNNB1; NbExp=20; IntAct=EBI-373586, EBI-491549;
CC       P49841; Q5VWQ8: DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-2871881;
CC       P49841; Q5VWQ8-2: DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-9543020;
CC       P49841; Q9NYF0: DACT1; NbExp=3; IntAct=EBI-373586, EBI-3951744;
CC       P49841; O75398: DEAF1; NbExp=2; IntAct=EBI-373586, EBI-718185;
CC       P49841; Q13144: EIF2B5; NbExp=2; IntAct=EBI-373586, EBI-4401110;
CC       P49841; Q92837: FRAT1; NbExp=5; IntAct=EBI-373586, EBI-3934879;
CC       P49841; Q9P0R6: GSKIP; NbExp=10; IntAct=EBI-373586, EBI-1052580;
CC       P49841; P13807: GYS1; NbExp=4; IntAct=EBI-373586, EBI-740553;
CC       P49841; O75581: LRP6; NbExp=4; IntAct=EBI-373586, EBI-910915;
CC       P49841; Q5S007: LRRK2; NbExp=7; IntAct=EBI-373586, EBI-5323863;
CC       P49841; P10636: MAPT; NbExp=4; IntAct=EBI-373586, EBI-366182;
CC       P49841; P10636-8: MAPT; NbExp=12; IntAct=EBI-373586, EBI-366233;
CC       P49841; Q14596: NBR1; NbExp=4; IntAct=EBI-373586, EBI-742698;
CC       P49841; Q8N4C6: NIN; NbExp=3; IntAct=EBI-373586, EBI-1164022;
CC       P49841; P17612: PRKACA; NbExp=7; IntAct=EBI-373586, EBI-476586;
CC       P49841; Q01201: RELB; NbExp=4; IntAct=EBI-373586, EBI-357837;
CC       P49841; Q13485: SMAD4; NbExp=5; IntAct=EBI-373586, EBI-347263;
CC       P49841; Q9NRG4: SMYD2; NbExp=2; IntAct=EBI-373586, EBI-1055671;
CC       P49841; O95863: SNAI1; NbExp=5; IntAct=EBI-373586, EBI-1045459;
CC       P49841; P37840: SNCA; NbExp=2; IntAct=EBI-373586, EBI-985879;
CC       P49841; Q6J9G0: STYK1; NbExp=2; IntAct=EBI-373586, EBI-6424915;
CC       P49841; P04637: TP53; NbExp=3; IntAct=EBI-373586, EBI-366083;
CC       P49841; Q14134: TRIM29; NbExp=2; IntAct=EBI-373586, EBI-702370;
CC       P49841; O95071: UBR5; NbExp=8; IntAct=EBI-373586, EBI-358329;
CC       P49841; P67809: YBX1; NbExp=2; IntAct=EBI-373586, EBI-354065;
CC       P49841; P16989: YBX3; NbExp=2; IntAct=EBI-373586, EBI-358193;
CC       P49841; P63104: YWHAZ; NbExp=4; IntAct=EBI-373586, EBI-347088;
CC       P49841; Q8IX07: ZFPM1; NbExp=2; IntAct=EBI-373586, EBI-3942619;
CC       P49841; O35625: Axin1; Xeno; NbExp=5; IntAct=EBI-373586, EBI-2365912;
CC       P49841; Q14DJ8: Axin1; Xeno; NbExp=2; IntAct=EBI-373586, EBI-4312125;
CC       P49841; Q02248: Ctnnb1; Xeno; NbExp=3; IntAct=EBI-373586, EBI-397872;
CC       P49841; Q811T9: Disc1; Xeno; NbExp=4; IntAct=EBI-373586, EBI-2298259;
CC       P49841; P63085: Mapk1; Xeno; NbExp=2; IntAct=EBI-373586, EBI-397697;
CC       P49841; P0DTC9: N; Xeno; NbExp=3; IntAct=EBI-373586, EBI-25475856;
CC       P49841-2; P05067: APP; NbExp=3; IntAct=EBI-15870655, EBI-77613;
CC       P49841-2; P35637: FUS; NbExp=3; IntAct=EBI-15870655, EBI-400434;
CC       P49841-2; P01106: MYC; NbExp=3; IntAct=EBI-15870655, EBI-447544;
CC       P49841-2; Q8BMD2-1: Dzip1; Xeno; NbExp=3; IntAct=EBI-15870655, EBI-16153101;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21029237,
CC       ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:25733715,
CC       ECO:0000269|PubMed:35606353}. Nucleus {ECO:0000269|PubMed:15448698,
CC       ECO:0000269|PubMed:21029237}. Cell membrane
CC       {ECO:0000269|PubMed:20937854}. Note=The phosphorylated form shows
CC       localization to cytoplasm and cell membrane (PubMed:20937854). The
CC       MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the
CC       phosphorylated form to the cell membrane (PubMed:20937854).
CC       {ECO:0000269|PubMed:20937854}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1; Synonyms=GSK-3beta1;
CC         IsoId=P49841-1; Sequence=Displayed;
CC       Name=2; Synonyms=GSK-3beta2, neuron-specific;
CC         IsoId=P49841-2; Sequence=VSP_004790;
CC   -!- TISSUE SPECIFICITY: Expressed in testis, thymus, prostate and ovary and
CC       weakly expressed in lung, brain and kidney. Colocalizes with
CC       EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain.
CC       {ECO:0000269|PubMed:21029237}.
CC   -!- PTM: Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling,
CC       the activated PKB/AKT1 protein kinase phosphorylates and deactivates
CC       GSK3B, resulting in the dephosphorylation and activation of GYS1.
CC       Activated by phosphorylation at Tyr-216 (PubMed:25169422). Inactivated
CC       by phosphorylation at Ser-9 (Probable). Phosphorylated in a circadian
CC       manner in the hippocampus (By similarity).
CC       {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:12054501,
CC       ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:16484495,
CC       ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21029237,
CC       ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:8250835,
CC       ECO:0000305|PubMed:25169422}.
CC   -!- PTM: Mono-ADP-ribosylation by PARP10 negatively regulates kinase
CC       activity. {ECO:0000269|PubMed:23332125}.
CC   -!- PTM: Palmitoylated. Palmitoylation by ZDHHC4 prevents AKT1-mediated
CC       phosphorylation. {ECO:0000269|PubMed:35606353}.
CC   -!- MISCELLANEOUS: Higher expression and activity of GSK3B are found in the
CC       skeletal muscle (vastus lateralis) of patients with type 2 diabetes
CC       (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors
CC       have been identified and characterized in preclinical models for
CC       treatments of type 2 diabetes (PubMed:19366350).
CC       {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}.
CC   -!- MISCELLANEOUS: [Isoform 2]: May play a specific role in axon growth and
CC       neurite outgrowth. Reduced binding to AXIN1, reduced ability to
CC       phosphorylate MAPT/TAU. {ECO:0000269|PubMed:20067585}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. GSK-3 subfamily. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/40761/GSK3B";
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DR   EMBL; L33801; AAA66475.1; -; mRNA.
DR   EMBL; CH471052; EAW79533.1; -; Genomic_DNA.
DR   EMBL; CH471052; EAW79536.1; -; Genomic_DNA.
DR   EMBL; BC000251; AAH00251.1; -; mRNA.
DR   EMBL; BC012760; AAH12760.1; -; mRNA.
DR   EMBL; AF074333; AAD48517.1; -; Genomic_DNA.
DR   EMBL; AF098789; AAC69340.1; -; Genomic_DNA.
DR   CCDS; CCDS2996.1; -. [P49841-2]
DR   CCDS; CCDS54628.1; -. [P49841-1]
DR   PIR; S53324; S53324.
DR   RefSeq; NP_001139628.1; NM_001146156.2. [P49841-1]
DR   RefSeq; NP_002084.2; NM_002093.3. [P49841-2]
DR   PDB; 1GNG; X-ray; 2.60 A; A/B=27-393.
DR   PDB; 1H8F; X-ray; 2.80 A; A/B=35-386.
DR   PDB; 1I09; X-ray; 2.70 A; A/B=1-420.
DR   PDB; 1J1B; X-ray; 1.80 A; A/B=1-420.
DR   PDB; 1J1C; X-ray; 2.10 A; A/B=1-420.
DR   PDB; 1O6K; X-ray; 1.70 A; C=3-12.
DR   PDB; 1O6L; X-ray; 1.60 A; C=3-12.
DR   PDB; 1O9U; X-ray; 2.40 A; A=35-384.
DR   PDB; 1PYX; X-ray; 2.40 A; A/B=1-420.
DR   PDB; 1Q3D; X-ray; 2.20 A; A/B=2-420.
DR   PDB; 1Q3W; X-ray; 2.30 A; A/B=2-420.
DR   PDB; 1Q41; X-ray; 2.10 A; A/B=2-420.
DR   PDB; 1Q4L; X-ray; 2.77 A; A/B=2-420.
DR   PDB; 1Q5K; X-ray; 1.94 A; A/B=7-420.
DR   PDB; 1R0E; X-ray; 2.25 A; A/B=35-420.
DR   PDB; 1UV5; X-ray; 2.80 A; A=35-384.
DR   PDB; 2JDO; X-ray; 1.80 A; C=3-12.
DR   PDB; 2JDR; X-ray; 2.30 A; C=3-12.
DR   PDB; 2JLD; X-ray; 2.35 A; A/B=1-420.
DR   PDB; 2O5K; X-ray; 3.20 A; A=29-393.
DR   PDB; 2OW3; X-ray; 2.80 A; A/B=35-386.
DR   PDB; 2UW9; X-ray; 2.10 A; C=3-12.
DR   PDB; 2X39; X-ray; 1.93 A; C=3-12.
DR   PDB; 2XH5; X-ray; 2.72 A; C=3-12.
DR   PDB; 3CQU; X-ray; 2.20 A; C=3-12.
DR   PDB; 3CQW; X-ray; 2.00 A; C=3-12.
DR   PDB; 3DU8; X-ray; 2.20 A; A/B=1-420.
DR   PDB; 3E87; X-ray; 2.30 A; C/D=3-12.
DR   PDB; 3E88; X-ray; 2.50 A; C/D=3-12.
DR   PDB; 3E8D; X-ray; 2.70 A; C/D=3-12.
DR   PDB; 3F7Z; X-ray; 2.40 A; A/B=35-383.
DR   PDB; 3F88; X-ray; 2.60 A; A/B=35-383.
DR   PDB; 3GB2; X-ray; 2.40 A; A=34-383.
DR   PDB; 3I4B; X-ray; 2.30 A; A/B=7-420.
DR   PDB; 3L1S; X-ray; 2.90 A; A/B=7-420.
DR   PDB; 3M1S; X-ray; 3.13 A; A/B=1-420.
DR   PDB; 3MV5; X-ray; 2.47 A; C=3-12.
DR   PDB; 3OW4; X-ray; 2.60 A; C/D=3-12.
DR   PDB; 3PUP; X-ray; 2.99 A; A/B=1-420.
DR   PDB; 3Q3B; X-ray; 2.70 A; A/B=2-420.
DR   PDB; 3QKK; X-ray; 2.30 A; C=3-12.
DR   PDB; 3QKL; X-ray; 1.90 A; C=3-12.
DR   PDB; 3SAY; X-ray; 2.23 A; A/B=1-420.
DR   PDB; 3SD0; X-ray; 2.70 A; A/B=35-384.
DR   PDB; 3ZDI; X-ray; 2.64 A; A=35-384.
DR   PDB; 3ZRK; X-ray; 2.37 A; A/B=23-393.
DR   PDB; 3ZRL; X-ray; 2.48 A; A/B=23-393.
DR   PDB; 3ZRM; X-ray; 2.49 A; A/B=23-393.
DR   PDB; 4ACC; X-ray; 2.21 A; A/B=1-420.
DR   PDB; 4ACD; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 4ACG; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 4ACH; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 4AFJ; X-ray; 1.98 A; A/B=27-393.
DR   PDB; 4B7T; X-ray; 2.77 A; A=35-384.
DR   PDB; 4DIT; X-ray; 2.60 A; A=27-393.
DR   PDB; 4EKK; X-ray; 2.80 A; C/D=3-12.
DR   PDB; 4IQ6; X-ray; 3.12 A; A/B=1-420.
DR   PDB; 4J1R; X-ray; 2.70 A; A/B/C/D=1-420.
DR   PDB; 4J71; X-ray; 2.31 A; A/B=1-420.
DR   PDB; 4NM0; X-ray; 2.50 A; A=1-383.
DR   PDB; 4NM3; X-ray; 2.10 A; A=1-383.
DR   PDB; 4NM5; X-ray; 2.30 A; A=13-383.
DR   PDB; 4NM7; X-ray; 2.30 A; A=13-383.
DR   PDB; 4PTC; X-ray; 2.71 A; A/B=1-420.
DR   PDB; 4PTE; X-ray; 2.03 A; A/B=1-420.
DR   PDB; 4PTG; X-ray; 2.36 A; A/B=1-420.
DR   PDB; 5F94; X-ray; 2.51 A; A/B=36-385.
DR   PDB; 5F95; X-ray; 2.52 A; A/B=36-385.
DR   PDB; 5HLN; X-ray; 3.10 A; A/B=1-420.
DR   PDB; 5HLP; X-ray; 2.45 A; A/B=1-420.
DR   PDB; 5K5N; X-ray; 2.20 A; A/B=28-384.
DR   PDB; 5KPK; X-ray; 2.40 A; A/B=1-420.
DR   PDB; 5KPL; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 5KPM; X-ray; 2.69 A; A/B=1-420.
DR   PDB; 5OY4; X-ray; 3.20 A; A/B=1-420.
DR   PDB; 5T31; X-ray; 2.85 A; A/B=1-420.
DR   PDB; 6B8J; X-ray; 2.60 A; A=1-420.
DR   PDB; 6BUU; X-ray; 2.40 A; F/G=3-12.
DR   PDB; 6GJO; X-ray; 2.91 A; A/B=7-420.
DR   PDB; 6GN1; X-ray; 2.60 A; A/B=27-393.
DR   PDB; 6H0U; X-ray; 2.30 A; A/B=1-420.
DR   PDB; 6HK3; X-ray; 2.35 A; A/B=35-384.
DR   PDB; 6HK4; X-ray; 2.50 A; A/B=35-384.
DR   PDB; 6HK7; X-ray; 3.20 A; A=36-382.
DR   PDB; 6NPZ; X-ray; 2.12 A; F/G=3-12.
DR   PDB; 6TCU; X-ray; 2.14 A; A=35-386.
DR   PDB; 6V6L; X-ray; 2.19 A; A=1-420.
DR   PDB; 6Y9R; X-ray; 2.08 A; A=35-384.
DR   PDB; 6Y9S; X-ray; 2.03 A; A/B=35-384.
DR   PDB; 7B6F; X-ray; 2.05 A; A=26-383.
DR   PDB; 7OY5; X-ray; 2.57 A; A/B=35-385.
DR   PDB; 7SXH; X-ray; 2.09 A; A=37-383.
DR   PDB; 7SXJ; X-ray; 1.85 A; A=34-383.
DR   PDB; 7U2Z; X-ray; 2.21 A; A/B=35-382.
DR   PDB; 7U31; X-ray; 2.38 A; A/B=36-385.
DR   PDB; 7U33; X-ray; 2.60 A; A/B=35-385.
DR   PDB; 7U36; X-ray; 2.75 A; A/B=35-385.
DR   PDB; 7Z1F; X-ray; 3.00 A; A/B=26-383.
DR   PDB; 7Z1G; X-ray; 2.85 A; A=26-383.
DR   PDB; 8AUZ; X-ray; 2.66 A; A/B=26-383.
DR   PDB; 8AV1; X-ray; 2.15 A; A/B=26-383.
DR   PDB; 8DJC; X-ray; 2.46 A; A/B=1-420.
DR   PDB; 8DJD; X-ray; 2.21 A; A/B=1-420.
DR   PDB; 8DJE; X-ray; 2.37 A; A/B=1-420.
DR   PDB; 8FF8; X-ray; 2.33 A; A/B=1-420.
DR   PDB; 8QJI; X-ray; 3.02 A; A=26-383.
DR   PDB; 8XN6; X-ray; 2.40 A; A/B=2-420.
DR   PDB; 9HUK; X-ray; 3.50 A; A/B=2-420.
DR   PDB; 9HUL; X-ray; 2.90 A; A/B=2-420.
DR   PDB; 9HV3; X-ray; 2.90 A; A/B=2-420.
DR   PDBsum; 1GNG; -.
DR   PDBsum; 1H8F; -.
DR   PDBsum; 1I09; -.
DR   PDBsum; 1J1B; -.
DR   PDBsum; 1J1C; -.
DR   PDBsum; 1O6K; -.
DR   PDBsum; 1O6L; -.
DR   PDBsum; 1O9U; -.
DR   PDBsum; 1PYX; -.
DR   PDBsum; 1Q3D; -.
DR   PDBsum; 1Q3W; -.
DR   PDBsum; 1Q41; -.
DR   PDBsum; 1Q4L; -.
DR   PDBsum; 1Q5K; -.
DR   PDBsum; 1R0E; -.
DR   PDBsum; 1UV5; -.
DR   PDBsum; 2JDO; -.
DR   PDBsum; 2JDR; -.
DR   PDBsum; 2JLD; -.
DR   PDBsum; 2O5K; -.
DR   PDBsum; 2OW3; -.
DR   PDBsum; 2UW9; -.
DR   PDBsum; 2X39; -.
DR   PDBsum; 2XH5; -.
DR   PDBsum; 3CQU; -.
DR   PDBsum; 3CQW; -.
DR   PDBsum; 3DU8; -.
DR   PDBsum; 3E87; -.
DR   PDBsum; 3E88; -.
DR   PDBsum; 3E8D; -.
DR   PDBsum; 3F7Z; -.
DR   PDBsum; 3F88; -.
DR   PDBsum; 3GB2; -.
DR   PDBsum; 3I4B; -.
DR   PDBsum; 3L1S; -.
DR   PDBsum; 3M1S; -.
DR   PDBsum; 3MV5; -.
DR   PDBsum; 3OW4; -.
DR   PDBsum; 3PUP; -.
DR   PDBsum; 3Q3B; -.
DR   PDBsum; 3QKK; -.
DR   PDBsum; 3QKL; -.
DR   PDBsum; 3SAY; -.
DR   PDBsum; 3SD0; -.
DR   PDBsum; 3ZDI; -.
DR   PDBsum; 3ZRK; -.
DR   PDBsum; 3ZRL; -.
DR   PDBsum; 3ZRM; -.
DR   PDBsum; 4ACC; -.
DR   PDBsum; 4ACD; -.
DR   PDBsum; 4ACG; -.
DR   PDBsum; 4ACH; -.
DR   PDBsum; 4AFJ; -.
DR   PDBsum; 4B7T; -.
DR   PDBsum; 4DIT; -.
DR   PDBsum; 4EKK; -.
DR   PDBsum; 4IQ6; -.
DR   PDBsum; 4J1R; -.
DR   PDBsum; 4J71; -.
DR   PDBsum; 4NM0; -.
DR   PDBsum; 4NM3; -.
DR   PDBsum; 4NM5; -.
DR   PDBsum; 4NM7; -.
DR   PDBsum; 4PTC; -.
DR   PDBsum; 4PTE; -.
DR   PDBsum; 4PTG; -.
DR   PDBsum; 5F94; -.
DR   PDBsum; 5F95; -.
DR   PDBsum; 5HLN; -.
DR   PDBsum; 5HLP; -.
DR   PDBsum; 5K5N; -.
DR   PDBsum; 5KPK; -.
DR   PDBsum; 5KPL; -.
DR   PDBsum; 5KPM; -.
DR   PDBsum; 5OY4; -.
DR   PDBsum; 5T31; -.
DR   PDBsum; 6B8J; -.
DR   PDBsum; 6BUU; -.
DR   PDBsum; 6GJO; -.
DR   PDBsum; 6GN1; -.
DR   PDBsum; 6H0U; -.
DR   PDBsum; 6HK3; -.
DR   PDBsum; 6HK4; -.
DR   PDBsum; 6HK7; -.
DR   PDBsum; 6NPZ; -.
DR   PDBsum; 6TCU; -.
DR   PDBsum; 6V6L; -.
DR   PDBsum; 6Y9R; -.
DR   PDBsum; 6Y9S; -.
DR   PDBsum; 7B6F; -.
DR   PDBsum; 7OY5; -.
DR   PDBsum; 7SXH; -.
DR   PDBsum; 7SXJ; -.
DR   PDBsum; 7U2Z; -.
DR   PDBsum; 7U31; -.
DR   PDBsum; 7U33; -.
DR   PDBsum; 7U36; -.
DR   PDBsum; 7Z1F; -.
DR   PDBsum; 7Z1G; -.
DR   PDBsum; 8AUZ; -.
DR   PDBsum; 8AV1; -.
DR   PDBsum; 8DJC; -.
DR   PDBsum; 8DJD; -.
DR   PDBsum; 8DJE; -.
DR   PDBsum; 8FF8; -.
DR   PDBsum; 8QJI; -.
DR   PDBsum; 8XN6; -.
DR   PDBsum; 9HUK; -.
DR   PDBsum; 9HUL; -.
DR   PDBsum; 9HV3; -.
DR   AlphaFoldDB; P49841; -.
DR   SMR; P49841; -.
DR   BioGRID; 109187; 867.
DR   ComplexPortal; CPX-109; Beta-catenin destruction core complex, APC-AXIN1-GSK3B variant.
DR   ComplexPortal; CPX-439; Beta-catenin destruction core complex, APC-AXIN2-GSK3B variant.
DR   ComplexPortal; CPX-440; Beta-catenin destruction core complex, APC2-AXIN2-GSK3B variant.
DR   ComplexPortal; CPX-459; Nuclear export complex FRAT1-GSK3B.
DR   ComplexPortal; CPX-462; Nuclear export complex FRAT2-GSK3B.
DR   ComplexPortal; CPX-99; Beta-catenin destruction core complex, APC2-AXIN1-GSK3B variant.
DR   CORUM; P49841; -.
DR   DIP; DIP-878N; -.
DR   ELM; P49841; -.
DR   FunCoup; P49841; 3788.
DR   IntAct; P49841; 399.
DR   MINT; P49841; -.
DR   STRING; 9606.ENSP00000324806; -.
DR   BindingDB; P49841; -.
DR   ChEMBL; CHEMBL262; -.
DR   DrugBank; DB08073; (2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE.
DR   DrugBank; DB07149; (7S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoroethyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.
DR   DrugBank; DB07014; 2-(1,3-benzodioxol-5-yl)-5-[(3-fluoro-4-methoxybenzyl)sulfanyl]-1,3,4-oxadiazole.
DR   DrugBank; DB07676; 3-({[(3S)-3,4-dihydroxybutyl]oxy}amino)-1H,2'H-2,3'-biindol-2'-one.
DR   DrugBank; DB01772; 3-[3-(2,3-Dihydroxy-Propylamino)-Phenyl]-4-(5-Fluoro-1-Methyl-1h-Indol-3-Yl)-Pyrrole-2,5-Dione.
DR   DrugBank; DB07859; 4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE.
DR   DrugBank; DB07585; 5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine.
DR   DrugBank; DB07058; 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2(3H)-thione.
DR   DrugBank; DB03444; 6-bromoindirubin-3'-oxime.
DR   DrugBank; DB04014; Alsterpaullone.
DR   DrugBank; DB01950; AR-AO-14418.
DR   DrugBank; DB03777; Bisindolylmaleimide I.
DR   DrugBank; DB12429; CI-1040.
DR   DrugBank; DB08846; Ellagic acid.
DR   DrugBank; DB16047; Elraglusib.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugBank; DB02052; Indirubin-3'-monoxime.
DR   DrugBank; DB07947; ISOQUINOLINE-5-SULFONIC ACID (2-(2-(4-CHLOROBENZYLOXY)ETHYLAMINO)ETHYL)AMIDE.
DR   DrugBank; DB14509; Lithium carbonate.
DR   DrugBank; DB01356; Lithium cation.
DR   DrugBank; DB14507; Lithium citrate.
DR   DrugBank; DB14508; Lithium succinate.
DR   DrugBank; DB11913; LY-2090314.
DR   DrugBank; DB08454; N-(5-METHYL-1H-PYRAZOL-3-YL)-2-PHENYLQUINAZOLIN-4-AMINE.
DR   DrugBank; DB07812; N-[(1S)-2-amino-1-phenylethyl]-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide.
DR   DrugBank; DB07584; N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
DR   DrugBank; DB07126; O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINE.
DR   DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester.
DR   DrugBank; DB01793; SB-409513.
DR   DrugBank; DB02010; Staurosporine.
DR   DrugBank; DB04462; Tetrabromo-2-Benzotriazole.
DR   DrugBank; DB12129; Tideglusib.
DR   DrugCentral; P49841; -.
DR   GuidetoPHARMACOLOGY; 2030; -.
DR   GlyCosmos; P49841; 3 sites, 1 glycan.
DR   GlyGen; P49841; 24 sites, 1 O-linked glycan (24 sites).
DR   iPTMnet; P49841; -.
DR   PhosphoSitePlus; P49841; -.
DR   SwissPalm; P49841; -.
DR   BioMuta; GSK3B; -.
DR   DMDM; 20455502; -.
DR   CPTAC; CPTAC-3038; -.
DR   CPTAC; CPTAC-3039; -.
DR   CPTAC; CPTAC-5749; -.
DR   CPTAC; CPTAC-5750; -.
DR   CPTAC; CPTAC-5751; -.
DR   CPTAC; CPTAC-5790; -.
DR   CPTAC; CPTAC-5791; -.
DR   CPTAC; CPTAC-804; -.
DR   CPTAC; non-CPTAC-5401; -.
DR   CPTAC; non-CPTAC-5403; -.
DR   CPTAC; non-CPTAC-5404; -.
DR   CPTAC; non-CPTAC-5554; -.
DR   CPTAC; non-CPTAC-5556; -.
DR   CPTAC; non-CPTAC-5705; -.
DR   jPOST; P49841; -.
DR   MassIVE; P49841; -.
DR   PaxDb; 9606-ENSP00000324806; -.
DR   PeptideAtlas; P49841; -.
DR   ProteomicsDB; 56151; -. [P49841-1]
DR   ProteomicsDB; 56152; -. [P49841-2]
DR   Pumba; P49841; -.
DR   Antibodypedia; 4266; 1367 antibodies from 55 providers.
DR   CPTC; P49841; 10 antibodies.
DR   DNASU; 2932; -.
DR   Ensembl; ENST00000264235.13; ENSP00000264235.9; ENSG00000082701.18. [P49841-1]
DR   Ensembl; ENST00000316626.6; ENSP00000324806.5; ENSG00000082701.18. [P49841-2]
DR   GeneID; 2932; -.
DR   KEGG; hsa:2932; -.
DR   MANE-Select; ENST00000264235.13; ENSP00000264235.9; NM_001146156.2; NP_001139628.1.
DR   UCSC; uc003edn.4; human. [P49841-1]
DR   AGR; HGNC:4617; -.
DR   ClinPGx; PA29009; -.
DR   CTD; 2932; -.
DR   DisGeNET; 2932; -.
DR   GeneCards; GSK3B; -.
DR   HGNC; HGNC:4617; GSK3B.
DR   HPA; ENSG00000082701; Low tissue specificity.
DR   MalaCards; GSK3B; -.
DR   MIM; 605004; gene.
DR   OpenTargets; ENSG00000082701; -.
DR   VEuPathDB; HostDB:ENSG00000082701; -.
DR   eggNOG; KOG0658; Eukaryota.
DR   GeneTree; ENSGT00520000055635; -.
DR   HOGENOM; CLU_000288_181_20_1; -.
DR   InParanoid; P49841; -.
DR   OMA; MKTTMPM; -.
DR   OrthoDB; 272141at2759; -.
DR   PAN-GO; P49841; 14 GO annotations based on evolutionary models.
DR   PhylomeDB; P49841; -.
DR   BRENDA; 2.7.11.26; 2681.
DR   PathwayCommons; P49841; -.
DR   Reactome; R-HSA-195253; Degradation of beta-catenin by the destruction complex.
DR   Reactome; R-HSA-196299; Beta-catenin phosphorylation cascade.
DR   Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
DR   Reactome; R-HSA-3371453; Regulation of HSF1-mediated heat shock response.
DR   Reactome; R-HSA-399956; CRMPs in Sema3A signaling.
DR   Reactome; R-HSA-4641262; Disassembly of the destruction complex and recruitment of AXIN to the membrane.
DR   Reactome; R-HSA-5250924; B-WICH complex positively regulates rRNA expression.
DR   Reactome; R-HSA-5339716; Signaling by GSK3beta mutants.
DR   Reactome; R-HSA-5358747; CTNNB1 S33 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5358749; CTNNB1 S37 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5358751; CTNNB1 S45 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5358752; CTNNB1 T41 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5467337; APC truncation mutants have impaired AXIN binding.
DR   Reactome; R-HSA-5467340; AXIN missense mutants destabilize the destruction complex.
DR   Reactome; R-HSA-5467348; Truncations of AMER1 destabilize the destruction complex.
DR   Reactome; R-HSA-5610783; Degradation of GLI2 by the proteasome.
DR   Reactome; R-HSA-5610785; GLI3 is processed to GLI3R by the proteasome.
DR   Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR   Reactome; R-HSA-75815; Ubiquitin-dependent degradation of Cyclin D.
DR   Reactome; R-HSA-8939902; Regulation of RUNX2 expression and activity.
DR   Reactome; R-HSA-9683610; Maturation of nucleoprotein.
DR   Reactome; R-HSA-9694631; Maturation of nucleoprotein.
DR   Reactome; R-HSA-9762114; GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2.
DR   Reactome; R-HSA-9856649; Transcriptional and post-translational regulation of MITF-M expression and activity.
DR   SignaLink; P49841; -.
DR   SIGNOR; P49841; -.
DR   Agora; ENSG00000082701; -.
DR   BioGRID-ORCS; 2932; 75 hits in 1226 CRISPR screens.
DR   CD-CODE; 804901D1; Nuclear speckle.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; GSK3B; human.
DR   EvolutionaryTrace; P49841; -.
DR   GeneWiki; GSK3B; -.
DR   GenomeRNAi; 2932; -.
DR   Pharos; P49841; Tclin.
DR   PRO; PR:P49841; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; P49841; protein.
DR   Bgee; ENSG00000082701; Expressed in calcaneal tendon and 197 other cell types or tissues.
DR   ExpressionAtlas; P49841; baseline and differential.
DR   GO; GO:0030424; C:axon; ISS:ARUK-UCL.
DR   GO; GO:0030877; C:beta-catenin destruction complex; IDA:UniProtKB.
DR   GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0030425; C:dendrite; ISS:ARUK-UCL.
DR   GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR   GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0098794; C:postsynapse; IEA:GOC.
DR   GO; GO:0098793; C:presynapse; IEA:GOC.
DR   GO; GO:1990909; C:Wnt signalosome; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0008013; F:beta-catenin binding; IPI:BHF-UCL.
DR   GO; GO:0034452; F:dynactin binding; IPI:ARUK-UCL.
DR   GO; GO:0016301; F:kinase activity; IDA:UniProtKB.
DR   GO; GO:0051059; F:NF-kappaB binding; IPI:UniProtKB.
DR   GO; GO:0002039; F:p53 binding; IDA:MGI.
DR   GO; GO:0002020; F:protease binding; IPI:ParkinsonsUK-UCL.
DR   GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:BHF-UCL.
DR   GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IGI:ARUK-UCL.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB.
DR   GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL.
DR   GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR   GO; GO:0050321; F:tau-protein kinase activity; IDA:UniProtKB.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL.
DR   GO; GO:0160213; P:beta-arrestin-dependent dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0060070; P:canonical Wnt signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; ISS:ARUK-UCL.
DR   GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR   GO; GO:0071300; P:cellular response to retinoic acid; IMP:ARUK-UCL.
DR   GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0001837; P:epithelial to mesenchymal transition; IMP:UniProtKB.
DR   GO; GO:0006983; P:ER overload response; IDA:MGI.
DR   GO; GO:0030010; P:establishment of cell polarity; ISS:ARUK-UCL.
DR   GO; GO:0060079; P:excitatory postsynaptic potential; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB.
DR   GO; GO:0005977; P:glycogen metabolic process; IDA:BHF-UCL.
DR   GO; GO:0003170; P:heart valve development; ISS:BHF-UCL.
DR   GO; GO:0021766; P:hippocampus development; IMP:BHF-UCL.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; IBA:GO_Central.
DR   GO; GO:0035556; P:intracellular signal transduction; IDA:MGI.
DR   GO; GO:0030011; P:maintenance of cell polarity; ISS:ARUK-UCL.
DR   GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IDA:MGI.
DR   GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; IMP:UniProtKB.
DR   GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:ARUK-UCL.
DR   GO; GO:0030336; P:negative regulation of cell migration; IDA:UniProt.
DR   GO; GO:1904339; P:negative regulation of dopaminergic neuron differentiation; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IDA:UniProtKB.
DR   GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IMP:UniProtKB.
DR   GO; GO:0010629; P:negative regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:2000466; P:negative regulation of glycogen (starch) synthase activity; TAS:UniProtKB.
DR   GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; TAS:UniProtKB.
DR   GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:ARUK-UCL.
DR   GO; GO:0045668; P:negative regulation of osteoblast differentiation; IMP:ARUK-UCL.
DR   GO; GO:1900181; P:negative regulation of protein localization to nucleus; ISS:BHF-UCL.
DR   GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IMP:BHF-UCL.
DR   GO; GO:0032007; P:negative regulation of TOR signaling; IBA:GO_Central.
DR   GO; GO:1903940; P:negative regulation of TORC2 signaling; IDA:UniProtKB.
DR   GO; GO:2000077; P:negative regulation of type B pancreatic cell development; TAS:UniProtKB.
DR   GO; GO:0031175; P:neuron projection development; IDA:UniProtKB.
DR   GO; GO:0106027; P:neuron projection organization; ISS:ARUK-UCL.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:MGI.
DR   GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR   GO; GO:0045597; P:positive regulation of cell differentiation; IMP:ARUK-UCL.
DR   GO; GO:0001954; P:positive regulation of cell-matrix adhesion; IMP:BHF-UCL.
DR   GO; GO:0045724; P:positive regulation of cilium assembly; ISS:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; ISS:UniProtKB.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:FlyBase.
DR   GO; GO:0032092; P:positive regulation of protein binding; ISS:UniProtKB.
DR   GO; GO:0045732; P:positive regulation of protein catabolic process; IC:BHF-UCL.
DR   GO; GO:0046827; P:positive regulation of protein export from nucleus; IDA:MGI.
DR   GO; GO:1904781; P:positive regulation of protein localization to centrosome; IMP:ARUK-UCL.
DR   GO; GO:1903566; P:positive regulation of protein localization to cilium; ISS:UniProtKB.
DR   GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProt.
DR   GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL.
DR   GO; GO:0032481; P:positive regulation of type I interferon production; ISS:UniProtKB.
DR   GO; GO:0099171; P:presynaptic modulation of chemical synaptic transmission; IDA:SynGO.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ComplexPortal.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:0030516; P:regulation of axon extension; ISS:ARUK-UCL.
DR   GO; GO:0050770; P:regulation of axonogenesis; ISS:ARUK-UCL.
DR   GO; GO:1900034; P:regulation of cellular response to heat; TAS:Reactome.
DR   GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:ARUK-UCL.
DR   GO; GO:1900271; P:regulation of long-term synaptic potentiation; ISS:UniProtKB.
DR   GO; GO:0150101; P:regulation of microtubule anchoring at centrosome; IMP:ARUK-UCL.
DR   GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:ARUK-UCL.
DR   GO; GO:0032886; P:regulation of microtubule-based process; IMP:UniProtKB.
DR   GO; GO:0010975; P:regulation of neuron projection development; IBA:GO_Central.
DR   GO; GO:0046825; P:regulation of protein export from nucleus; IDA:ComplexPortal.
DR   GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:UniProt.
DR   GO; GO:0071109; P:superior temporal gyrus development; IMP:BHF-UCL.
DR   GO; GO:0019082; P:viral protein processing; TAS:Reactome.
DR   GO; GO:0016055; P:Wnt signaling pathway; IMP:BHF-UCL.
DR   CDD; cd14137; STKc_GSK3; 1.
DR   DisProt; DP00385; -.
DR   FunFam; 1.10.510.10:FF:000055; Glycogen synthase kinase-3 beta; 1.
DR   FunFam; 3.30.200.20:FF:000009; Glycogen synthase kinase-3 beta; 1.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   IDEAL; IID00052; -.
DR   InterPro; IPR050591; GSK-3.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR039192; STKc_GSK3.
DR   PANTHER; PTHR24057; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1.
DR   PANTHER; PTHR24057:SF8; GLYCOGEN SYNTHASE KINASE-3 BETA; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; ADP-ribosylation; Alternative splicing; Alzheimer disease;
KW   ATP-binding; Biological rhythms; Carbohydrate metabolism; Cell membrane;
KW   Cytoplasm; Developmental protein; Diabetes mellitus; Differentiation;
KW   Glycogen metabolism; Kinase; Lipoprotein; Membrane; Neurogenesis;
KW   Nucleotide-binding; Nucleus; Palmitate; Phosphoprotein;
KW   Proteomics identification; Reference proteome;
KW   Serine/threonine-protein kinase; Signal transduction inhibitor;
KW   Transferase; Wnt signaling pathway.
FT   CHAIN           1..420
FT                   /note="Glycogen synthase kinase-3 beta"
FT                   /id="PRO_0000085980"
FT   DOMAIN          56..340
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..53
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          386..420
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..22
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        386..401
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        409..420
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        181
FT                   /note="Proton acceptor"
FT   BINDING         62..70
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         85
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000305|PubMed:17050006"
FT   MOD_RES         9
FT                   /note="Phosphoserine; by PKB/AKT1, RPS6KA3, SGK3 and NME7"
FT                   /evidence="ECO:0000269|PubMed:12054501,
FT                   ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:20937854,
FT                   ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25169422,
FT                   ECO:0000269|PubMed:34764205, ECO:0000269|PubMed:35606353,
FT                   ECO:0000269|PubMed:8250835"
FT   MOD_RES         216
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:12554650,
FT                   ECO:0000269|PubMed:25169422"
FT   MOD_RES         389
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WV60"
FT   MOD_RES         390
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         402
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18691976"
FT   LIPID           14
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:35606353"
FT   VAR_SEQ         303
FT                   /note="K -> KDSSGTGHFTSGVR (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_004790"
FT   MUTAGEN         9
FT                   /note="S->A: Loss of phosphorylation; abolished inhibition
FT                   of activity, leading to constitutively active."
FT                   /evidence="ECO:0000269|PubMed:17050006,
FT                   ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:7980435"
FT   MUTAGEN         14
FT                   /note="C->A: Significantly reduced palmitoylation."
FT                   /evidence="ECO:0000269|PubMed:35606353"
FT   MUTAGEN         85..86
FT                   /note="KK->AA: Abolished serine/threonine-protein kinase
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:17050006"
FT   MUTAGEN         96
FT                   /note="R->A: Prevents the phosphorylation of phosphate-
FT                   primed glycogen synthase."
FT                   /evidence="ECO:0000269|PubMed:11430833"
FT   MUTAGEN         128
FT                   /note="L->A: Abolishes activity toward AXIN1."
FT                   /evidence="ECO:0000269|PubMed:11430833"
FT   CONFLICT        28
FT                   /note="V -> G (in Ref. 4; AAD48517)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        350
FT                   /note="L -> H (in Ref. 1; AAA66475)"
FT                   /evidence="ECO:0000305"
FT   STRAND          10..12
FT                   /evidence="ECO:0007829|PDB:2JDO"
FT   STRAND          26..30
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          32..34
FT                   /evidence="ECO:0007829|PDB:4NM5"
FT   STRAND          38..48
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          52..64
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          66..75
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            76..78
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          81..88
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          91..93
FT                   /evidence="ECO:0007829|PDB:1Q5K"
FT   HELIX           96..102
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          112..120
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            121..124
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          125..133
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          136..138
FT                   /evidence="ECO:0007829|PDB:7SXJ"
FT   HELIX           139..148
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           155..173
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            174..176
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           184..186
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          187..190
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            191..194
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          195..198
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           201..203
FT                   /evidence="ECO:0007829|PDB:7SXJ"
FT   STRAND          209..211
FT                   /evidence="ECO:0007829|PDB:6HK4"
FT   HELIX           220..222
FT                   /evidence="ECO:0007829|PDB:7SXJ"
FT   HELIX           225..228
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           237..252
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           262..273
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           278..284
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           286..288
FT                   /evidence="ECO:0007829|PDB:7B6F"
FT   STRAND          289..291
FT                   /evidence="ECO:0007829|PDB:4ACC"
FT   HELIX           301..304
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           311..320
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           325..327
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           331..335
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           338..344
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          345..347
FT                   /evidence="ECO:0007829|PDB:1UV5"
FT   STRAND          353..355
FT                   /evidence="ECO:0007829|PDB:6HK4"
FT   HELIX           364..367
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           371..373
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           374..377
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            380..383
FT                   /evidence="ECO:0007829|PDB:1J1B"
SQ   SEQUENCE   420 AA;  46744 MW;  4ACC24D00CDBB9C3 CRC64;
     MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK
     VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG
     EKKDEVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR
     DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDV
     WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP
     WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL PNGRDTPALF
     NFTTQELSSN PPLATILIPP HARIQAAAST PTNATAASDA NTGDRGQTNN AASASASNST
//
ID   HCD2_HUMAN              Reviewed;         261 AA.
AC   Q99714; Q5H927; Q6IBS9; Q8TCV9; Q96HD5;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   28-JAN-2026, entry version 240.
DE   RecName: Full=3-hydroxyacyl-CoA dehydrogenase type-2;
DE            EC=1.1.1.35 {ECO:0000269|PubMed:10600649, ECO:0000269|PubMed:12917011, ECO:0000269|PubMed:25925575, ECO:0000269|PubMed:26950678, ECO:0000269|PubMed:9553139};
DE   AltName: Full=17-beta-estradiol 17-dehydrogenase;
DE            EC=1.1.1.62 {ECO:0000269|PubMed:10600649, ECO:0000269|PubMed:12917011};
DE   AltName: Full=2-methyl-3-hydroxybutyryl-CoA dehydrogenase {ECO:0000303|PubMed:16148061};
DE            Short=MHBD {ECO:0000303|PubMed:16148061};
DE   AltName: Full=3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+));
DE            EC=1.1.1.239 {ECO:0000269|PubMed:12917011};
DE   AltName: Full=3-hydroxy-2-methylbutyryl-CoA dehydrogenase;
DE            EC=1.1.1.178 {ECO:0000269|PubMed:18996107, ECO:0000269|PubMed:19706438, ECO:0000269|PubMed:20077426};
DE   AltName: Full=3-hydroxyacyl-CoA dehydrogenase type II;
DE   AltName: Full=3alpha(or 20beta)-hydroxysteroid dehydrogenase;
DE            EC=1.1.1.53 {ECO:0000269|PubMed:12917011};
DE   AltName: Full=7-alpha-hydroxysteroid dehydrogenase;
DE            EC=1.1.1.159 {ECO:0000269|PubMed:12917011};
DE   AltName: Full=Endoplasmic reticulum-associated amyloid beta-peptide-binding protein;
DE   AltName: Full=Mitochondrial ribonuclease P protein 2;
DE            Short=Mitochondrial RNase P protein 2;
DE   AltName: Full=Short chain dehydrogenase/reductase family 5C member 1;
DE   AltName: Full=Short-chain type dehydrogenase/reductase XH98G2;
DE   AltName: Full=Type II HADH;
GN   Name=HSD17B10; Synonyms=ERAB, HADH2, MRPP2, SCHAD, SDR5C1, XH98G2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=9338779; DOI=10.1038/39522;
RA   Yan S.D., Fu J., Soto C., Chen X., Zhu H., Al-Mohanna F., Collinson K.,
RA   Zhu A., Stern E., Saido T., Tohyama M., Ogawa S., Roher A., Stern D.;
RT   "An intracellular protein that binds amyloid-beta peptide and mediates
RT   neurotoxicity in Alzheimer's disease.";
RL   Nature 389:689-695(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Zhuchenko O.P., Wehnert M., Bailey J., Sun Z.S., Lee C.C.;
RL   Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=9671743; DOI=10.1073/pnas.95.15.8709;
RA   Miller A.P., Willard H.F.;
RT   "Chromosomal basis of X chromosome inactivation: identification of a
RT   multigene domain in Xp11.21-p11.22 that escapes X inactivation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:8709-8714(1998).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), FUNCTION, CATALYTIC
RP   ACTIVITY, AND PATHWAY.
RC   TISSUE=Brain;
RX   PubMed=9553139; DOI=10.1074/jbc.273.17.10741;
RA   He X.Y., Schulz H., Yang S.Y.;
RT   "A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an
RT   amyloid beta-peptide-binding protein involved in Alzheimer's disease.";
RL   J. Biol. Chem. 273:10741-10746(1998).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15772651; DOI=10.1038/nature03440;
RA   Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA   Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA   Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA   Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA   Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA   Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA   Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA   Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA   Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA   Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA   Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA   Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA   Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA   Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA   Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA   Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA   Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA   Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA   Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA   Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA   Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA   Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA   Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA   Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA   Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA   Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA   Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA   Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA   Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA   Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA   McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA   Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA   Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA   Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA   Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA   Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA   Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA   Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA   Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA   Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA   d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA   Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA   Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA   Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA   Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA   Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA   Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA   Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA   Rogers J., Bentley D.R.;
RT   "The DNA sequence of the human X chromosome.";
RL   Nature 434:325-337(2005).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Brain, and Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 51-246.
RA   Deininger M.H., Meyermann R., Schluesener H.J.;
RT   "Expression, release and induction of endoplasmic reticulum-associated
RT   amyloid beta-binding protein in brain disease.";
RL   Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX   PubMed=10600649; DOI=10.1042/bj3450139;
RA   He X.Y., Yang Y.Z., Schulz H., Yang S.Y.;
RT   "Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase
RT   activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA
RT   dehydrogenase.";
RL   Biochem. J. 345:139-143(2000).
RN   [11]
RP   FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR
RP   LOCATION, AND PATHWAY.
RX   PubMed=12917011; DOI=10.1042/bj20030877;
RA   Shafqat N., Marschall H.U., Filling C., Nordling E., Wu X.Q., Bjork L.,
RA   Thyberg J., Martensson E., Salim S., Jornvall H., Oppermann U.;
RT   "Expanded substrate screenings of human and Drosophila type 10 17beta-
RT   hydroxysteroid dehydrogenases (HSDs) reveal multiple specificities in bile
RT   acid and steroid hormone metabolism: characterization of multifunctional
RT   3alpha/7alpha/7beta/17beta/20beta/21-HSD.";
RL   Biochem. J. 376:49-60(2003).
RN   [12]
RP   INVOLVEMENT IN HSD10MD.
RX   PubMed=17236142; DOI=10.1086/511527;
RA   Lenski C., Kooy R.F., Reyniers E., Loessner D., Wanders R.J.A.,
RA   Winnepenninckx B., Hellebrand H., Engert S., Schwartz C.E., Meindl A.,
RA   Ramser J.;
RT   "The reduced expression of the HADH2 protein causes X-linked mental
RT   retardation, choreoathetosis, and abnormal behavior.";
RL   Am. J. Hum. Genet. 80:372-377(2007).
RN   [13]
RP   IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, INTERACTION WITH KIAA0391
RP   AND TRMT10C, AND SUBCELLULAR LOCATION.
RX   PubMed=18984158; DOI=10.1016/j.cell.2008.09.013;
RA   Holzmann J., Frank P., Loeffler E., Bennett K.L., Gerner C., Rossmanith W.;
RT   "RNase P without RNA: identification and functional reconstitution of the
RT   human mitochondrial tRNA processing enzyme.";
RL   Cell 135:462-474(2008).
RN   [14]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [15]
RP   FUNCTION, INTERACTION WITH TRMT10C, AND MUTAGENESIS OF SER-20 AND LYS-172.
RX   PubMed=23042678; DOI=10.1093/nar/gks910;
RA   Vilardo E., Nachbagauer C., Buzet A., Taschner A., Holzmann J.,
RA   Rossmanith W.;
RT   "A subcomplex of human mitochondrial RNase P is a bifunctional
RT   methyltransferase--extensive moonlighting in mitochondrial tRNA
RT   biogenesis.";
RL   Nucleic Acids Res. 40:11583-11593(2012).
RN   [16]
RP   IDENTIFICATION BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND FUNCTION.
RX   PubMed=24703694; DOI=10.1016/j.cmet.2014.03.013;
RA   Bogenhagen D.F., Martin D.W., Koller A.;
RT   "Initial steps in RNA processing and ribosome assembly occur at
RT   mitochondrial DNA nucleoids.";
RL   Cell Metab. 19:618-629(2014).
RN   [17]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [18]
RP   FUNCTION, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, AND VARIANTS
RP   HSD10MD GLY-86; CYS-130 AND HIS-165.
RX   PubMed=26338420; DOI=10.1101/gad.268482.115;
RA   Boynton T.O., Shimkets L.J.;
RT   "Myxococcus CsgA, Drosophila Sniffer, and human HSD10 are cardiolipin
RT   phospholipases.";
RL   Genes Dev. 29:1903-1914(2015).
RN   [19]
RP   INVOLVEMENT IN HSD10MD.
RX   PubMed=25575635; DOI=10.1016/j.mito.2014.12.005;
RA   Chatfield K.C., Coughlin C.R. II, Friederich M.W., Gallagher R.C.,
RA   Hesselberth J.R., Lovell M.A., Ofman R., Swanson M.A., Thomas J.A.,
RA   Wanders R.J., Wartchow E.P., Van Hove J.L.;
RT   "Mitochondrial energy failure in HSD10 disease is due to defective mtDNA
RT   transcript processing.";
RL   Mitochondrion 21:1-10(2015).
RN   [20]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [21]
RP   FUNCTION, AND INTERACTION WITH TRMT10C.
RX   PubMed=29040705; DOI=10.1093/nar/gkx902;
RA   Reinhard L., Sridhara S., Haellberg B.M.;
RT   "The MRPP1/MRPP2 complex is a tRNA-maturation platform in human
RT   mitochondria.";
RL   Nucleic Acids Res. 45:12469-12480(2017).
RN   [22] {ECO:0007744|PDB:1U7T}
RP   X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH NAD.
RX   PubMed=15342248; DOI=10.1016/j.jmb.2004.07.071;
RA   Kissinger C.R., Rejto P.A., Pelletier L.A., Thomson J.A., Showalter R.E.,
RA   Abreo M.A., Agree C.S., Margosiak S., Meng J.J., Aust R.M., Vanderpool D.,
RA   Li B., Tempczyk-Russell A., Villafranca J.E.;
RT   "Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications
RT   for design of Alzheimer's disease therapeutics.";
RL   J. Mol. Biol. 342:943-952(2004).
RN   [23]
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX   PubMed=15087549; DOI=10.1126/science.1091230;
RA   Lustbader J.W., Cirilli M., Lin C., Xu H.W., Takuma K., Wang N.,
RA   Caspersen C., Chen X., Pollak S., Chaney M., Trinchese F., Liu S.,
RA   Gunn-Moore F., Lue L.-F., Walker D.G., Kuppusamy P., Zewier Z.L.,
RA   Arancio O., Stern D., Yan S.-S., Wu H.;
RT   "ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's
RT   disease.";
RL   Science 304:448-452(2004).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (1.20 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP   SUBUNIT, VARIANTS HSD10MD GLY-86; CYS-130 AND HIS-165, AND CHARACTERIZATION
RP   OF VARIANTS HSD10MD GLY-86; CYS-130 AND HIS-165.
RX   PubMed=20077426; DOI=10.1002/emmm.200900055;
RA   Rauschenberger K., Schoeler K., Sass J.O., Sauer S., Djuric Z., Rumig C.,
RA   Wolf N.I., Okun J.G., Koelker S., Schwarz H., Fischer C., Grziwa B.,
RA   Runz H., Nuemann A., Shafqat N., Kavanagh K.L., Haemmerling G.,
RA   Wanders R.J., Shield J.P., Wendel U., Stern D., Nawroth P., Hoffmann G.F.,
RA   Bartram C.R., Arnold B., Bierhaus A., Oppermann U., Steinbeisser H.,
RA   Zschocke J.;
RT   "A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is
RT   required for mitochondrial integrity and cell survival.";
RL   EMBO Mol. Med. 2:51-62(2010).
RN   [25]
RP   VARIANTS HSD10MD VAL-122 AND CYS-130.
RX   PubMed=12696021; DOI=10.1086/375116;
RA   Ofman R., Ruiter J.P.N., Feenstra M., Duran M., Poll-The B.T., Zschocke J.,
RA   Ensenauer R., Lehnert W., Sass J.O., Sperl W., Wanders R.J.A.;
RT   "2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by
RT   mutations in the HADH2 gene.";
RL   Am. J. Hum. Genet. 72:1300-1307(2003).
RN   [26]
RP   VARIANTS HSD10MD CYS-130 AND SER-247, AND CHARACTERIZATION OF VARIANT
RP   HSD10MD SER-247.
RX   PubMed=16148061; DOI=10.1203/01.pdr.0000176916.94328.cd;
RA   Perez-Cerda C., Garcia-Villoria J., Ofman R., Sala P.R., Merinero B.,
RA   Ramos J., Garcia-Silva M.T., Beseler B., Dalmau J., Wanders R.J.A.,
RA   Ugarte M., Ribes A.;
RT   "2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: an X-linked
RT   inborn error of isoleucine metabolism that may mimic a mitochondrial
RT   disease.";
RL   Pediatr. Res. 58:488-491(2005).
RN   [27]
RP   ERRATUM OF PUBMED:16148061.
RA   Perez-Cerda C., Garcia-Villoria J., Ofman R., Sala P.R., Merinero B.,
RA   Ramos J., Garcia-Silva M.T., Beseler B., Dalmau J., Wanders R.J.,
RA   Ugarte M., Ribes A.;
RL   Pediatr. Res. 59:162-162(2006).
RN   [28]
RP   VARIANTS HSD10MD CYS-130; SER-210; GLN-226 AND SER-247, FUNCTION, AND
RP   CATALYTIC ACTIVITY.
RX   PubMed=18996107; DOI=10.1016/j.clinbiochem.2008.10.006;
RA   Garcia-Villoria J., Navarro-Sastre A., Fons C., Perez-Cerda C.,
RA   Baldellou A., Fuentes-Castello M.A., Gonzalez I., Hernandez-Gonzalez A.,
RA   Fernandez C., Campistol J., Delpiccolo C., Cortes N., Messeguer A.,
RA   Briones P., Ribes A.;
RT   "Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA
RT   dehydrogenase (MHBD) deficiency: difficulties in the diagnosis.";
RL   Clin. Biochem. 42:27-33(2009).
RN   [29]
RP   VARIANTS HSD10MD CYS-130 AND GLN-249, CHARACTERIZATION OF VARIANTS HSD10MD
RP   CYS-130 AND GLN-249, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP   PROPERTIES, AND PATHWAY.
RX   PubMed=19706438; DOI=10.1073/pnas.0902377106;
RA   Yang S.Y., He X.Y., Olpin S.E., Sutton V.R., McMenamin J., Philipp M.,
RA   Denman R.B., Malik M.;
RT   "Mental retardation linked to mutations in the HSD17B10 gene interfering
RT   with neurosteroid and isoleucine metabolism.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:14820-14824(2009).
RN   [30]
RP   VARIANT HSD10MD ALA-65.
RX   PubMed=22132097; DOI=10.1371/journal.pone.0027348;
RA   Seaver L.H., He X.Y., Abe K., Cowan T., Enns G.M., Sweetman L., Philipp M.,
RA   Lee S., Malik M., Yang S.Y.;
RT   "A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory
RT   epilepsy, choreoathetosis and learning disability.";
RL   PLoS ONE 6:E27348-E27348(2011).
RN   [31]
RP   VARIANTS HSD10MD CYS-130 AND HIS-165, CHARACTERIZATION OF VARIANT HSD10MD
RP   CYS-130, AND FUNCTION.
RX   PubMed=24549042; DOI=10.1093/hmg/ddu072;
RA   Deutschmann A.J., Amberger A., Zavadil C., Steinbeisser H., Mayr J.A.,
RA   Feichtinger R.G., Oerum S., Yue W.W., Zschocke J.;
RT   "Mutation or knock-down of 17beta-hydroxysteroid dehydrogenase type 10
RT   cause loss of MRPP1 and impaired processing of mitochondrial heavy strand
RT   transcripts.";
RL   Hum. Mol. Genet. 23:3618-3628(2014).
RN   [32]
RP   VARIANTS HSD10MD CYS-130; SER-210; GLN-226 AND SER-247, FUNCTION, CATALYTIC
RP   ACTIVITY, SUBUNIT, MUTAGENESIS OF LYS-172, AND CHARACTERIZATION OF VARIANTS
RP   HSD10MD CYS-130; SER-210; GLN-226 AND SER-247.
RX   PubMed=25925575; DOI=10.1093/nar/gkv408;
RA   Vilardo E., Rossmanith W.;
RT   "Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the
RT   human mitochondrial RNase P complex.";
RL   Nucleic Acids Res. 43:5112-5119(2015).
RN   [33]
RP   VARIANT HSD10MD GLU-212, FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH
RP   TRMT10C, AND CHARACTERIZATION OF VARIANT HSD10MD GLU-212.
RX   PubMed=26950678; DOI=10.1080/15476286.2016.1159381;
RA   Falk M.J., Gai X., Shigematsu M., Vilardo E., Takase R., McCormick E.,
RA   Christian T., Place E., Pierce E.A., Consugar M., Gamper H.B.,
RA   Rossmanith W., Hou Y.M.;
RT   "A novel HSD17B10 mutation impairing the activities of the mitochondrial
RT   RNase P complex causes X-linked intractable epilepsy and neurodevelopmental
RT   regression.";
RL   RNA Biol. 13:477-485(2016).
RN   [34]
RP   VARIANTS HSD10MD LEU-12 AND MET-176, FUNCTION, CATALYTIC ACTIVITY,
RP   BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND CHARACTERIZATION OF VARIANTS
RP   HSD10MD LEU-12 AND MET-176.
RX   PubMed=28888424; DOI=10.1016/j.bbadis.2017.09.002;
RA   Oerum S., Roovers M., Leichsenring M., Acquaviva-Bourdain C., Beermann F.,
RA   Gemperle-Britschgi C., Fouilhoux A., Korwitz-Reichelt A., Bailey H.J.,
RA   Droogmans L., Oppermann U., Sass J.O., Yue W.W.;
RT   "Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase
RT   and mitochondrial tRNA modification functions of the encoded protein.";
RL   Biochim. Biophys. Acta 1863:3294-3302(2017).
CC   -!- FUNCTION: Mitochondrial dehydrogenase involved in pathways of fatty
CC       acid, branched-chain amino acid and steroid metabolism
CC       (PubMed:10600649, PubMed:12917011, PubMed:18996107, PubMed:19706438,
CC       PubMed:20077426, PubMed:25925575, PubMed:26950678, PubMed:28888424,
CC       PubMed:9553139). Acts as (S)-3-hydroxyacyl-CoA dehydrogenase in
CC       mitochondrial fatty acid beta-oxidation, a major degradation pathway of
CC       fatty acids. Catalyzes the third step in the beta-oxidation cycle,
CC       namely the reversible conversion of (S)-3-hydroxyacyl-CoA to 3-
CC       ketoacyl-CoA. Preferentially accepts straight medium- and short-chain
CC       acyl-CoA substrates with highest efficiency for (3S)-hydroxybutanoyl-
CC       CoA (PubMed:10600649, PubMed:12917011, PubMed:25925575,
CC       PubMed:26950678, PubMed:9553139). Acts as 3-hydroxy-2-methylbutyryl-CoA
CC       dehydrogenase in branched-chain amino acid catabolic pathway. Catalyzes
CC       the oxidation of 3-hydroxy-2-methylbutanoyl-CoA into 2-methyl-3-
CC       oxobutanoyl-CoA, a step in isoleucine degradation pathway
CC       (PubMed:18996107, PubMed:19706438, PubMed:20077426). Has hydroxysteroid
CC       dehydrogenase activity toward steroid hormones and bile acids.
CC       Catalyzes the oxidation of 3alpha-, 17beta-, 20beta- and 21-
CC       hydroxysteroids and 7alpha- and 7beta-hydroxy bile acids
CC       (PubMed:10600649, PubMed:12917011). Oxidizes
CC       allopregnanolone/brexanolone at the 3alpha-hydroxyl group, which is
CC       known to be critical for the activation of gamma-aminobutyric acid
CC       receptors (GABAARs) chloride channel (PubMed:19706438,
CC       PubMed:28888424). Has phospholipase C-like activity toward cardiolipin
CC       and its oxidized species. Likely oxidizes the 2'-hydroxyl in the head
CC       group of cardiolipin to form a ketone intermediate that undergoes
CC       nucleophilic attack by water and fragments into diacylglycerol,
CC       dihydroxyacetone and orthophosphate. Has higher affinity for
CC       cardiolipin with oxidized fatty acids and may degrade these species
CC       during the oxidative stress response to protect cells from apoptosis
CC       (PubMed:26338420). By interacting with intracellular amyloid-beta, it
CC       may contribute to the neuronal dysfunction associated with Alzheimer
CC       disease (AD) (PubMed:9338779). Essential for structural and functional
CC       integrity of mitochondria (PubMed:20077426).
CC       {ECO:0000269|PubMed:10600649, ECO:0000269|PubMed:12917011,
CC       ECO:0000269|PubMed:18996107, ECO:0000269|PubMed:19706438,
CC       ECO:0000269|PubMed:20077426, ECO:0000269|PubMed:25925575,
CC       ECO:0000269|PubMed:26338420, ECO:0000269|PubMed:26950678,
CC       ECO:0000269|PubMed:28888424, ECO:0000269|PubMed:9553139}.
CC   -!- FUNCTION: In addition to mitochondrial dehydrogenase activity,
CC       moonlights as a component of mitochondrial ribonuclease P, a complex
CC       that cleaves tRNA molecules in their 5'-ends (PubMed:18984158,
CC       PubMed:24549042, PubMed:25925575, PubMed:26950678, PubMed:28888424).
CC       Together with TRMT10C/MRPP1, forms a subcomplex of the mitochondrial
CC       ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions
CC       that are independent of the ribonuclease P activity (PubMed:23042678,
CC       PubMed:29040705). The MRPP1-MRPP2 subcomplex catalyzes the formation of
CC       N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9,
CC       respectively) in tRNAs; HSD17B10/MRPP2 acting as a non-catalytic
CC       subunit (PubMed:23042678, PubMed:25925575, PubMed:28888424). The MRPP1-
CC       MRPP2 subcomplex also acts as a tRNA maturation platform: following 5'-
CC       end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-
CC       MRPP2 subcomplex enhances the efficiency of 3'-processing catalyzed by
CC       ELAC2, retains the tRNA product after ELAC2 processing and presents the
CC       nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1
CC       enzyme (PubMed:29040705). Associates with mitochondrial DNA complexes
CC       at the nucleoids to initiate RNA processing and ribosome assembly.
CC       {ECO:0000269|PubMed:18984158, ECO:0000269|PubMed:23042678,
CC       ECO:0000269|PubMed:24549042, ECO:0000269|PubMed:24703694,
CC       ECO:0000269|PubMed:25925575, ECO:0000269|PubMed:26950678,
CC       ECO:0000269|PubMed:28888424, ECO:0000269|PubMed:29040705}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a (3S)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH +
CC         H(+); Xref=Rhea:RHEA:22432, ChEBI:CHEBI:15378, ChEBI:CHEBI:57318,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:90726; EC=1.1.1.35;
CC         Evidence={ECO:0000269|PubMed:10600649, ECO:0000269|PubMed:12917011,
CC         ECO:0000269|PubMed:25925575, ECO:0000269|PubMed:26950678,
CC         ECO:0000269|PubMed:9553139};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22433;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:22434;
CC         Evidence={ECO:0000305|PubMed:10600649, ECO:0000305|PubMed:12917011,
CC         ECO:0000305|PubMed:25925575, ECO:0000305|PubMed:26950678,
CC         ECO:0000305|PubMed:9553139};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD(+) = 2-methyl-3-
CC         oxobutanoyl-CoA + NADH + H(+); Xref=Rhea:RHEA:13281,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:57312, ChEBI:CHEBI:57335,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.178;
CC         Evidence={ECO:0000269|PubMed:18996107, ECO:0000269|PubMed:19706438,
CC         ECO:0000269|PubMed:20077426};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13282;
CC         Evidence={ECO:0000305|PubMed:18996107, ECO:0000305|PubMed:19706438,
CC         ECO:0000305|PubMed:20077426};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=testosterone + NAD(+) = androst-4-ene-3,17-dione + NADH +
CC         H(+); Xref=Rhea:RHEA:14929, ChEBI:CHEBI:15378, ChEBI:CHEBI:16422,
CC         ChEBI:CHEBI:17347, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC         EC=1.1.1.239; Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14930;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=5alpha-androstane-3alpha,17beta-diol + NAD(+) = 17beta-
CC         hydroxy-5alpha-androstan-3-one + NADH + H(+); Xref=Rhea:RHEA:42004,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:16330, ChEBI:CHEBI:36713,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.53;
CC         Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42006;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=17beta-estradiol + NAD(+) = estrone + NADH + H(+);
CC         Xref=Rhea:RHEA:24612, ChEBI:CHEBI:15378, ChEBI:CHEBI:16469,
CC         ChEBI:CHEBI:17263, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.62;
CC         Evidence={ECO:0000269|PubMed:10600649, ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24613;
CC         Evidence={ECO:0000305|PubMed:10600649, ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cholate + NAD(+) = 3alpha,12alpha-dihydroxy-7-oxo-5beta-
CC         cholanate + NADH + H(+); Xref=Rhea:RHEA:19409, ChEBI:CHEBI:11893,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:29747, ChEBI:CHEBI:57540,
CC         ChEBI:CHEBI:57945; EC=1.1.1.159;
CC         Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19410;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(3S)-3-hydroxybutanoyl-CoA + NAD(+) = acetoacetyl-CoA + NADH +
CC         H(+); Xref=Rhea:RHEA:30799, ChEBI:CHEBI:15378, ChEBI:CHEBI:57286,
CC         ChEBI:CHEBI:57316, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC         Evidence={ECO:0000269|PubMed:10600649, ECO:0000269|PubMed:12917011,
CC         ECO:0000269|PubMed:9553139};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:30800;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:30801;
CC         Evidence={ECO:0000305|PubMed:10600649, ECO:0000305|PubMed:25925575,
CC         ECO:0000305|PubMed:9553139};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(3S)-hydroxyoctanoyl-CoA + NAD(+) = 3-oxooctanoyl-CoA + NADH +
CC         H(+); Xref=Rhea:RHEA:31195, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC         ChEBI:CHEBI:57945, ChEBI:CHEBI:62617, ChEBI:CHEBI:62619;
CC         Evidence={ECO:0000269|PubMed:9553139};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31196;
CC         Evidence={ECO:0000305};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:31197;
CC         Evidence={ECO:0000305|PubMed:9553139};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(3S)-hydroxyhexadecanoyl-CoA + NAD(+) = 3-oxohexadecanoyl-CoA
CC         + NADH + H(+); Xref=Rhea:RHEA:31159, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:57349, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC         ChEBI:CHEBI:62613; Evidence={ECO:0000269|PubMed:9553139};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31160;
CC         Evidence={ECO:0000305};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:31161;
CC         Evidence={ECO:0000305|PubMed:9553139};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=17beta-hydroxy-5alpha-androstan-3-one + NAD(+) = 5alpha-
CC         androstan-3,17-dione + NADH + H(+); Xref=Rhea:RHEA:41992,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15994, ChEBI:CHEBI:16330,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC         Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41993;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=5alpha-pregnan-20beta-ol-3-one + NAD(+) = 5alpha-pregnane-
CC         3,20-dione + NADH + H(+); Xref=Rhea:RHEA:42008, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:28952, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC         ChEBI:CHEBI:78594; Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42009;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3alpha-hydroxy-5alpha-pregnan-20-one + NAD(+) = 5alpha-
CC         pregnane-3,20-dione + NADH + H(+); Xref=Rhea:RHEA:41980,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:28952, ChEBI:CHEBI:50169,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC         Evidence={ECO:0000269|PubMed:19706438, ECO:0000269|PubMed:28888424};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41981;
CC         Evidence={ECO:0000305|PubMed:19706438, ECO:0000305|PubMed:28888424};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cortisone + NAD(+) = 17alpha-hydroxypregn-4-en-3,11,20-trione-
CC         21-al + NADH + H(+); Xref=Rhea:RHEA:42016, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16962, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC         ChEBI:CHEBI:78596; Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42017;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=11-dehydrocorticosterone + NAD(+) = pregn-4-ene-3,11,20,21-
CC         tetraone + NADH + H(+); Xref=Rhea:RHEA:42020, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:78600,
CC         ChEBI:CHEBI:78601; Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42021;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cortisol + NAD(+) = 11beta,17alpha-dihydroxypregn-4-ene-
CC         3,20,21-trione + NADH + H(+); Xref=Rhea:RHEA:42012,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:17650, ChEBI:CHEBI:57540,
CC         ChEBI:CHEBI:57945, ChEBI:CHEBI:78595;
CC         Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42013;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=chenodeoxycholate + NAD(+) = 7-oxolithocholate + NADH + H(+);
CC         Xref=Rhea:RHEA:42036, ChEBI:CHEBI:15378, ChEBI:CHEBI:36234,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:78605;
CC         Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42037;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ursodeoxycholate + NAD(+) = 7-oxolithocholate + NADH + H(+);
CC         Xref=Rhea:RHEA:42028, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC         ChEBI:CHEBI:57945, ChEBI:CHEBI:78604, ChEBI:CHEBI:78605;
CC         Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42029;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3beta,7beta-dihydroxy-5beta-cholan-24-oate + NAD(+) = 3beta-
CC         hydroxy-7-oxo-5beta-cholan-24-oate + NADH + H(+);
CC         Xref=Rhea:RHEA:42024, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC         ChEBI:CHEBI:57945, ChEBI:CHEBI:78602, ChEBI:CHEBI:78603;
CC         Evidence={ECO:0000269|PubMed:12917011};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42025;
CC         Evidence={ECO:0000305|PubMed:12917011};
CC   -!- ACTIVITY REGULATION: The phospholipase C-like activity toward
CC       cardiolipin is inhibited by amyloid-beta peptide.
CC       {ECO:0000269|PubMed:26338420}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=25.7 uM for acetoacetyl-CoA (in the presence of 0.2 mM NADH, at pH
CC         7.0 and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=85.2 uM for beta-hydroxybutyryl-CoA (in the presence of 1 mM NAD,
CC         at pH 9.3 and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=41 uM for androsterone (in the presence of 1 mM NAD, at pH 9.3 and
CC         25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=5 uM for 5-alpha-pregnan-20-beta-ol-3-one (in the presence of 1 mM
CC         NAD, at pH 9.3 and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=219 uM for isoursodeoxycholic acid (in the presence of 1 mM NAD,
CC         at pH 9.3 and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=36.4 uM for chenodeoxycholic acid (in the presence of 1 mM NAD, at
CC         pH 9.3 and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=1.7 uM for dehydrocorticosterone (in the presence of 1 mM NAD, at
CC         pH 9.3 and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=30.6 uM for NADH (in the presence of acetoacetyl-CoA, at pH 7.0
CC         and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=42.3 uM for NAD (in the presence of beta-hydroxybutyryl-CoA, at pH
CC         9.3 and 25 degrees Celsius) {ECO:0000269|PubMed:12917011};
CC         KM=69 uM for DL-3-hydroxybutyryl-CoA {ECO:0000269|PubMed:28888424};
CC         KM=7.7 uM for 3alpha-hydroxy-5alpha-pregnan-20-one/allopregnanolone
CC         {ECO:0000269|PubMed:28888424};
CC         KM=30 uM for 3alpha-hydroxy-5alpha-pregnan-20-one/allopregnanolone
CC         {ECO:0000269|PubMed:19706438};
CC         KM=140 uM for tetramyristoyl cardiolipin
CC         {ECO:0000269|PubMed:26338420};
CC         KM=148 uM for tetralinoleoyl cardiolipin
CC         {ECO:0000269|PubMed:26338420};
CC         KM=40 uM for oxidized tetralinoleoyl cardiolipin
CC         {ECO:0000269|PubMed:26338420};
CC         KM=7.1 uM for (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA
CC         {ECO:0000269|PubMed:19706438};
CC         Vmax=14.8 umol/min/mg enzyme toward (2S,3S)-3-hydroxy-2-
CC         methylbutanoyl-CoA {ECO:0000269|PubMed:19706438};
CC         Vmax=150 umol/min/mg enzyme 3alpha-hydroxy-5alpha-pregnan-20-
CC         one/allopregnanolone {ECO:0000269|PubMed:19706438};
CC         Note=kcat is 458 min(-1) for DL-3-hydroxybutyryl-CoA
CC         (PubMed:28888424). kcat is 706 min(-1) for allopregnanolone
CC         (PubMed:28888424). {ECO:0000269|PubMed:28888424};
CC       pH dependence:
CC         Optimum pH is 9.3 for the dehydrogenase reaction at 25 degrees
CC         Celsius, and 7.0 for the reductase reaction at 25 degrees Celsius.
CC         {ECO:0000269|PubMed:12917011};
CC   -!- PATHWAY: Amino-acid degradation; L-isoleucine degradation.
CC       {ECO:0000269|PubMed:19706438}.
CC   -!- PATHWAY: Lipid metabolism; fatty acid beta-oxidation.
CC       {ECO:0000269|PubMed:10600649, ECO:0000269|PubMed:12917011,
CC       ECO:0000269|PubMed:9553139}.
CC   -!- PATHWAY: Steroid metabolism. {ECO:0000269|PubMed:10600649,
CC       ECO:0000269|PubMed:12917011}.
CC   -!- PATHWAY: Lipid metabolism; bile acid biosynthesis.
CC       {ECO:0000269|PubMed:12917011}.
CC   -!- SUBUNIT: Homotetramer (PubMed:15342248, PubMed:20077426,
CC       PubMed:25925575). Component of mitochondrial ribonuclease P, a complex
CC       composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3
CC       (PubMed:18984158, PubMed:25925575, PubMed:26950678, PubMed:28888424).
CC       Interacts with TRMT10C/MRPP1; forming the MRPP1-MRPP2 subcomplex of the
CC       mitochondrial ribonuclease P complex (PubMed:23042678,
CC       PubMed:29040705). {ECO:0000269|PubMed:15342248,
CC       ECO:0000269|PubMed:18984158, ECO:0000269|PubMed:20077426,
CC       ECO:0000269|PubMed:23042678, ECO:0000269|PubMed:25925575,
CC       ECO:0000269|PubMed:26950678, ECO:0000269|PubMed:28888424,
CC       ECO:0000269|PubMed:29040705}.
CC   -!- INTERACTION:
CC       Q99714; P05067: APP; NbExp=7; IntAct=EBI-79964, EBI-77613;
CC       Q99714; PRO_0000000092 [P05067]: APP; NbExp=2; IntAct=EBI-79964, EBI-821758;
CC       Q99714; P13639: EEF2; NbExp=3; IntAct=EBI-79964, EBI-352560;
CC       Q99714; Q12931: TRAP1; NbExp=3; IntAct=EBI-79964, EBI-1055869;
CC       Q99714; Q7L0Y3: TRMT10C; NbExp=24; IntAct=EBI-79964, EBI-2107046;
CC       Q99714-2; P05067: APP; NbExp=3; IntAct=EBI-25939412, EBI-77613;
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:12917011,
CC       ECO:0000269|PubMed:18984158}. Mitochondrion matrix, mitochondrion
CC       nucleoid {ECO:0000269|PubMed:24703694}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q99714-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q99714-2; Sequence=VSP_007830;
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed in normal tissues but is
CC       overexpressed in neurons affected in AD. {ECO:0000269|PubMed:9338779}.
CC   -!- DISEASE: HSD10 mitochondrial disease (HSD10MD) [MIM:300438]: An X-
CC       linked multisystemic disorder with highly variable severity. Age at
CC       onset ranges from the neonatal period to early childhood. Features
CC       include progressive neurodegeneration, psychomotor retardation, loss of
CC       mental and motor skills, seizures, cardiomyopathy, and visual and
CC       hearing impairment. Some patients manifest lactic acidosis and
CC       metabolic acidosis. {ECO:0000269|PubMed:12696021,
CC       ECO:0000269|PubMed:16148061, ECO:0000269|PubMed:17236142,
CC       ECO:0000269|PubMed:18996107, ECO:0000269|PubMed:19706438,
CC       ECO:0000269|PubMed:20077426, ECO:0000269|PubMed:22132097,
CC       ECO:0000269|PubMed:24549042, ECO:0000269|PubMed:25575635,
CC       ECO:0000269|PubMed:25925575, ECO:0000269|PubMed:26338420,
CC       ECO:0000269|PubMed:26950678, ECO:0000269|PubMed:28888424}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC       family. {ECO:0000305}.
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DR   EMBL; U96132; AAC51812.1; -; mRNA.
DR   EMBL; U73514; AAB68958.1; -; mRNA.
DR   EMBL; AF069134; AAC39900.1; -; mRNA.
DR   EMBL; AF035555; AAC15902.1; -; mRNA.
DR   EMBL; AF037438; AAC16419.1; -; Genomic_DNA.
DR   EMBL; CR456723; CAG33004.1; -; mRNA.
DR   EMBL; Z97054; CAI42652.1; -; Genomic_DNA.
DR   EMBL; Z97054; CAI42653.1; -; Genomic_DNA.
DR   EMBL; CH471154; EAW93157.1; -; Genomic_DNA.
DR   EMBL; CH471154; EAW93158.1; -; Genomic_DNA.
DR   EMBL; BC000372; AAH00372.1; -; mRNA.
DR   EMBL; BC008708; AAH08708.1; -; mRNA.
DR   EMBL; AY092415; AAM18189.1; -; mRNA.
DR   CCDS; CCDS14354.1; -. [Q99714-1]
DR   CCDS; CCDS35300.1; -. [Q99714-2]
DR   RefSeq; NP_001032900.1; NM_001037811.2. [Q99714-2]
DR   RefSeq; NP_004484.1; NM_004493.3. [Q99714-1]
DR   PDB; 1SO8; X-ray; 2.30 A; A=1-261.
DR   PDB; 1U7T; X-ray; 2.00 A; A/B/C/D=1-261.
DR   PDB; 2O23; X-ray; 1.20 A; A/B=1-261.
DR   PDB; 7ONU; EM; 3.00 A; A/B/C/D=1-261.
DR   PDB; 8CBK; EM; 2.76 A; A/B/C/D=1-261.
DR   PDB; 8CBL; EM; 2.79 A; A/B/C/D=1-261.
DR   PDB; 8CBM; EM; 3.14 A; A/B/C/D=1-261.
DR   PDB; 8CBO; EM; 3.20 A; A/B/C/D=7-261.
DR   PDB; 8RR1; EM; 2.93 A; A/B/C/D=1-261.
DR   PDB; 8RR3; EM; 3.40 A; A/B/C/D=1-261.
DR   PDB; 8RR4; EM; 3.20 A; A/B/C/D=1-261.
DR   PDB; 9EY0; EM; 2.78 A; A/B/C/D=1-261.
DR   PDB; 9EY1; EM; 2.90 A; A/B/C/D=1-261.
DR   PDB; 9EY2; EM; 2.96 A; A/B/C/D=1-261.
DR   PDB; 9GCH; EM; 1.90 A; A/B/C/D=1-261.
DR   PDBsum; 1SO8; -.
DR   PDBsum; 1U7T; -.
DR   PDBsum; 2O23; -.
DR   PDBsum; 7ONU; -.
DR   PDBsum; 8CBK; -.
DR   PDBsum; 8CBL; -.
DR   PDBsum; 8CBM; -.
DR   PDBsum; 8CBO; -.
DR   PDBsum; 8RR1; -.
DR   PDBsum; 8RR3; -.
DR   PDBsum; 8RR4; -.
DR   PDBsum; 9EY0; -.
DR   PDBsum; 9EY1; -.
DR   PDBsum; 9EY2; -.
DR   PDBsum; 9GCH; -.
DR   AlphaFoldDB; Q99714; -.
DR   EMDB; EMD-13002; -.
DR   EMDB; EMD-16543; -.
DR   EMDB; EMD-16544; -.
DR   EMDB; EMD-16545; -.
DR   EMDB; EMD-16547; -.
DR   EMDB; EMD-19453; -.
DR   EMDB; EMD-19455; -.
DR   EMDB; EMD-19457; -.
DR   EMDB; EMD-50050; -.
DR   EMDB; EMD-50051; -.
DR   EMDB; EMD-50052; -.
DR   EMDB; EMD-51230; -.
DR   SMR; Q99714; -.
DR   BioGRID; 109278; 571.
DR   ComplexPortal; CPX-2240; Mitochondrial RNase Z complex.
DR   ComplexPortal; CPX-26028; Mitochondrial CCA tRNA nucleotidyltransferase 1 complex.
DR   ComplexPortal; CPX-6155; Mitochondrial ribonuclease P complex.
DR   ComplexPortal; CPX-6161; Mitochondrial tRNA:m(1)R9 methyltransferase complex.
DR   CORUM; Q99714; -.
DR   FunCoup; Q99714; 589.
DR   IntAct; Q99714; 239.
DR   MINT; Q99714; -.
DR   STRING; 9606.ENSP00000168216; -.
DR   BindingDB; Q99714; -.
DR   ChEMBL; CHEMBL4159; -.
DR   DrugBank; DB02820; 1-Azepan-1-Yl-2-Phenyl-2-(4-Thioxo-1,4-Dihydro-Pyrazolo[3,4-D]Pyrimidin-5-Yl)Ethanone Adduct.
DR   DrugBank; DB00157; NADH.
DR   DrugBank; DB09568; Omega-3-carboxylic acids.
DR   SwissLipids; SLP:000000787; -.
DR   GlyGen; Q99714; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q99714; -.
DR   MetOSite; Q99714; -.
DR   PhosphoSitePlus; Q99714; -.
DR   SwissPalm; Q99714; -.
DR   BioMuta; HSD17B10; -.
DR   DMDM; 2492759; -.
DR   REPRODUCTION-2DPAGE; IPI00017726; -.
DR   REPRODUCTION-2DPAGE; Q99714; -.
DR   CPTAC; CPTAC-522; -.
DR   CPTAC; CPTAC-523; -.
DR   jPOST; Q99714; -.
DR   MassIVE; Q99714; -.
DR   PaxDb; 9606-ENSP00000168216; -.
DR   PeptideAtlas; Q99714; -.
DR   ProteomicsDB; 78427; -. [Q99714-1]
DR   ProteomicsDB; 78428; -. [Q99714-2]
DR   Pumba; Q99714; -.
DR   TopDownProteomics; Q99714-1; -. [Q99714-1]
DR   TopDownProteomics; Q99714-2; -. [Q99714-2]
DR   Antibodypedia; 357; 563 antibodies from 42 providers.
DR   DNASU; 3028; -.
DR   Ensembl; ENST00000168216.11; ENSP00000168216.6; ENSG00000072506.15. [Q99714-1]
DR   Ensembl; ENST00000375304.9; ENSP00000364453.5; ENSG00000072506.15. [Q99714-2]
DR   GeneID; 3028; -.
DR   KEGG; hsa:3028; -.
DR   MANE-Select; ENST00000168216.11; ENSP00000168216.6; NM_004493.3; NP_004484.1.
DR   UCSC; uc004dsl.2; human. [Q99714-1]
DR   AGR; HGNC:4800; -.
DR   ClinPGx; PA162391638; -.
DR   CTD; 3028; -.
DR   DisGeNET; 3028; -.
DR   GeneCards; HSD17B10; -.
DR   HGNC; HGNC:4800; HSD17B10.
DR   HPA; ENSG00000072506; Low tissue specificity.
DR   MalaCards; HSD17B10; -.
DR   MIM; 300256; gene.
DR   MIM; 300438; phenotype.
DR   OpenTargets; ENSG00000072506; -.
DR   Orphanet; 85295; HSD10 disease, atypical type.
DR   Orphanet; 391428; HSD10 disease, infantile type.
DR   Orphanet; 391457; HSD10 disease, neonatal type.
DR   VEuPathDB; HostDB:ENSG00000072506; -.
DR   eggNOG; KOG1199; Eukaryota.
DR   GeneTree; ENSGT00940000155170; -.
DR   HOGENOM; CLU_010194_42_0_1; -.
DR   InParanoid; Q99714; -.
DR   OMA; RHIFEND; -.
DR   OrthoDB; 1274115at2759; -.
DR   PAN-GO; Q99714; 5 GO annotations based on evolutionary models.
DR   PhylomeDB; Q99714; -.
DR   BioCyc; MetaCyc:HS01071-MONOMER; -.
DR   BRENDA; 1.1.1.135; 2681.
DR   BRENDA; 1.1.1.178; 2681.
DR   BRENDA; 1.1.1.35; 2681.
DR   BRENDA; 1.1.1.62; 2681.
DR   PathwayCommons; Q99714; -.
DR   Reactome; R-HSA-6785470; tRNA processing in the mitochondrion.
DR   Reactome; R-HSA-6787450; tRNA modification in the mitochondrion.
DR   Reactome; R-HSA-70895; Branched-chain amino acid catabolism.
DR   Reactome; R-HSA-8868766; rRNA processing in the mitochondrion.
DR   Reactome; R-HSA-9837999; Mitochondrial protein degradation.
DR   SABIO-RK; Q99714; -.
DR   SignaLink; Q99714; -.
DR   SIGNOR; Q99714; -.
DR   UniPathway; UPA00221; -.
DR   UniPathway; UPA00364; -.
DR   UniPathway; UPA00659; -.
DR   Agora; ENSG00000072506; -.
DR   BioGRID-ORCS; 3028; 179 hits in 813 CRISPR screens.
DR   CD-CODE; 5965E019; mtRNA granule.
DR   ChiTaRS; HSD17B10; human.
DR   EvolutionaryTrace; Q99714; -.
DR   GeneWiki; HSD17B10; -.
DR   GenomeRNAi; 3028; -.
DR   Pharos; Q99714; Tchem.
DR   PRO; PR:Q99714; -.
DR   Proteomes; UP000005640; Chromosome X.
DR   RNAct; Q99714; protein.
DR   Bgee; ENSG00000072506; Expressed in right lobe of liver and 111 other cell types or tissues.
DR   ExpressionAtlas; Q99714; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR   GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR   GO; GO:0042645; C:mitochondrial nucleoid; IDA:UniProtKB.
DR   GO; GO:0030678; C:mitochondrial ribonuclease P complex; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:CAFA.
DR   GO; GO:0005886; C:plasma membrane; TAS:ProtInc.
DR   GO; GO:0043527; C:tRNA methyltransferase complex; IPI:ComplexPortal.
DR   GO; GO:0003857; F:(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR   GO; GO:0044594; F:17-beta-hydroxysteroid dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR   GO; GO:0047015; F:3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity; IDA:UniProtKB.
DR   GO; GO:0047044; F:androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity; IEA:UniProtKB-EC.
DR   GO; GO:0160241; F:cardiolipin dehydrogenase (NAD+) activity; IDA:FlyBase.
DR   GO; GO:0106281; F:chenodeoxycholate 7-alpha-dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR   GO; GO:0008709; F:cholate 7-alpha-dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR   GO; GO:0004303; F:estradiol 17-beta-dehydrogenase [NAD(P)+] activity; IBA:GO_Central.
DR   GO; GO:0106282; F:isoursodeoxycholate 7-beta-dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR   GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR   GO; GO:0047035; F:testosterone dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR   GO; GO:0000049; F:tRNA binding; IDA:UniProtKB.
DR   GO; GO:0106283; F:ursodeoxycholate 7-beta-dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR   GO; GO:0008209; P:androgen metabolic process; IDA:UniProtKB.
DR   GO; GO:0006699; P:bile acid biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0062173; P:brexanolone metabolic process; IDA:UniProtKB.
DR   GO; GO:0008207; P:C21-steroid hormone metabolic process; IDA:UniProtKB.
DR   GO; GO:0008210; P:estrogen metabolic process; IDA:UniProtKB.
DR   GO; GO:0006635; P:fatty acid beta-oxidation; IDA:UniProtKB.
DR   GO; GO:0006631; P:fatty acid metabolic process; IBA:GO_Central.
DR   GO; GO:0006550; P:L-isoleucine catabolic process; IDA:UniProtKB.
DR   GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc.
DR   GO; GO:1990180; P:mitochondrial tRNA 3'-end processing; IDA:UniProtKB.
DR   GO; GO:0097745; P:mitochondrial tRNA 5'-end processing; IDA:UniProtKB.
DR   GO; GO:0070901; P:mitochondrial tRNA methylation; IDA:UniProtKB.
DR   GO; GO:0007005; P:mitochondrion organization; IMP:UniProtKB.
DR   GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
DR   CDD; cd05371; HSD10-like_SDR_c; 1.
DR   DisProt; DP03854; -.
DR   FunFam; 3.40.50.720:FF:000215; 3-hydroxyacyl-CoA dehydrogenase type-2; 1.
DR   Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR   InterPro; IPR002347; SDR_fam.
DR   PANTHER; PTHR43658:SF8; 17-BETA-HYDROXYSTEROID DEHYDROGENASE 14-RELATED; 1.
DR   PANTHER; PTHR43658; SHORT-CHAIN DEHYDROGENASE/REDUCTASE; 1.
DR   Pfam; PF00106; adh_short; 1.
DR   PRINTS; PR00081; GDHRDH.
DR   PRINTS; PR00080; SDRFAMILY.
DR   SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR   PROSITE; PS00061; ADH_SHORT; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Disease variant;
KW   Fatty acid metabolism; Intellectual disability; Lipid metabolism;
KW   Mitochondrion; Mitochondrion nucleoid; NAD; Neurodegeneration;
KW   Oxidoreductase; Proteomics identification; Reference proteome;
KW   Steroid metabolism; tRNA processing.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:25944712"
FT   CHAIN           2..261
FT                   /note="3-hydroxyacyl-CoA dehydrogenase type-2"
FT                   /id="PRO_0000054810"
FT   ACT_SITE        168
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000269|PubMed:15087549"
FT   BINDING         20
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         22
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         41
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         64
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         65
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         91
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         155
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000269|PubMed:15087549"
FT   BINDING         168
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         172
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         201
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   BINDING         203
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:15342248,
FT                   ECO:0007744|PDB:1U7T"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:25944712"
FT   MOD_RES         53
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:O08756"
FT   MOD_RES         53
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:O08756"
FT   MOD_RES         69
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:O08756"
FT   MOD_RES         99
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:O08756"
FT   MOD_RES         105
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:O08756"
FT   MOD_RES         212
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:O08756"
FT   MOD_RES         212
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:O08756"
FT   VAR_SEQ         191..199
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_007830"
FT   VARIANT         12
FT                   /note="V -> L (in HSD10MD; decreased dehydrogenase
FT                   activity; decreased tRNA methylation; decreased
FT                   mitochondrial tRNA 5'-end processing)"
FT                   /evidence="ECO:0000269|PubMed:28888424"
FT                   /id="VAR_080049"
FT   VARIANT         65
FT                   /note="V -> A (in HSD10MD; uncertain significance;
FT                   dbSNP:rs104886492)"
FT                   /evidence="ECO:0000269|PubMed:22132097"
FT                   /id="VAR_078863"
FT   VARIANT         86
FT                   /note="D -> G (in HSD10MD; decreased 3-hydroxy-2-
FT                   methylbutyryl-CoA dehydrogenase activity; no effect on
FT                   NAD(+) binding; complete loss of phospholipase C-like
FT                   activity toward cardiolipin; dbSNP:rs587777651)"
FT                   /evidence="ECO:0000269|PubMed:20077426,
FT                   ECO:0000269|PubMed:26338420"
FT                   /id="VAR_078864"
FT   VARIANT         122
FT                   /note="L -> V (in HSD10MD; dbSNP:rs28935476)"
FT                   /evidence="ECO:0000269|PubMed:12696021"
FT                   /id="VAR_015987"
FT   VARIANT         130
FT                   /note="R -> C (in HSD10MD; decreased stability; decreased
FT                   3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity;
FT                   decreased mitochondrial tRNA 5'-end processing; decreased
FT                   tRNA methylation; does not affect homotetramerization;
FT                   complete loss of phospholipase C-like activity toward
FT                   cardiolipin; dbSNP:rs28935475)"
FT                   /evidence="ECO:0000269|PubMed:12696021,
FT                   ECO:0000269|PubMed:16148061, ECO:0000269|PubMed:18996107,
FT                   ECO:0000269|PubMed:19706438, ECO:0000269|PubMed:20077426,
FT                   ECO:0000269|PubMed:24549042, ECO:0000269|PubMed:25925575,
FT                   ECO:0000269|PubMed:26338420"
FT                   /id="VAR_015988"
FT   VARIANT         165
FT                   /note="Q -> H (in HSD10MD; loss of 3-hydroxy-2-
FT                   methylbutyryl-CoA dehydrogenase activity; does not bind
FT                   NAD(+); complete loss of phospholipase C-like activity
FT                   toward cardiolipin)"
FT                   /evidence="ECO:0000269|PubMed:20077426,
FT                   ECO:0000269|PubMed:24549042, ECO:0000269|PubMed:26338420"
FT                   /id="VAR_078865"
FT   VARIANT         176
FT                   /note="V -> M (in HSD10MD; decreased dehydrogenase
FT                   activity; strongly decreased tRNA methylation; strongly
FT                   decreased mitochondrial tRNA 5'-end processing)"
FT                   /evidence="ECO:0000269|PubMed:28888424"
FT                   /id="VAR_080050"
FT   VARIANT         210
FT                   /note="P -> S (in HSD10MD; decreased 3-hydroxyacyl-CoA
FT                   dehydrogenase activity; decreased mitochondrial tRNA 5'-end
FT                   processing; decreased tRNA methylation; does not affect
FT                   homotetramerization)"
FT                   /evidence="ECO:0000269|PubMed:18996107,
FT                   ECO:0000269|PubMed:25925575"
FT                   /id="VAR_080051"
FT   VARIANT         212
FT                   /note="K -> E (in HSD10MD; 4-fold decrease of 3-
FT                   hydroxyacyl-CoA dehydrogenase activity; decreased
FT                   interaction with TRMT10C; decreased function in
FT                   mitochondrial tRNA methylation; decreased function in
FT                   mitochondrial tRNA processing; dbSNP:rs886041974)"
FT                   /evidence="ECO:0000269|PubMed:26950678"
FT                   /id="VAR_078866"
FT   VARIANT         226
FT                   /note="R -> Q (in HSD10MD; strongly decreased 3-
FT                   hydroxyacyl-CoA dehydrogenase activity; abolished
FT                   mitochondrial tRNA 5'-end processing; abolished tRNA
FT                   methylation; impaired homotetramerization;
FT                   dbSNP:rs1556894502)"
FT                   /evidence="ECO:0000269|PubMed:18996107,
FT                   ECO:0000269|PubMed:25925575"
FT                   /id="VAR_080052"
FT   VARIANT         247
FT                   /note="N -> S (in HSD10MD; strongly decreased 3-
FT                   hydroxyacyl-CoA dehydrogenase activity; abolished
FT                   mitochondrial tRNA 5'-end processing; abolished tRNA
FT                   methylation; impaired homotetramerization;
FT                   dbSNP:rs122461163)"
FT                   /evidence="ECO:0000269|PubMed:16148061,
FT                   ECO:0000269|PubMed:18996107, ECO:0000269|PubMed:25925575"
FT                   /id="VAR_032093"
FT   VARIANT         249
FT                   /note="E -> Q (in HSD10MD; decreased 3-hydroxy-2-
FT                   methylbutyryl-CoA dehydrogenase activity;
FT                   dbSNP:rs62626305)"
FT                   /evidence="ECO:0000269|PubMed:19706438"
FT                   /id="VAR_078867"
FT   MUTAGEN         20
FT                   /note="S->F: Decreased dehydrogenase activity. Does not
FT                   affect mitochondrial tRNA 5'-end processing. Does not
FT                   affect tRNA methylation."
FT                   /evidence="ECO:0000269|PubMed:23042678,
FT                   ECO:0000269|PubMed:25925575"
FT   MUTAGEN         172
FT                   /note="K->A: Abolishes dehydrogenase activity. Does not
FT                   affect mitochondrial tRNA 5'-end processing. Does not
FT                   affect tRNA methylation. Does not affect
FT                   homotetramerization."
FT                   /evidence="ECO:0000269|PubMed:23042678,
FT                   ECO:0000269|PubMed:25925575"
FT   STRAND          12..16
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   TURN            17..19
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           21..32
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          36..41
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           43..45
FT                   /evidence="ECO:0007829|PDB:9EY0"
FT   HELIX           47..54
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          58..62
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           68..82
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          87..90
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          100..102
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   TURN            103..106
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           111..121
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           123..136
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          148..153
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           157..160
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           166..186
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           187..189
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          191..198
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          200..203
FT                   /evidence="ECO:0007829|PDB:9GCH"
FT   HELIX           204..207
FT                   /evidence="ECO:0007829|PDB:9GCH"
FT   HELIX           216..219
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          222..224
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   HELIX           230..242
FT                   /evidence="ECO:0007829|PDB:2O23"
FT   STRAND          250..254
FT                   /evidence="ECO:0007829|PDB:2O23"
SQ   SEQUENCE   261 AA;  26923 MW;  9E74F242E3E6FEF1 CRC64;
     MAAACRSVKG LVAVITGGAS GLGLATAERL VGQGASAVLL DLPNSGGEAQ AKKLGNNCVF
     APADVTSEKD VQTALALAKG KFGRVDVAVN CAGIAVASKT YNLKKGQTHT LEDFQRVLDV
     NLMGTFNVIR LVAGEMGQNE PDQGGQRGVI INTASVAAFE GQVGQAAYSA SKGGIVGMTL
     PIARDLAPIG IRVMTIAPGL FGTPLLTSLP EKVCNFLASQ VPFPSRLGDP AEYAHLVQAI
     IENPFLNGEV IRLDGAIRMQ P
//
ID   HMGB1_HUMAN             Reviewed;         215 AA.
AC   P09429; A5D8W9; Q14321; Q5T7C3; Q6IBE1;
DT   01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   28-JAN-2026, entry version 248.
DE   RecName: Full=High mobility group protein B1;
DE   AltName: Full=High mobility group protein 1;
DE            Short=HMG-1;
GN   Name=HMGB1 {ECO:0000312|HGNC:HGNC:4983}; Synonyms=HMG1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=2922262; DOI=10.1093/nar/17.3.1197;
RA   Wen L., Huang J.K., Johnson B.H., Reeck G.R.;
RT   "A human placental cDNA clone that encodes nonhistone chromosomal protein
RT   HMG-1.";
RL   Nucleic Acids Res. 17:1197-1214(1989).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=8661151; DOI=10.1006/geno.1996.0369;
RA   Ferrari S., Finelli P., Rocchi M., Bianchi M.E.;
RT   "The active gene that encodes human high mobility group 1 protein (HMG1)
RT   contains introns and maps to chromosome 13.";
RL   Genomics 35:367-371(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ARG-11; GLU-149 AND GLY-190.
RX   PubMed=9036861;
RX   DOI=10.1002/(sici)1097-0215(19970220)74:1<1::aid-ijc1>3.0.co;2-6;
RA   Xiang Y.-Y., Wang D.-Y., Tanaka M., Suzuki M., Kiyokawa E., Igarashi H.,
RA   Niato Y., Shen Q., Sugimura H.;
RT   "Expression of high-mobility group-1 mRNA in human gastrointestinal
RT   adenocarcinoma and corresponding non-cancerous mucosa.";
RL   Int. J. Cancer 74:1-6(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=17610420; DOI=10.1111/j.1399-0039.2007.00854.x;
RA   Kornblit B., Munthe-Fog L., Petersen S., Madsen H., Vindeloev L.,
RA   Garred P.;
RT   "The genetic variation of the human HMGB1 gene.";
RL   Tissue Antigens 70:151-156(2007).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   He F.T., Yang Z.H., Ji Q., Li R., Peng J., Jiang Y., Zhong X.;
RL   Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Cerebellum;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Small intestine;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLN-156.
RG   SeattleSNPs variation discovery resource;
RL   Submitted (JUL-2007) to the EMBL/GenBank/DDBJ databases.
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057823; DOI=10.1038/nature02379;
RA   Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA   Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
RA   Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
RA   Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
RA   Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
RA   Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA   Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
RA   Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
RA   Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
RA   Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
RA   Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
RA   Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
RA   Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
RA   Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
RA   Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA   Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
RA   Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
RA   Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
RA   Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
RA   Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
RA   Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
RA   Rogers J., Ross M.T.;
RT   "The DNA sequence and analysis of human chromosome 13.";
RL   Nature 428:522-528(2004).
RN   [12]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, Cervix, and Testis;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [14]
RP   PROTEIN SEQUENCE OF 58-65 AND 113-127.
RC   TISSUE=Mammary carcinoma;
RX   PubMed=9150946; DOI=10.1002/elps.1150180342;
RA   Rasmussen R.K., Ji H., Eddes J.S., Moritz R.L., Reid G.E., Simpson R.J.,
RA   Dorow D.S.;
RT   "Two-dimensional electrophoretic analysis of human breast carcinoma
RT   proteins: mapping of proteins that bind to the SH3 domain of mixed lineage
RT   kinase MLK2.";
RL   Electrophoresis 18:588-598(1997).
RN   [15]
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=11154118;
RA   Rouhiainen A., Imai S., Rauvala H., Parkkinen J.;
RT   "Occurrence of amphoterin (HMG1) as an endogenous protein of human
RT   platelets that is exported to the cell surface upon platelet activation.";
RL   Thromb. Haemost. 84:1087-1094(2000).
RN   [16]
RP   SUBCELLULAR LOCATION.
RX   PubMed=12231511; DOI=10.1093/embo-reports/kvf198;
RA   Gardella S., Andrei C., Ferrera D., Lotti L.V., Torrisi M.R., Bianchi M.E.,
RA   Rubartelli A.;
RT   "The nuclear protein HMGB1 is secreted by monocytes via a non-classical,
RT   vesicle-mediated secretory pathway.";
RL   EMBO Rep. 3:995-1001(2002).
RN   [17]
RP   SUBCELLULAR LOCATION.
RX   PubMed=14532127; DOI=10.1093/emboj/cdg516;
RA   Bonaldi T., Talamo F., Scaffidi P., Ferrera D., Porto A., Bachi A.,
RA   Rubartelli A., Agresti A., Bianchi M.E.;
RT   "Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it
RT   towards secretion.";
RL   EMBO J. 22:5551-5560(2003).
RN   [18]
RP   FUNCTION, AND DOMAIN.
RX   PubMed=12765338; DOI=10.1007/bf03402105;
RA   Li J., Kokkola R., Tabibzadeh S., Yang R., Ochani M., Qiang X.,
RA   Harris H.E., Czura C.J., Wang H., Ulloa L., Wang H., Warren H.S.,
RA   Moldawer L.L., Fink M.P., Andersson U., Tracey K.J., Yang H.;
RT   "Structural basis for the proinflammatory cytokine activity of high
RT   mobility group box 1.";
RL   Mol. Med. 9:37-45(2003).
RN   [19]
RP   FUNCTION, AND INTERACTION WITH MSH2.
RX   PubMed=15014079; DOI=10.1074/jbc.m401931200;
RA   Yuan F., Gu L., Guo S., Wang C., Li G.M.;
RT   "Evidence for involvement of HMGB1 protein in human DNA mismatch repair.";
RL   J. Biol. Chem. 279:20935-20940(2004).
RN   [20]
RP   INVOLVEMENT IN INFLAMMATORY DISEASES.
RX   PubMed=14695889; DOI=10.1073/pnas.2434651100;
RA   Yang H., Ochani M., Li J., Qiang X., Tanovic M., Harris H.E., Susarla S.M.,
RA   Ulloa L., Wang H., DiRaimo R., Czura C.J., Wang H., Roth J., Warren H.S.,
RA   Fink M.P., Fenton M.J., Andersson U., Tracey K.J.;
RT   "Reversing established sepsis with antagonists of endogenous high-mobility
RT   group box 1.";
RL   Proc. Natl. Acad. Sci. U.S.A. 101:296-301(2004).
RN   [21]
RP   FUNCTION.
RX   PubMed=16143102; DOI=10.1016/j.cell.2005.06.027;
RA   Zhang Y., Yuan F., Presnell S.R., Tian K., Gao Y., Tomkinson A.E., Gu L.,
RA   Li G.-M.;
RT   "Reconstitution of 5'-directed human mismatch repair in a purified
RT   system.";
RL   Cell 122:693-705(2005).
RN   [22]
RP   INTERACTION WITH THBD.
RX   PubMed=15841214; DOI=10.1172/jci22782;
RA   Abeyama K., Stern D.M., Ito Y., Kawahara K., Yoshimoto Y., Tanaka M.,
RA   Uchimura T., Ida N., Yamazaki Y., Yamada S., Yamamoto Y., Yamamoto H.,
RA   Iino S., Taniguchi N., Maruyama I.;
RT   "The N-terminal domain of thrombomodulin sequesters high-mobility group-B1
RT   protein, a novel antiinflammatory mechanism.";
RL   J. Clin. Invest. 115:1267-1274(2005).
RN   [23]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=15944249; DOI=10.4049/jimmunol.174.12.7506;
RA   Dumitriu I.E., Baruah P., Valentinis B., Voll R.E., Herrmann M.,
RA   Nawroth P.P., Arnold B., Bianchi M.E., Manfredi A.A., Rovere-Querini P.;
RT   "Release of high mobility group box 1 by dendritic cells controls T cell
RT   activation via the receptor for advanced glycation end products.";
RL   J. Immunol. 174:7506-7515(2005).
RN   [24]
RP   FUNCTION.
RX   PubMed=15607795; DOI=10.1016/j.molimm.2004.07.023;
RA   DeMarco R.A., Fink M.P., Lotze M.T.;
RT   "Monocytes promote natural killer cell interferon gamma production in
RT   response to the endogenous danger signal HMGB1.";
RL   Mol. Immunol. 42:433-444(2005).
RN   [25]
RP   SUBCELLULAR LOCATION.
RX   PubMed=16855214; DOI=10.1152/ajpcell.00616.2005;
RA   Bell C.W., Jiang W., Reich C.F., Pisetsky D.S.;
RT   "The extracellular release of HMGB1 during apoptotic cell death.";
RL   Am. J. Physiol. 291:C1318-C1325(2006).
RN   [26]
RP   DISULFIDE BRIDGE, AND REDOX FORMS.
RX   PubMed=16962095; DOI=10.1016/j.yexcr.2006.07.020;
RA   Hoppe G., Talcott K.E., Bhattacharya S.K., Crabb J.W., Sears J.E.;
RT   "Molecular basis for the redox control of nuclear transport of the
RT   structural chromatin protein Hmgb1.";
RL   Exp. Cell Res. 312:3526-3538(2006).
RN   [27]
RP   PHOSPHORYLATION, MUTAGENESIS OF SER-35; SER-39; SER-42; SER-46; SER-53 AND
RP   SER-181, SUBCELLULAR LOCATION, AND INTERACTION WITH KPNA1.
RX   PubMed=17114460; DOI=10.4049/jimmunol.177.11.7889;
RA   Youn J.H., Shin J.S.;
RT   "Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that
RT   redirects it toward secretion.";
RL   J. Immunol. 177:7889-7897(2006).
RN   [28]
RP   FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-106.
RX   PubMed=18631454; DOI=10.1016/j.immuni.2008.05.013;
RA   Kazama H., Ricci J.E., Herndon J.M., Hoppe G., Green D.R., Ferguson T.A.;
RT   "Induction of immunological tolerance by apoptotic cells requires caspase-
RT   dependent oxidation of high-mobility group box-1 protein.";
RL   Immunity 29:21-32(2008).
RN   [29]
RP   FUNCTION.
RX   PubMed=17803946; DOI=10.1016/j.molcel.2007.06.029;
RA   Prasad R., Liu Y., Deterding L.J., Poltoratsky V.P., Kedar P.S.,
RA   Horton J.K., Kanno S., Asagoshi K., Hou E.W., Khodyreva S.N., Lavrik O.I.,
RA   Tomer K.B., Yasui A., Wilson S.H.;
RT   "HMGB1 is a cofactor in mammalian base excision repair.";
RL   Mol. Cell 27:829-841(2007).
RN   [30]
RP   FUNCTION, TISSUE SPECIFICITY, AND INVOLVEMENT IN AUTOIMMUNE DISEASES.
RX   PubMed=19064698; DOI=10.1084/jem.20081165;
RA   Urbonaviciute V., Furnrohr B.G., Meister S., Munoz L., Heyder P.,
RA   De Marchis F., Bianchi M.E., Kirschning C., Wagner H., Manfredi A.A.,
RA   Kalden J.R., Schett G., Rovere-Querini P., Herrmann M., Voll R.E.;
RT   "Induction of inflammatory and immune responses by HMGB1-nucleosome
RT   complexes: implications for the pathogenesis of SLE.";
RL   J. Exp. Med. 205:3007-3018(2008).
RN   [31]
RP   FUNCTION, AND INTERACTION WITH IL1B.
RX   PubMed=18250463; DOI=10.4049/jimmunol.180.4.2531;
RA   Sha Y., Zmijewski J., Xu Z., Abraham E.;
RT   "HMGB1 develops enhanced proinflammatory activity by binding to
RT   cytokines.";
RL   J. Immunol. 180:2531-2537(2008).
RN   [32]
RP   FUNCTION.
RX   PubMed=18354232; DOI=10.4049/jimmunol.180.7.5067;
RA   Youn J.H., Oh Y.J., Kim E.S., Choi J.E., Shin J.S.;
RT   "High mobility group box 1 protein binding to lipopolysaccharide
RT   facilitates transfer of lipopolysaccharide to CD14 and enhances
RT   lipopolysaccharide-mediated TNF-alpha production in human monocytes.";
RL   J. Immunol. 180:5067-5074(2008).
RN   [33]
RP   INTERACTION WITH HNF1A.
RX   PubMed=18160415; DOI=10.1093/nar/gkm1131;
RA   Yu M., Wang J., Li W., Yuan Y.Z., Li C.Y., Qian X.H., Xu W.X., Zhan Y.Q.,
RA   Yang X.M.;
RT   "Proteomic screen defines the hepatocyte nuclear factor 1alpha-binding
RT   partners and identifies HMGB1 as a new cofactor of HNF1alpha.";
RL   Nucleic Acids Res. 36:1209-1219(2008).
RN   [34]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35 AND SER-100, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [35]
RP   REDOX FORMS, AND SUBCELLULAR LOCATION.
RX   PubMed=19811284; DOI=10.1080/08916930902831803;
RA   Urbonaviciute V., Meister S., Furnrohr B.G., Frey B., Guckel E., Schett G.,
RA   Herrmann M., Voll R.E.;
RT   "Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during
RT   apoptosis.";
RL   Autoimmunity 42:305-307(2009).
RN   [36]
RP   FUNCTION, AND INTERACTION WITH XPA AND XPC.
RX   PubMed=19446504; DOI=10.1016/j.dnarep.2009.04.001;
RA   Lange S.S., Reddy M.C., Vasquez K.M.;
RT   "Human HMGB1 directly facilitates interactions between nucleotide excision
RT   repair proteins on triplex-directed psoralen interstrand crosslinks.";
RL   DNA Repair 8:865-872(2009).
RN   [37]
RP   REVIEW ON FUNCTION RELATED TO DNA REPAIR.
RX   PubMed=19360789; DOI=10.1002/mc.20544;
RA   Lange S.S., Vasquez K.M.;
RT   "HMGB1: the jack-of-all-trades protein is a master DNA repair mechanic.";
RL   Mol. Carcinog. 48:571-580(2009).
RN   [38]
RP   FUNCTION, INTERACTION WITH CD24, AND LIGAND FOR CD24:SIGLEC10 RECEPTOR
RP   COMPLEX.
RX   PubMed=19264983; DOI=10.1126/science.1168988;
RA   Chen G.Y., Tang J., Zheng P., Liu Y.;
RT   "CD24 and Siglec-10 selectively repress tissue damage-induced immune
RT   responses.";
RL   Science 323:1722-1725(2009).
RN   [39]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-30, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19608861; DOI=10.1126/science.1175371;
RA   Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA   Olsen J.V., Mann M.;
RT   "Lysine acetylation targets protein complexes and co-regulates major
RT   cellular functions.";
RL   Science 325:834-840(2009).
RN   [40]
RP   REVIEW ON FUNCTION RELATED TO DNA-BINDING.
RX   PubMed=20123072; DOI=10.1016/j.bbagrm.2009.09.008;
RA   Stros M.;
RT   "HMGB proteins: interactions with DNA and chromatin.";
RL   Biochim. Biophys. Acta 1799:101-113(2010).
RN   [41]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH BECN1.
RX   PubMed=20819940; DOI=10.1083/jcb.200911078;
RA   Tang D., Kang R., Livesey K.M., Cheh C.W., Farkas A., Loughran P.,
RA   Hoppe G., Bianchi M.E., Tracey K.J., Zeh H.J. III, Lotze M.T.;
RT   "Endogenous HMGB1 regulates autophagy.";
RL   J. Cell Biol. 190:881-892(2010).
RN   [42]
RP   FUNCTION, LIGAND FOR TLR4:LY96 RECEPTOR COMPLEX, AND DOMAIN.
RX   PubMed=20547845; DOI=10.1073/pnas.1003893107;
RA   Yang H., Hreggvidsdottir H.S., Palmblad K., Wang H., Ochani M., Li J.,
RA   Lu B., Chavan S., Rosas-Ballina M., Al-Abed Y., Akira S., Bierhaus A.,
RA   Erlandsson-Harris H., Andersson U., Tracey K.J.;
RT   "A critical cysteine is required for HMGB1 binding to Toll-like receptor 4
RT   and activation of macrophage cytokine release.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:11942-11947(2010).
RN   [43]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [44]
RP   FUNCTION.
RX   PubMed=21395369; DOI=10.1089/ars.2010.3666;
RA   Tang D., Kang R., Livesey K.M., Zeh H.J., Lotze M.T.;
RT   "High mobility group box 1 (HMGB1) activates an autophagic response to
RT   oxidative stress.";
RL   Antioxid. Redox Signal. 15:2185-2195(2011).
RN   [45]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [46]
RP   LPS-BINDING.
RX   PubMed=21660935; DOI=10.1002/eji.201141391;
RA   Youn J.H., Kwak M.S., Wu J., Kim E.S., Ji Y., Min H.J., Yoo J.H.,
RA   Choi J.E., Cho H.S., Shin J.S.;
RT   "Identification of lipopolysaccharide-binding peptide regions within HMGB1
RT   and their effects on subclinical endotoxemia in a mouse model.";
RL   Eur. J. Immunol. 41:2753-2762(2011).
RN   [47]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA   Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA   Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT   "System-wide temporal characterization of the proteome and phosphoproteome
RT   of human embryonic stem cell differentiation.";
RL   Sci. Signal. 4:RS3-RS3(2011).
RN   [48]
RP   FUNCTION (MICROBIAL INFECTION), INTERACTION WITH INFLUENZA A VIRUS PROTEIN
RP   NP (MICROBIAL INFECTION), AND SUBCELLULAR LOCATION.
RX   PubMed=22696656; DOI=10.1128/jvi.00789-12;
RA   Moisy D., Avilov S.V., Jacob Y., Laoide B.M., Ge X., Baudin F., Naffakh N.,
RA   Jestin J.L.;
RT   "HMGB1 protein binds to influenza virus nucleoprotein and promotes viral
RT   replication.";
RL   J. Virol. 86:9122-9133(2012).
RN   [49]
RP   FUNCTION.
RX   PubMed=22473704; DOI=10.1093/intimm/dxs051;
RA   Wild C.A., Bergmann C., Fritz G., Schuler P., Hoffmann T.K., Lotfi R.,
RA   Westendorf A., Brandau S., Lang S.;
RT   "HMGB1 conveys immunosuppressive characteristics on regulatory and
RT   conventional T cells.";
RL   Int. Immunol. 24:485-494(2012).
RN   [50]
RP   FUNCTION, AND INTERACTION WITH CXCL12.
RX   PubMed=22370717; DOI=10.1084/jem.20111739;
RA   Schiraldi M., Raucci A., Munoz L.M., Livoti E., Celona B., Venereau E.,
RA   Apuzzo T., De Marchis F., Pedotti M., Bachi A., Thelen M., Varani L.,
RA   Mellado M., Proudfoot A., Bianchi M.E., Uguccioni M.;
RT   "HMGB1 promotes recruitment of inflammatory cells to damaged tissues by
RT   forming a complex with CXCL12 and signaling via CXCR4.";
RL   J. Exp. Med. 209:551-563(2012).
RN   [51]
RP   REDOX FORMS, AND SUBCELLULAR LOCATION.
RX   PubMed=22869893; DOI=10.1084/jem.20120189;
RA   Venereau E., Casalgrandi M., Schiraldi M., Antoine D.J., Cattaneo A.,
RA   De Marchis F., Liu J., Antonelli A., Preti A., Raeli L., Shams S.S.,
RA   Yang H., Varani L., Andersson U., Tracey K.J., Bachi A., Uguccioni M.,
RA   Bianchi M.E.;
RT   "Mutually exclusive redox forms of HMGB1 promote cell recruitment or
RT   proinflammatory cytokine release.";
RL   J. Exp. Med. 209:1519-1528(2012).
RN   [52]
RP   ACETYLATION.
RX   PubMed=22801494; DOI=10.1038/nature11290;
RA   Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbaeck P.,
RA   Valdes-Ferrer S.I., Olofsson P.S., Kalb T., Roth J., Zou Y.,
RA   Erlandsson-Harris H., Yang H., Ting J.P., Wang H., Andersson U.,
RA   Antoine D.J., Chavan S.S., Hotamisligil G.S., Tracey K.J.;
RT   "Novel role of PKR in inflammasome activation and HMGB1 release.";
RL   Nature 488:670-674(2012).
RN   [53]
RP   INVOLVEMENT IN CANCER THERAPY.
RX   PubMed=23040637; DOI=10.1016/j.ejca.2012.09.016;
RA   Luo Y., Chihara Y., Fujimoto K., Sasahira T., Kuwada M., Fujiwara R.,
RA   Fujii K., Ohmori H., Kuniyasu H.;
RT   "High mobility group box 1 released from necrotic cells enhances regrowth
RT   and metastasis of cancer cells that have survived chemotherapy.";
RL   Eur. J. Cancer 49:741-751(2013).
RN   [54]
RP   REVIEW ON FUNCTION RELATED TO ADAPTIVE IMMUNITY.
RX   PubMed=23519706; DOI=10.3389/fimmu.2013.00068;
RA   Li G., Liang X., Lotze M.T.;
RT   "HMGB1: The central cytokine for all lymphoid cells.";
RL   Front. Immunol. 4:68-68(2013).
RN   [55]
RP   FUNCTION, AND INTERACTION WITH HTT.
RX   PubMed=23303669; DOI=10.4049/jimmunol.1202472;
RA   Min H.J., Ko E.A., Wu J., Kim E.S., Kwon M.K., Kwak M.S., Choi J.E.,
RA   Lee J.E., Shin J.S.;
RT   "Chaperone-like activity of high-mobility group box 1 protein and its role
RT   in reducing the formation of polyglutamine aggregates.";
RL   J. Immunol. 190:1797-1806(2013).
RN   [56]
RP   REVIEW ON FUNCTION RELATED TO INFLAMMATION.
RX   PubMed=23446148; DOI=10.1189/jlb.1212662;
RA   Yang H., Antoine D.J., Andersson U., Tracey K.J.;
RT   "The many faces of HMGB1: molecular structure-functional activity in
RT   inflammation, apoptosis, and chemotaxis.";
RL   J. Leukoc. Biol. 93:865-873(2013).
RN   [57]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [58]
RP   REVIEW.
RX   PubMed=23994764; DOI=10.1016/j.semcancer.2013.08.002;
RA   Li G., Tang D., Lotze M.T.;
RT   "Menage a Trois in stress: DAMPs, redox and autophagy.";
RL   Semin. Cancer Biol. 23:380-390(2013).
RN   [59]
RP   FUNCTION.
RX   PubMed=24971542; DOI=10.1016/j.bbrc.2014.06.074;
RA   Liu L., Yang M., Kang R., Dai Y., Yu Y., Gao F., Wang H., Sun X., Li X.,
RA   Li J., Wang H., Cao L., Tang D.;
RT   "HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome activation
RT   through RAGE.";
RL   Biochem. Biophys. Res. Commun. 450:851-856(2014).
RN   [60]
RP   FUNCTION, MUTAGENESIS OF ASP-67, INTERACTION WITH AGER, DOMAIN, AND
RP   PROTEOLYTIC CLEAVAGE.
RX   PubMed=24474694; DOI=10.1074/jbc.m113.541474;
RA   LeBlanc P.M., Doggett T.A., Choi J., Hancock M.A., Durocher Y., Frank F.,
RA   Nagar B., Ferguson T.A., Saleh M.;
RT   "An immunogenic peptide in the A-box of HMGB1 protein reverses apoptosis-
RT   induced tolerance through RAGE receptor.";
RL   J. Biol. Chem. 289:7777-7786(2014).
RN   [61]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [62]
RP   NOMENCLATURE OF REDOX FORMS.
RX   PubMed=24531895; DOI=10.2119/molmed.2014.00022;
RA   Antoine D.J., Harris H.E., Andersson U., Tracey K.J., Bianchi M.E.;
RT   "A systematic nomenclature for the redox states of high mobility group box
RT   (HMGB) proteins.";
RL   Mol. Med. 20:135-137(2014).
RN   [63]
RP   REVIEW ON INVOLVEMENT IN DISEASES AND THERAPEUTIC TARGET.
RX   PubMed=24220159; DOI=10.1016/j.pharmthera.2013.11.001;
RA   Musumeci D., Roviello G.N., Montesarchio D.;
RT   "An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-
RT   related pathologies.";
RL   Pharmacol. Ther. 141:347-357(2014).
RN   [64]
RP   FUNCTION.
RX   PubMed=25549101; DOI=10.1371/journal.pone.0115809;
RA   Lee L.C., Chen C.M., Wang P.R., Su M.T., Lee-Chen G.J., Chang C.Y.;
RT   "Role of high mobility group box 1 (HMGB1) in SCA17 pathogenesis.";
RL   PLoS ONE 9:E115809-E115809(2014).
RN   [65]
RP   REVIEW ON FUNCTION RELATED TO INNATE IMMUNITY.
RX   PubMed=25048472; DOI=10.3349/ymj.2014.55.5.1165;
RA   Lee S.A., Kwak M.S., Kim S., Shin J.S.;
RT   "The role of high mobility group box 1 in innate immunity.";
RL   Yonsei Med. J. 55:1165-1176(2014).
RN   [66]
RP   INVOLVEMENT AUTOIMMUNE DISEASES.
RX   PubMed=26078984; DOI=10.1155/2015/946748;
RA   Lu M., Yu S., Xu W., Gao B., Xiong S.;
RT   "HMGB1 promotes systemic lupus erythematosus by enhancing macrophage
RT   inflammatory response.";
RL   J. Immunol. Res. 2015:946748-946748(2015).
RN   [67]
RP   FUNCTION.
RX   PubMed=25660311; DOI=10.1159/000369972;
RA   Kwak M.S., Lim M., Lee Y.J., Lee H.S., Kim Y.H., Youn J.H., Choi J.E.,
RA   Shin J.S.;
RT   "HMGB1 binds to lipoteichoic acid and enhances TNF-alpha and IL-6
RT   production through HMGB1-mediated transfer of lipoteichoic acid to CD14 and
RT   TLR2.";
RL   J. Innate Immun. 7:405-416(2015).
RN   [68]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [69]
RP   FUNCTION, INTERACTION WITH ADENOVIRUS PROTEIN PVII (MICROBIAL INFECTION),
RP   AND SUBCELLULAR LOCATION.
RX   PubMed=27362237; DOI=10.1038/nature18317;
RA   Avgousti D.C., Herrmann C., Kulej K., Pancholi N.J., Sekulic N.,
RA   Petrescu J., Molden R.C., Blumenthal D., Paris A.J., Reyes E.D.,
RA   Ostapchuk P., Hearing P., Seeholzer S.H., Worthen G.S., Black B.E.,
RA   Garcia B.A., Weitzman M.D.;
RT   "A core viral protein binds host nucleosomes to sequester immune danger
RT   signals.";
RL   Nature 535:173-177(2016).
RN   [70]
RP   ADP-RIBOSYLATION AT SER-181.
RX   PubMed=28190768; DOI=10.1016/j.molcel.2017.01.003;
RA   Bonfiglio J.J., Fontana P., Zhang Q., Colby T., Gibbs-Seymour I.,
RA   Atanassov I., Bartlett E., Zaja R., Ahel I., Matic I.;
RT   "Serine ADP-ribosylation depends on HPF1.";
RL   Mol. Cell 0:0-0(2017).
RN   [71]
RP   SUBCELLULAR LOCATION, AND TRANSGLUTAMINATION AT LYS-28; LYS-43; LYS-44;
RP   LYS-68; LYS-177; LYS-180; LYS-182; LYS-183 AND LYS-184.
RX   PubMed=29618516; DOI=10.1074/jbc.ra117.001078;
RA   Willis W.L., Wang L., Wada T.T., Gardner M., Abdouni O., Hampton J.,
RA   Valiente G., Young N., Ardoin S., Agarwal S., Freitas M.A., Wu L.C.,
RA   Jarjour W.N.;
RT   "The proinflammatory protein HMGB1 is a substrate of transglutaminase-2 and
RT   forms high-molecular weight complexes with autoantigens.";
RL   J. Biol. Chem. 293:8394-8409(2018).
RN   [72]
RP   FUNCTION, FUNCTION (MICROBIAL INFECTION), SUBCELLULAR LOCATION, AND
RP   INDUCTION BY SARS-COV2 (MICROBIAL INFECTION).
RX   PubMed=33147444; DOI=10.1016/j.cell.2020.10.028;
RA   Wei J., Alfajaro M.M., DeWeirdt P.C., Hanna R.E., Lu-Culligan W.J.,
RA   Cai W.L., Strine M.S., Zhang S.M., Graziano V.R., Schmitz C.O., Chen J.S.,
RA   Mankowski M.C., Filler R.B., Ravindra N.G., Gasque V., de Miguel F.J.,
RA   Patil A., Chen H., Oguntuyo K.Y., Abriola L., Surovtseva Y.V.,
RA   Orchard R.C., Lee B., Lindenbach B.D., Politi K., van Dijk D., Kadoch C.,
RA   Simon M.D., Yan Q., Doench J.G., Wilen C.B.;
RT   "Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2
RT   Infection.";
RL   Cell 184:76-91.e13(2021).
RN   [73]
RP   FUNCTION, AND INTERACTION WITH AGER.
RX   PubMed=34743181; DOI=10.1038/s41420-021-00729-0;
RA   Wang G., Jin S., Huang W., Li Y., Wang J., Ling X., Huang Y., Hu Y., Li C.,
RA   Meng Y., Li X.;
RT   "LPS-induced macrophage HMGB1-loaded extracellular vesicles trigger
RT   hepatocyte pyroptosis by activating the NLRP3 inflammasome.";
RL   Cell. Death. Discov. 7:337-337(2021).
RN   [74]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=34922257; DOI=10.1016/j.virol.2021.12.002;
RA   Reinhart N.M., Akinyemi I.A., Frey T.R., Xu H., Agudelo C., Brathwaite J.,
RA   Burton E.M., Burgula S., McIntosh M.T., Bhaduri-McIntosh S.;
RT   "The danger molecule HMGB1 cooperates with the NLRP3 inflammasome to
RT   sustain expression of the EBV lytic switch protein in Burkitt lymphoma
RT   cells.";
RL   Virology 566:136-142(2022).
RN   [75]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=36585612; DOI=10.1186/s10020-022-00596-0;
RA   Shin J., Kim Y.H., Lee B., Chang J.H., Choi H.Y., Lee H., Song K.C.,
RA   Kwak M.S., Choi J.E., Shin J.S.;
RT   "USP13 regulates HMGB1 stability and secretion through its deubiquitinase
RT   activity.";
RL   Mol. Med. 28:164-164(2022).
RN   [76]
RP   FUNCTION (MICROBIAL INFECTION), AND SUBCELLULAR LOCATION.
RX   PubMed=34971702; DOI=10.1016/j.virusres.2021.198668;
RA   Chaudhary N., Srivastava S., Dave U., Ojha A., Guchhait P., Chandele A.,
RA   Patel A.K.;
RT   "High-mobility group box 1 protein promotes dengue virus replication by
RT   interacting with untranslated regions of viral genome.";
RL   Virus Res. 309:198668-198668(2022).
RN   [77]
RP   FUNCTION (MICROBIAL INFECTION), INTERACTION WITH SARS-COV-2 ORF3A, AND
RP   SUBCELLULAR LOCATION (MICROBIAL INFECTION).
RX   PubMed=35239449; DOI=10.1080/15548627.2022.2039992;
RA   Zhang X., Yang Z., Pan T., Long X., Sun Q., Wang P.H., Li X., Kuang E.;
RT   "SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulophagy and
RT   triggers sequential ER stress and inflammatory responses during SARS-CoV-2
RT   infection.";
RL   Autophagy 0:0-0(2022).
RN   [78]
RP   STRUCTURE BY NMR OF 1-166.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the tandem HMG box domain from human high mobility
RT   group protein B1.";
RL   Submitted (FEB-2008) to the PDB data bank.
RN   [79]
RP   STRUCTURE BY NMR OF 2-84 IN COMPLEX WITH TP53, FUNCTION, AND DOMAIN.
RX   PubMed=23063560; DOI=10.1016/j.str.2012.09.004;
RA   Rowell J.P., Simpson K.L., Stott K., Watson M., Thomas J.O.;
RT   "HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 transactivation
RT   domain interaction, regulated by the acidic tail.";
RL   Structure 20:2014-2024(2012).
RN   [80]
RP   STRUCTURE BY NMR OF 1-84.
RX   PubMed=24427810; DOI=10.1016/j.bbrc.2013.10.085;
RA   Wang J., Tochio N., Takeuchi A., Uewaki J., Kobayashi N., Tate S.;
RT   "Redox-sensitive structural change in the A-domain of HMGB1 and its
RT   implication for the binding to cisplatin modified DNA.";
RL   Biochem. Biophys. Res. Commun. 441:701-706(2013).
CC   -!- FUNCTION: Multifunctional redox sensitive protein with various roles in
CC       different cellular compartments. In the nucleus is one of the major
CC       chromatin-associated non-histone proteins and acts as a DNA chaperone
CC       involved in replication, transcription, chromatin remodeling, V(D)J
CC       recombination, DNA repair and genome stability (PubMed:33147444).
CC       Proposed to be an universal biosensor for nucleic acids. Promotes host
CC       inflammatory response to sterile and infectious signals and is involved
CC       in the coordination and integration of innate and adaptive immune
CC       responses. In the cytoplasm functions as a sensor and/or chaperone for
CC       immunogenic nucleic acids implicating the activation of TLR9-mediated
CC       immune responses, and mediates autophagy. Acts as a danger-associated
CC       molecular pattern (DAMP) molecule that amplifies immune responses
CC       during tissue injury (PubMed:27362237). Released to the extracellular
CC       environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform
CC       2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and
CC       activates cells through engagement of multiple surface receptors
CC       (PubMed:34743181). In the extracellular compartment fully reduced HMGB1
CC       (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively
CC       secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic
CC       cells) promotes immunological tolerance (PubMed:23446148,
CC       PubMed:23519706, PubMed:23994764, PubMed:25048472). Has proangiogdenic
CC       activity (By similarity). May be involved in platelet activation (By
CC       similarity). Binds to phosphatidylserine and phosphatidylethanolamide
CC       (By similarity). Bound to RAGE mediates signaling for neuronal
CC       outgrowth (By similarity). May play a role in accumulation of expanded
CC       polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP
CC       (PubMed:23303669, PubMed:25549101). {ECO:0000250|UniProtKB:P10103,
CC       ECO:0000250|UniProtKB:P12682, ECO:0000250|UniProtKB:P63158,
CC       ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:23303669,
CC       ECO:0000269|PubMed:25549101, ECO:0000269|PubMed:27362237,
CC       ECO:0000269|PubMed:33147444, ECO:0000269|PubMed:34743181,
CC       ECO:0000305|PubMed:23446148, ECO:0000305|PubMed:23519706,
CC       ECO:0000305|PubMed:23994764, ECO:0000305|PubMed:25048472}.
CC   -!- FUNCTION: Nuclear functions are attributed to fully reduced HGMB1.
CC       Associates with chromatin and binds DNA with a preference to non-
CC       canonical DNA structures such as single-stranded DNA, DNA-containing
CC       cruciforms or bent structures, supercoiled DNA and ZDNA. Can bent DNA
CC       and enhance DNA flexibility by looping thus providing a mechanism to
CC       promote activities on various gene promoters by enhancing transcription
CC       factor binding and/or bringing distant regulatory sequences into close
CC       proximity (PubMed:20123072). May have an enhancing role in nucleotide
CC       excision repair (NER) (By similarity). However, effects in NER using in
CC       vitro systems have been reported conflictingly (PubMed:19360789,
CC       PubMed:19446504). May be involved in mismatch repair (MMR) and base
CC       excision repair (BER) pathways (PubMed:15014079, PubMed:16143102,
CC       PubMed:17803946). May be involved in double strand break repair such as
CC       non-homologous end joining (NHEJ) (By similarity). Involved in V(D)J
CC       recombination by acting as a cofactor of the RAG complex: acts by
CC       stimulating cleavage and RAG protein binding at the 23 bp spacer of
CC       conserved recombination signal sequences (RSS) (By similarity). In
CC       vitro can displace histone H1 from highly bent DNA (By similarity). Can
CC       restructure the canonical nucleosome leading to relaxation of
CC       structural constraints for transcription factor-binding (By
CC       similarity). Enhances binding of sterol regulatory element-binding
CC       proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and
CC       increases their transcriptional activities (By similarity). Facilitates
CC       binding of TP53 to DNA (PubMed:23063560). Proposed to be involved in
CC       mitochondrial quality control and autophagy in a transcription-
CC       dependent fashion implicating HSPB1; however, this function has been
CC       questioned (By similarity). Can modulate the activity of the telomerase
CC       complex and may be involved in telomere maintenance (By similarity).
CC       {ECO:0000250|UniProtKB:P10103, ECO:0000250|UniProtKB:P63158,
CC       ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:15014079,
CC       ECO:0000269|PubMed:16143102, ECO:0000269|PubMed:17803946,
CC       ECO:0000269|PubMed:19446504, ECO:0000269|PubMed:23063560,
CC       ECO:0000305|PubMed:19360789, ECO:0000305|PubMed:20123072}.
CC   -!- FUNCTION: In the cytoplasm proposed to dissociate the BECN1:BCL2
CC       complex via competitive interaction with BECN1 leading to autophagy
CC       activation (PubMed:20819940). Involved in oxidative stress-mediated
CC       autophagy (PubMed:21395369). Can protect BECN1 and ATG5 from calpain-
CC       mediated cleavage and thus proposed to control their proautophagic and
CC       proapoptotic functions and to regulate the extent and severity of
CC       inflammation-associated cellular injury (By similarity). In myeloid
CC       cells has a protective role against endotoxemia and bacterial infection
CC       by promoting autophagy (By similarity). Involved in endosomal
CC       translocation and activation of TLR9 in response to CpG-DNA in
CC       macrophages (By similarity). {ECO:0000250|UniProtKB:P63158,
CC       ECO:0000269|PubMed:20819940, ECO:0000269|PubMed:21395369}.
CC   -!- FUNCTION: In the extracellular compartment (following either active
CC       secretion or passive release) involved in regulation of the
CC       inflammatory response. Fully reduced HGMB1 (which subsequently gets
CC       oxidized after release) in association with CXCL12 mediates the
CC       recruitment of inflammatory cells during the initial phase of tissue
CC       injury; the CXCL12:HMGB1 complex triggers CXCR4 homodimerization
CC       (PubMed:22370717). Induces the migration of monocyte-derived immature
CC       dendritic cells and seems to regulate adhesive and migratory functions
CC       of neutrophils implicating AGER/RAGE and ITGAM (By similarity). Can
CC       bind to various types of DNA and RNA including microbial unmethylated
CC       CpG-DNA to enhance the innate immune response to nucleic acids.
CC       Proposed to act in promiscuous DNA/RNA sensing which cooperates with
CC       subsequent discriminative sensing by specific pattern recognition
CC       receptors (By similarity). Promotes extracellular DNA-induced AIM2
CC       inflammasome activation implicating AGER/RAGE (PubMed:24971542).
CC       Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE,
CC       TLR2, TLR4 and probably TREM1, thus activating their signal
CC       transduction pathways. Mediates the release of cytokines/chemokines
CC       such as TNF, IL-1, IL-6, IL-8, CCL2, CCL3, CCL4 and CXCL10
CC       (PubMed:12765338, PubMed:18354232, PubMed:19264983, PubMed:20547845,
CC       PubMed:24474694). Promotes secretion of interferon-gamma by macrophage-
CC       stimulated natural killer (NK) cells in concert with other cytokines
CC       like IL-2 or IL-12 (PubMed:15607795). TLR4 is proposed to be the
CC       primary receptor promoting macrophage activation and signaling through
CC       TLR4 seems to implicate LY96/MD-2 (PubMed:20547845). In bacterial
CC       LPS- or LTA-mediated inflammatory responses binds to the endotoxins and
CC       transfers them to CD14 for signaling to the respective TLR4:LY96 and
CC       TLR2 complexes (PubMed:18354232, PubMed:21660935, PubMed:25660311).
CC       Contributes to tumor proliferation by association with ACER/RAGE (By
CC       similarity). Can bind to IL1-beta and signals through the IL1R1:IL1RAP
CC       receptor complex (PubMed:18250463). Binding to class A CpG activates
CC       cytokine production in plasmacytoid dendritic cells implicating TLR9,
CC       MYD88 and AGER/RAGE and can activate autoreactive B cells. Via HMGB1-
CC       containing chromatin immune complexes may also promote B cell responses
CC       to endogenous TLR9 ligands through a B-cell receptor (BCR)-dependent
CC       and ACER/RAGE-independent mechanism (By similarity). Inhibits
CC       phagocytosis of apoptotic cells by macrophages; the function is
CC       dependent on poly-ADP-ribosylation and involves binding to
CC       phosphatidylserine on the cell surface of apoptotic cells (By
CC       similarity). In adaptive immunity may be involved in enhancing immunity
CC       through activation of effector T cells and suppression of regulatory T
CC       (TReg) cells (PubMed:15944249, PubMed:22473704). In contrast, without
CC       implicating effector or regulatory T-cells, required for tumor
CC       infiltration and activation of T-cells expressing the lymphotoxin
CC       LTA:LTB heterotrimer thus promoting tumor malignant progression (By
CC       similarity). Also reported to limit proliferation of T-cells (By
CC       similarity). Released HMGB1:nucleosome complexes formed during
CC       apoptosis can signal through TLR2 to induce cytokine production
CC       (PubMed:19064698). Involved in induction of immunological tolerance by
CC       apoptotic cells; its pro-inflammatory activities when released by
CC       apoptotic cells are neutralized by reactive oxygen species (ROS)-
CC       dependent oxidation specifically on Cys-106 (PubMed:18631454). During
CC       macrophage activation by activated lymphocyte-derived self apoptotic
CC       DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes (By
CC       similarity). {ECO:0000250|UniProtKB:P10103,
CC       ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159,
CC       ECO:0000269|PubMed:12765338, ECO:0000269|PubMed:15607795,
CC       ECO:0000269|PubMed:15944249, ECO:0000269|PubMed:18250463,
CC       ECO:0000269|PubMed:18354232, ECO:0000269|PubMed:18631454,
CC       ECO:0000269|PubMed:19064698, ECO:0000269|PubMed:19264983,
CC       ECO:0000269|PubMed:20547845, ECO:0000269|PubMed:21660935,
CC       ECO:0000269|PubMed:22370717, ECO:0000269|PubMed:22473704,
CC       ECO:0000269|PubMed:24474694, ECO:0000269|PubMed:24971542,
CC       ECO:0000269|PubMed:25660311, ECO:0000269|Ref.8}.
CC   -!- FUNCTION: (Microbial infection) Critical for entry of human
CC       coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus
CC       NL63/HCoV-NL63 (PubMed:33147444). Regulates the expression of the pro-
CC       viral genes ACE2 and CTSL through chromatin modulation
CC       (PubMed:33147444). Required for SARS-CoV-2 ORF3A-induced reticulophagy
CC       which induces endoplasmic reticulum stress and inflammatory responses
CC       and facilitates viral infection (PubMed:35239449).
CC       {ECO:0000269|PubMed:33147444, ECO:0000269|PubMed:35239449}.
CC   -!- FUNCTION: (Microbial infection) Associates with the influenza A viral
CC       protein NP in the nucleus of infected cells, promoting viral growth and
CC       enhancing the activity of the viral polymerase.
CC       {ECO:0000269|PubMed:22696656}.
CC   -!- FUNCTION: (Microbial infection) Promotes Epstein-Barr virus (EBV)
CC       latent-to-lytic switch by sustaining the expression of the viral
CC       transcription factor BZLF1 that acts as a molecular switch to induce
CC       the transition from the latent to the lytic or productive phase of the
CC       virus cycle. Mechanistically, participates in EBV reactivation through
CC       the NLRP3 inflammasome. {ECO:0000269|PubMed:34922257}.
CC   -!- FUNCTION: (Microbial infection) Facilitates dengue virus propagation
CC       via interaction with the untranslated regions of viral genome. In turn,
CC       this interaction with viral RNA may regulate secondary structure of
CC       dengue RNA thus facilitating its recognition by the replication
CC       complex. {ECO:0000269|PubMed:34971702}.
CC   -!- SUBUNIT: Interacts (fully reduced HMGB1) with CXCL12; probably in a 1:2
CC       ratio involving two molecules of CXCL12, each interacting with one HMG
CC       box of HMGB1; inhibited by glycyrrhizin (PubMed:22370717). Associates
CC       with the TLR4:LY96 receptor complex (PubMed:20547845). Component of the
CC       RAG complex composed of core components RAG1 and RAG2, and associated
CC       component HMGB1 or HMGB2 (By similarity). Interacts (in cytoplasm upon
CC       starvation) with BECN1; inhibits the interaction of BECN1 and BCL2
CC       leading to promotion of autophagy (PubMed:20819940). Interacts with
CC       KPNA1; involved in nuclear import (PubMed:17114460). Interacts with
CC       SREBF1, TLR2, TLR4, TLR9, PTPRZ1, APEX1, FEN1, POLB, TERT (By
CC       similarity). Interacts with IL1B, AGER, MSH2, XPA, XPC, HNF1A, TP53
CC       (PubMed:15014079, PubMed:18160415, PubMed:18250463, PubMed:19446504,
CC       PubMed:23063560, PubMed:24474694). Interacts with CD24; the probable
CC       CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue
CC       damage immune response (PubMed:19264983). Interacts with THBD; prevents
CC       HGMB1 interaction with ACER/RAGE and inhibits HGMB1 pro-inflammatory
CC       activity (PubMed:15841214). Interacts with HAVCR2; impairs HMGB1
CC       binding to B-DNA and likely HMGB1-mediated innate immune response (By
CC       similarity). Interacts with XPO1; mediating nuclear export (By
CC       similarity). Interacts with HTT (wild-type and mutant HTT with expanded
CC       polyglutamine repeat) (PubMed:23303669). Interacts with receptor
CC       RAGE/AGER (PubMed:34743181). {ECO:0000250|UniProtKB:P63158,
CC       ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:15014079,
CC       ECO:0000269|PubMed:15841214, ECO:0000269|PubMed:17114460,
CC       ECO:0000269|PubMed:17803946, ECO:0000269|PubMed:18160415,
CC       ECO:0000269|PubMed:18250463, ECO:0000269|PubMed:19264983,
CC       ECO:0000269|PubMed:19446504, ECO:0000269|PubMed:20547845,
CC       ECO:0000269|PubMed:20819940, ECO:0000269|PubMed:22370717,
CC       ECO:0000269|PubMed:23063560, ECO:0000269|PubMed:23303669,
CC       ECO:0000269|PubMed:24474694, ECO:0000269|PubMed:34743181}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with adenovirus protein pVII;
CC       this interaction immobilizes HMGB1 on chromatin, thus preventing its
CC       release from cell and subsequent inflammation activation.
CC       {ECO:0000269|PubMed:27362237}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with SARS-CoV-2 ORF3A protein;
CC       the interaction promotes association of HMGB1 with BECN1, promoting
CC       reticulophagy which induces endoplasmic reticulum stress and
CC       inflammatory responses and facilitates viral infection.
CC       {ECO:0000269|PubMed:35239449}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with influenza A virus protein
CC       NP; this interaction promotes viral replication.
CC       {ECO:0000269|PubMed:22696656}.
CC   -!- INTERACTION:
CC       P09429; Q15109: AGER; NbExp=3; IntAct=EBI-389432, EBI-1646426;
CC       P09429; Q6RW13: AGTRAP; NbExp=3; IntAct=EBI-389432, EBI-741181;
CC       P09429; P05067: APP; NbExp=3; IntAct=EBI-389432, EBI-77613;
CC       P09429; Q14457: BECN1; NbExp=2; IntAct=EBI-389432, EBI-949378;
CC       P09429; O95273: CCNDBP1; NbExp=3; IntAct=EBI-389432, EBI-748961;
CC       P09429; Q00839: HNRNPU; NbExp=3; IntAct=EBI-389432, EBI-351126;
CC       P09429; P42858: HTT; NbExp=13; IntAct=EBI-389432, EBI-466029;
CC       P09429; P08729: KRT7; NbExp=6; IntAct=EBI-389432, EBI-297833;
CC       P09429; P43246: MSH2; NbExp=2; IntAct=EBI-389432, EBI-355888;
CC       P09429; P09874: PARP1; NbExp=2; IntAct=EBI-389432, EBI-355676;
CC       P09429; Q96T23: RSF1; NbExp=3; IntAct=EBI-389432, EBI-926768;
CC       P09429; P23497: SP100; NbExp=3; IntAct=EBI-389432, EBI-751145;
CC       P09429; P84103: SRSF3; NbExp=3; IntAct=EBI-389432, EBI-372557;
CC       P09429; P04637: TP53; NbExp=9; IntAct=EBI-389432, EBI-366083;
CC       P09429; Q96B54: ZNF428; NbExp=3; IntAct=EBI-389432, EBI-9995882;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12231511,
CC       ECO:0000269|PubMed:17114460, ECO:0000269|PubMed:20819940,
CC       ECO:0000269|PubMed:22696656, ECO:0000269|PubMed:22869893,
CC       ECO:0000269|PubMed:27362237, ECO:0000269|PubMed:29618516,
CC       ECO:0000269|PubMed:33147444}. Chromosome {ECO:0000250|UniProtKB:P10103,
CC       ECO:0000250|UniProtKB:P63159, ECO:0000305}. Cytoplasm
CC       {ECO:0000269|PubMed:11154118, ECO:0000269|PubMed:12231511,
CC       ECO:0000269|PubMed:17114460, ECO:0000269|PubMed:20819940,
CC       ECO:0000269|PubMed:22869893, ECO:0000269|PubMed:29618516,
CC       ECO:0000269|PubMed:33147444, ECO:0000269|PubMed:34971702}. Secreted
CC       {ECO:0000250|UniProtKB:P63158, ECO:0000269|PubMed:12231511,
CC       ECO:0000269|PubMed:14532127, ECO:0000269|PubMed:15944249,
CC       ECO:0000269|PubMed:19811284, ECO:0000269|PubMed:22869893,
CC       ECO:0000269|PubMed:33147444}. Cell membrane
CC       {ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159,
CC       ECO:0000269|PubMed:11154118}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159,
CC       ECO:0000269|PubMed:11154118}; Extracellular side
CC       {ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159,
CC       ECO:0000269|PubMed:11154118}. Endosome {ECO:0000250|UniProtKB:P63158}.
CC       Endoplasmic reticulum-Golgi intermediate compartment
CC       {ECO:0000250|UniProtKB:P63158}. Note=In basal state predominantly
CC       nuclear. Shuttles between the cytoplasm and the nucleus
CC       (PubMed:12231511, PubMed:17114460). Translocates from the nucleus to
CC       the cytoplasm upon autophagy stimulation (PubMed:20819940). Release
CC       from macrophages in the extracellular milieu requires the activation of
CC       NLRC4 or NLRP3 inflammasomes (By similarity). Passively released to the
CC       extracellular milieu from necrotic cells by diffusion, involving the
CC       fully reduced HGMB1 which subsequently gets oxidized (PubMed:19811284).
CC       Also released from apoptotic cells (PubMed:16855214, PubMed:18631454).
CC       Active secretion from a variety of immune and non-immune cells such as
CC       macrophages, monocytes, neutrophils, dendritic cells and natural killer
CC       cells in response to various stimuli such as LPS and cytokines involves
CC       a nonconventional secretory process via secretory lysosomes
CC       (PubMed:12231511, PubMed:14532127, PubMed:15944249). Secreted by plasma
CC       cells in response to LPS (By similarity). Found on the surface of
CC       activated platelets (PubMed:11154118). An increased chromatin
CC       association is observed when associated with the adenovirus protein
CC       pVII (PubMed:27362237). {ECO:0000250|UniProtKB:P63158,
CC       ECO:0000269|PubMed:11154118, ECO:0000269|PubMed:12231511,
CC       ECO:0000269|PubMed:14532127, ECO:0000269|PubMed:15944249,
CC       ECO:0000269|PubMed:16855214, ECO:0000269|PubMed:17114460,
CC       ECO:0000269|PubMed:18631454, ECO:0000269|PubMed:19811284,
CC       ECO:0000269|PubMed:20819940, ECO:0000269|PubMed:27362237,
CC       ECO:0000305|PubMed:20123072}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC       {ECO:0000269|PubMed:35239449}. Note=(Microbial infection) SARS-COV-2
CC       ORF3A promotes HMGB1 translocation from the nucleus to the cytoplasm
CC       where it is recruited by and colocalizes with ORF3A at the endoplasmic
CC       reticulum. {ECO:0000269|PubMed:35239449}.
CC   -!- TISSUE SPECIFICITY: Ubiquitous. Expressed in platelets
CC       (PubMed:11154118). {ECO:0000269|PubMed:11154118}.
CC   -!- INDUCTION: (Microbial infection) Protein levels increase upon infection
CC       by human coronavirus SARS-CoV-2. {ECO:0000269|PubMed:33147444}.
CC   -!- DOMAIN: HMG box 2 mediates pro-inflammatory cytokine-stimulating
CC       activity and binding to TLR4 (PubMed:12765338, PubMed:20547845).
CC       However, not involved in mediating immunogenic activity in the context
CC       of apoptosis-induced immune tolerance (PubMed:24474694).
CC       {ECO:0000269|PubMed:12765338, ECO:0000269|PubMed:20547845,
CC       ECO:0000269|PubMed:24474694}.
CC   -!- DOMAIN: The acidic C-terminal domain forms a flexible structure which
CC       can reversibly interact intramolecularily with the HMG boxes and
CC       modulate binding to DNA and other proteins (PubMed:23063560).
CC       {ECO:0000250|UniProtKB:P63159, ECO:0000305|PubMed:23063560}.
CC   -!- PTM: Phosphorylated at serine residues. Phosphorylation in both NLS
CC       regions is required for cytoplasmic translocation followed by secretion
CC       (PubMed:17114460). {ECO:0000269|PubMed:17114460}.
CC   -!- PTM: Acetylated on multiple sites upon stimulation with LPS
CC       (PubMed:22801494). Acetylation on lysine residues in the nuclear
CC       localization signals (NLS 1 and NLS 2) leads to cytoplasmic
CC       localization and subsequent secretion (By similarity). Acetylation on
CC       Lys-3 results in preferential binding to DNA ends and impairs DNA
CC       bending activity (By similarity). {ECO:0000250|UniProtKB:P10103,
CC       ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:22801494}.
CC   -!- PTM: Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys-
CC       106 and a possible intramolecular disulfide bond involving Cys-23 and
CC       Cys-45 give rise to different redox forms with specific functional
CC       activities in various cellular compartments: 1- fully reduced HMGB1
CC       (HMGB1C23hC45hC106h), 2- disulfide HMGB1 (HMGB1C23-C45C106h) and
CC       3- sulfonyl HMGB1 (HMGB1C23soC45soC106so).
CC       {ECO:0000269|PubMed:16962095, ECO:0000269|PubMed:19811284,
CC       ECO:0000269|PubMed:22869893, ECO:0000305|PubMed:24531895}.
CC   -!- PTM: Poly-ADP-ribosylated by PARP1 when secreted following stimulation
CC       with LPS (By similarity). {ECO:0000250|UniProtKB:P63158}.
CC   -!- PTM: In vitro cleavage by CASP1 is liberating a HMG box 1-containing
CC       peptide which may mediate immunogenic activity; the peptide antagonizes
CC       apoptosis-induced immune tolerance (PubMed:24474694). Can be
CC       proteolytically cleaved by a thrombin:thrombomodulin complex; reduces
CC       binding to heparin and pro-inflammatory activities (By similarity).
CC       {ECO:0000250|UniProtKB:P10103, ECO:0000269|PubMed:24474694}.
CC   -!- PTM: Forms covalent cross-links mediated by transglutaminase TGM2,
CC       between a glutamine and the epsilon-amino group of a lysine residue,
CC       forming homopolymers and heteropolymers. {ECO:0000269|PubMed:29618516}.
CC   -!- MISCELLANEOUS: Proposed to contribute to the pathogenesis of various
CC       chronic inflammatory and autoimmune diseases, and cancer. High serum
CC       levels are found in several inflammatory events including sepsis,
CC       rheumatoid arthritis, artherosclerosis chronic kidney disease, systemic
CC       lupus erythematosus (SLE). Seems to be implicated in other diseases
CC       characterized by cell death and damage, including diabetes and
CC       Alzheimer's disease. Its nucleosome-associated release during secondary
CC       necrosis may play a role in SLE (PubMed:19064698). During chemotherapy
CC       can mediate regrowth and metastasis of remaining cells in a AGER/RAGE-
CC       dependent manner (PubMed:23040637). Purified HMG box 1 acts as a
CC       specific antagonist to HGMB1 pro-inflammatory activities
CC       (PubMed:14695889). {ECO:0000269|PubMed:14695889,
CC       ECO:0000269|PubMed:23040637, ECO:0000305, ECO:0000305|PubMed:19064698,
CC       ECO:0000305|PubMed:24220159, ECO:0000305|PubMed:26078984}.
CC   -!- SIMILARITY: Belongs to the HMGB family. {ECO:0000305}.
CC   -!- CAUTION: Inconsistent experimental results may reflect the use of
CC       inconsistently defined redox forms. A recombinant fully reduced form
CC       has been used in a number of experiments. However, the redox states of
CC       HMGB1 administered in vivo, may interconvert among each other. Purified
CC       HMGB1 by itself has only weak pro-inflammatory activity. {ECO:0000305}.
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DR   EMBL; X12597; CAA31110.1; -; mRNA.
DR   EMBL; U51677; AAB08987.1; -; Genomic_DNA.
DR   EMBL; D63874; BAA09924.1; -; mRNA.
DR   EMBL; EF157968; ABM47301.1; -; Genomic_DNA.
DR   EMBL; AY377859; AAQ91389.1; -; mRNA.
DR   EMBL; AK291494; BAF84183.1; -; mRNA.
DR   EMBL; AK122825; BAG53745.1; -; mRNA.
DR   EMBL; CR749614; CAH18408.1; -; mRNA.
DR   EMBL; CR456863; CAG33144.1; -; mRNA.
DR   EMBL; BT006940; AAP35586.1; -; mRNA.
DR   EMBL; BT020159; AAV38961.1; -; mRNA.
DR   EMBL; EU012027; ABS29271.1; -; Genomic_DNA.
DR   EMBL; AL353648; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471075; EAX08457.1; -; Genomic_DNA.
DR   EMBL; BC003378; AAH03378.1; -; mRNA.
DR   EMBL; BC030981; AAH30981.1; -; mRNA.
DR   EMBL; BC066889; AAH66889.1; -; mRNA.
DR   EMBL; BC067732; AAH67732.1; -; mRNA.
DR   EMBL; BC141844; AAI41845.1; -; mRNA.
DR   CCDS; CCDS9335.1; -.
DR   PIR; S02826; S02826.
DR   RefSeq; NP_001300821.1; NM_001313892.2.
DR   RefSeq; NP_001300822.1; NM_001313893.1.
DR   RefSeq; NP_001357269.1; NM_001370340.1.
DR   RefSeq; NP_001357270.1; NM_001370341.1.
DR   RefSeq; NP_002119.1; NM_002128.7.
DR   RefSeq; XP_024305109.1; XM_024449341.2.
DR   RefSeq; XP_054230460.1; XM_054374485.1.
DR   PDB; 2LY4; NMR; -; A=2-84.
DR   PDB; 2RTU; NMR; -; A=1-84.
DR   PDB; 2YRQ; NMR; -; A=1-166.
DR   PDB; 6CG0; EM; 3.17 A; N=15-140.
DR   PDB; 6CIJ; EM; 3.90 A; N=1-163.
DR   PDB; 6CIK; X-ray; 3.15 A; N=1-163.
DR   PDB; 6CIL; X-ray; 4.15 A; N=1-163.
DR   PDB; 6CIM; X-ray; 3.60 A; N=1-163.
DR   PDB; 6OEM; EM; 3.60 A; H/N=15-155.
DR   PDB; 6OEN; EM; 4.30 A; H/N=1-163.
DR   PDB; 6OEO; EM; 3.69 A; N=1-163.
DR   PDB; 8I9M; EM; 5.19 A; A=89-163.
DR   PDB; 9CG9; EM; 2.94 A; K=1-215.
DR   PDBsum; 2LY4; -.
DR   PDBsum; 2RTU; -.
DR   PDBsum; 2YRQ; -.
DR   PDBsum; 6CG0; -.
DR   PDBsum; 6CIJ; -.
DR   PDBsum; 6CIK; -.
DR   PDBsum; 6CIL; -.
DR   PDBsum; 6CIM; -.
DR   PDBsum; 6OEM; -.
DR   PDBsum; 6OEN; -.
DR   PDBsum; 6OEO; -.
DR   PDBsum; 8I9M; -.
DR   PDBsum; 9CG9; -.
DR   AlphaFoldDB; P09429; -.
DR   BMRB; P09429; -.
DR   EMDB; EMD-20030; -.
DR   EMDB; EMD-20031; -.
DR   EMDB; EMD-20032; -.
DR   EMDB; EMD-35276; -.
DR   EMDB; EMD-45578; -.
DR   EMDB; EMD-7470; -.
DR   EMDB; EMD-7480; -.
DR   PCDDB; P09429; -.
DR   SMR; P09429; -.
DR   BioGRID; 109389; 481.
DR   CORUM; P09429; -.
DR   DIP; DIP-24195N; -.
DR   FunCoup; P09429; 1876.
DR   IntAct; P09429; 280.
DR   MINT; P09429; -.
DR   STRING; 9606.ENSP00000345347; -.
DR   BindingDB; P09429; -.
DR   ChEMBL; CHEMBL2311236; -.
DR   DrugBank; DB00608; Chloroquine.
DR   DrugBank; DB05869; Ethyl pyruvate.
DR   DrugCentral; P09429; -.
DR   GuidetoPHARMACOLOGY; 3279; -.
DR   MoonProt; P09429; -.
DR   GlyCosmos; P09429; 2 sites, 1 glycan.
DR   GlyGen; P09429; 6 sites, 3 N-linked glycans (2 sites), 1 O-linked glycan (3 sites).
DR   iPTMnet; P09429; -.
DR   MetOSite; P09429; -.
DR   PhosphoSitePlus; P09429; -.
DR   SwissPalm; P09429; -.
DR   BioMuta; HMGB1; -.
DR   DMDM; 123369; -.
DR   jPOST; P09429; -.
DR   MassIVE; P09429; -.
DR   PaxDb; 9606-ENSP00000345347; -.
DR   PeptideAtlas; P09429; -.
DR   ProteomicsDB; 52217; -.
DR   Pumba; P09429; -.
DR   TopDownProteomics; P09429; -.
DR   ABCD; P09429; 24 sequenced antibodies.
DR   Antibodypedia; 3132; 1697 antibodies from 47 providers.
DR   CPTC; P09429; 1 antibody.
DR   DNASU; 3146; -.
DR   Ensembl; ENST00000339872.8; ENSP00000343040.4; ENSG00000189403.16.
DR   Ensembl; ENST00000341423.10; ENSP00000345347.5; ENSG00000189403.16.
DR   Ensembl; ENST00000399494.5; ENSP00000382417.1; ENSG00000189403.16.
DR   Ensembl; ENST00000405805.5; ENSP00000384678.1; ENSG00000189403.16.
DR   GeneID; 3146; -.
DR   KEGG; hsa:3146; -.
DR   MANE-Select; ENST00000341423.10; ENSP00000345347.5; NM_002128.7; NP_002119.1.
DR   UCSC; uc001usx.5; human.
DR   AGR; HGNC:4983; -.
DR   ClinPGx; PA188; -.
DR   CTD; 3146; -.
DR   DisGeNET; 3146; -.
DR   GeneCards; HMGB1; -.
DR   HGNC; HGNC:4983; HMGB1.
DR   HPA; ENSG00000189403; Low tissue specificity.
DR   MalaCards; HMGB1; -.
DR   MIM; 163905; gene.
DR   OpenTargets; ENSG00000189403; -.
DR   VEuPathDB; HostDB:ENSG00000189403; -.
DR   eggNOG; KOG0381; Eukaryota.
DR   GeneTree; ENSGT00950000183120; -.
DR   InParanoid; P09429; -.
DR   OMA; PHSANEV; -.
DR   OrthoDB; 9484645at2759; -.
DR   PAN-GO; P09429; 2 GO annotations based on evolutionary models.
DR   PhylomeDB; P09429; -.
DR   PathwayCommons; P09429; -.
DR   Reactome; R-HSA-1236974; ER-Phagosome pathway.
DR   Reactome; R-HSA-140342; Apoptosis induced DNA fragmentation.
DR   Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR   Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR   Reactome; R-HSA-5602498; MyD88 deficiency (TLR2/4).
DR   Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4).
DR   Reactome; R-HSA-5620971; Pyroptosis.
DR   Reactome; R-HSA-5686938; Regulation of TLR by endogenous ligand.
DR   Reactome; R-HSA-6798695; Neutrophil degranulation.
DR   Reactome; R-HSA-879415; Advanced glycosylation endproduct receptor signaling.
DR   Reactome; R-HSA-933542; TRAF6 mediated NF-kB activation.
DR   SignaLink; P09429; -.
DR   SIGNOR; P09429; -.
DR   Agora; ENSG00000189403; -.
DR   BioGRID-ORCS; 3146; 313 hits in 1115 CRISPR screens.
DR   CD-CODE; 91857CE7; Nucleolus.
DR   ChiTaRS; HMGB1; human.
DR   EvolutionaryTrace; P09429; -.
DR   GeneWiki; HMGB1; -.
DR   GenomeRNAi; 3146; -.
DR   Pharos; P09429; Tchem.
DR   PRO; PR:P09429; -.
DR   Proteomes; UP000005640; Chromosome 13.
DR   RNAct; P09429; protein.
DR   Bgee; ENSG00000189403; Expressed in ventricular zone and 181 other cell types or tissues.
DR   ExpressionAtlas; P09429; baseline and differential.
DR   GO; GO:0035868; C:alphav-beta3 integrin-HMGB1 complex; IDA:BHF-UCL.
DR   GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR   GO; GO:0000793; C:condensed chromosome; IDA:UniProtKB.
DR   GO; GO:0005769; C:early endosome; IEA:Ensembl.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR   GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome.
DR   GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0034774; C:secretory granule lumen; TAS:Reactome.
DR   GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB.
DR   GO; GO:0000405; F:bubble DNA binding; ISS:AgBase.
DR   GO; GO:0019958; F:C-X-C chemokine binding; IDA:UniProtKB.
DR   GO; GO:0010858; F:calcium-dependent protein kinase regulator activity; IEA:Ensembl.
DR   GO; GO:0042056; F:chemoattractant activity; ISS:UniProtKB.
DR   GO; GO:0005125; F:cytokine activity; ISS:UniProtKB.
DR   GO; GO:0003684; F:damaged DNA binding; IDA:UniProtKB.
DR   GO; GO:0008301; F:DNA binding, bending; IMP:UniProtKB.
DR   GO; GO:0070182; F:DNA polymerase binding; IDA:UniProtKB.
DR   GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB.
DR   GO; GO:0003690; F:double-stranded DNA binding; ISS:UniProtKB.
DR   GO; GO:0003725; F:double-stranded RNA binding; IEA:Ensembl.
DR   GO; GO:0000400; F:four-way junction DNA binding; ISS:AgBase.
DR   GO; GO:0005178; F:integrin binding; IDA:BHF-UCL.
DR   GO; GO:0001530; F:lipopolysaccharide binding; IDA:UniProtKB.
DR   GO; GO:0016829; F:lyase activity; IDA:UniProtKB.
DR   GO; GO:0001786; F:phosphatidylserine binding; IDA:UniProtKB.
DR   GO; GO:0030295; F:protein kinase activator activity; IEA:Ensembl.
DR   GO; GO:0050786; F:RAGE receptor binding; ISS:UniProtKB.
DR   GO; GO:0048018; F:receptor ligand activity; IDA:UniProt.
DR   GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR   GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB.
DR   GO; GO:0003697; F:single-stranded DNA binding; ISS:UniProtKB.
DR   GO; GO:0003727; F:single-stranded RNA binding; IEA:Ensembl.
DR   GO; GO:0097100; F:supercoiled DNA binding; ISS:AgBase.
DR   GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR   GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR   GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB.
DR   GO; GO:0002218; P:activation of innate immune response; IDA:UniProtKB.
DR   GO; GO:0043277; P:apoptotic cell clearance; IDA:UniProtKB.
DR   GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR   GO; GO:0006284; P:base-excision repair; IEA:Ensembl.
DR   GO; GO:0098761; P:cellular response to interleukin-7; IEA:Ensembl.
DR   GO; GO:0071222; P:cellular response to lipopolysaccharide; ISS:ARUK-UCL.
DR   GO; GO:0006338; P:chromatin remodeling; IBA:GO_Central.
DR   GO; GO:0002407; P:dendritic cell chemotaxis; ISS:UniProtKB.
DR   GO; GO:0032392; P:DNA geometric change; ISS:AgBase.
DR   GO; GO:0006310; P:DNA recombination; ISS:UniProtKB.
DR   GO; GO:0006265; P:DNA topological change; ISS:UniProtKB.
DR   GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR   GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; ISS:UniProtKB.
DR   GO; GO:0035767; P:endothelial cell chemotaxis; IEA:Ensembl.
DR   GO; GO:0001935; P:endothelial cell proliferation; IEA:Ensembl.
DR   GO; GO:0001654; P:eye development; IEA:Ensembl.
DR   GO; GO:0005980; P:glycogen catabolic process; IEA:Ensembl.
DR   GO; GO:0031507; P:heterochromatin formation; IGI:GO_Central.
DR   GO; GO:0006954; P:inflammatory response; IDA:CACAO.
DR   GO; GO:0002437; P:inflammatory response to antigenic stimulus; IEP:UniProtKB.
DR   GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR   GO; GO:0030324; P:lung development; IEA:Ensembl.
DR   GO; GO:0002281; P:macrophage activation involved in immune response; IEA:Ensembl.
DR   GO; GO:0030099; P:myeloid cell differentiation; IEA:Ensembl.
DR   GO; GO:0001773; P:myeloid dendritic cell activation; ISS:UniProtKB.
DR   GO; GO:0002318; P:myeloid progenitor cell differentiation; IEA:Ensembl.
DR   GO; GO:2000426; P:negative regulation of apoptotic cell clearance; IDA:BHF-UCL.
DR   GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:CACAO.
DR   GO; GO:0043371; P:negative regulation of CD4-positive, alpha-beta T cell differentiation; IDA:UniProtKB.
DR   GO; GO:0017055; P:negative regulation of RNA polymerase II transcription preinitiation complex assembly; IDA:UniProtKB.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0032689; P:negative regulation of type II interferon production; IDA:UniProtKB.
DR   GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR   GO; GO:0097350; P:neutrophil clearance; IDA:UniProtKB.
DR   GO; GO:0002270; P:plasmacytoid dendritic cell activation; IEA:Ensembl.
DR   GO; GO:0042104; P:positive regulation of activated T cell proliferation; IMP:UniProtKB.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB.
DR   GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IMP:BHF-UCL.
DR   GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IDA:CACAO.
DR   GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IDA:UniProtKB.
DR   GO; GO:2001200; P:positive regulation of dendritic cell differentiation; IMP:UniProtKB.
DR   GO; GO:0043388; P:positive regulation of DNA binding; IDA:UniProtKB.
DR   GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR   GO; GO:0045819; P:positive regulation of glycogen catabolic process; IEA:Ensembl.
DR   GO; GO:0032727; P:positive regulation of interferon-alpha production; IEA:Ensembl.
DR   GO; GO:0032728; P:positive regulation of interferon-beta production; IEA:Ensembl.
DR   GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl.
DR   GO; GO:0032732; P:positive regulation of interleukin-1 production; IDA:UniProtKB.
DR   GO; GO:0032733; P:positive regulation of interleukin-10 production; IDA:UniProtKB.
DR   GO; GO:0032735; P:positive regulation of interleukin-12 production; IMP:UniProtKB.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:UniProtKB.
DR   GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:CACAO.
DR   GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB.
DR   GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB.
DR   GO; GO:0032425; P:positive regulation of mismatch repair; IDA:UniProtKB.
DR   GO; GO:0071639; P:positive regulation of monocyte chemotactic protein-1 production; IEA:Ensembl.
DR   GO; GO:0090026; P:positive regulation of monocyte chemotaxis; IDA:UniProtKB.
DR   GO; GO:0045639; P:positive regulation of myeloid cell differentiation; IEA:Ensembl.
DR   GO; GO:1905455; P:positive regulation of myeloid progenitor cell differentiation; IEA:Ensembl.
DR   GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IEA:Ensembl.
DR   GO; GO:1903672; P:positive regulation of sprouting angiogenesis; IEA:Ensembl.
DR   GO; GO:0034137; P:positive regulation of toll-like receptor 2 signaling pathway; IEA:Ensembl.
DR   GO; GO:0034145; P:positive regulation of toll-like receptor 4 signaling pathway; IEA:Ensembl.
DR   GO; GO:0034165; P:positive regulation of toll-like receptor 9 signaling pathway; ISS:UniProtKB.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:UniProtKB.
DR   GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IMP:BHF-UCL.
DR   GO; GO:0046598; P:positive regulation of viral entry into host cell; IMP:UniProtKB.
DR   GO; GO:0090303; P:positive regulation of wound healing; IEA:Ensembl.
DR   GO; GO:2000819; P:regulation of nucleotide-excision repair; IEA:Ensembl.
DR   GO; GO:0032072; P:regulation of restriction endodeoxyribonuclease activity; IDA:UniProtKB.
DR   GO; GO:0002840; P:regulation of T cell mediated immune response to tumor cell; ISS:UniProtKB.
DR   GO; GO:0002643; P:regulation of tolerance induction; IDA:UniProtKB.
DR   GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
DR   GO; GO:0035711; P:T-helper 1 cell activation; IDA:UniProtKB.
DR   GO; GO:0045063; P:T-helper 1 cell differentiation; IMP:UniProtKB.
DR   GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0033151; P:V(D)J recombination; IDA:UniProtKB.
DR   CDD; cd21978; HMG-box_HMGB_rpt1; 1.
DR   CDD; cd21979; HMG-box_HMGB_rpt2; 1.
DR   DisProt; DP01493; -.
DR   FunFam; 1.10.30.10:FF:000006; High mobility group protein B1; 1.
DR   FunFam; 1.10.30.10:FF:000015; high mobility group protein B1; 1.
DR   Gene3D; 1.10.30.10; High mobility group box domain; 2.
DR   IDEAL; IID00297; -.
DR   InterPro; IPR009071; HMG_box_dom.
DR   InterPro; IPR036910; HMG_box_dom_sf.
DR   InterPro; IPR017967; HMG_boxA_CS.
DR   InterPro; IPR050342; HMGB.
DR   PANTHER; PTHR48112:SF35; HIGH MOBILITY GROUP PROTEIN B1; 1.
DR   PANTHER; PTHR48112; HIGH MOBILITY GROUP PROTEIN DSP1; 1.
DR   Pfam; PF00505; HMG_box; 1.
DR   Pfam; PF09011; HMG_box_2; 1.
DR   PRINTS; PR00886; HIGHMOBLTY12.
DR   SMART; SM00398; HMG; 2.
DR   SUPFAM; SSF47095; HMG-box; 2.
DR   PROSITE; PS00353; HMG_BOX_1; 1.
DR   PROSITE; PS50118; HMG_BOX_2; 2.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Adaptive immunity; ADP-ribosylation; Autophagy;
KW   Cell membrane; Chemotaxis; Chromosome; Cytoplasm;
KW   Direct protein sequencing; Disulfide bond; DNA damage; DNA recombination;
KW   DNA repair; DNA-binding; Endoplasmic reticulum; Endosome;
KW   Host-virus interaction; Immunity; Inflammatory response; Innate immunity;
KW   Isopeptide bond; Membrane; Nucleus; Oxidation; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Repeat; Secreted.
FT   CHAIN           1..215
FT                   /note="High mobility group protein B1"
FT                   /id="PRO_0000048526"
FT   DNA_BIND        9..79
FT                   /note="HMG box 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00267"
FT   DNA_BIND        95..163
FT                   /note="HMG box 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00267"
FT   REGION          1..97
FT                   /note="Sufficient for interaction with HAVCR2"
FT                   /evidence="ECO:0000250|UniProtKB:P63158"
FT   REGION          3..15
FT                   /note="LPS binding (delipidated)"
FT                   /evidence="ECO:0000269|PubMed:21660935"
FT   REGION          76..95
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          80..96
FT                   /note="LPS binding (Lipid A)"
FT                   /evidence="ECO:0000269|PubMed:21660935"
FT   REGION          89..108
FT                   /note="Cytokine-stimulating activity"
FT                   /evidence="ECO:0000269|PubMed:12765338"
FT   REGION          150..183
FT                   /note="Binding to AGER/RAGE"
FT                   /evidence="ECO:0000250|UniProtKB:P63159"
FT   REGION          161..215
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           27..43
FT                   /note="Nuclear localization signal (NLS) 1"
FT                   /evidence="ECO:0000250|UniProtKB:P63159"
FT   MOTIF           178..184
FT                   /note="Nuclear localization signal (NLS) 2"
FT                   /evidence="ECO:0000250|UniProtKB:P63159"
FT   COMPBIAS        83..94
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        161..179
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        187..215
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         1..10
FT                   /ligand="heparin"
FT                   /ligand_id="ChEBI:CHEBI:28304"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   SITE            10..11
FT                   /note="Cleavage; by thrombin:thrombomodulin"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   SITE            67..68
FT                   /note="Cleavage; by CASP1"
FT                   /evidence="ECO:0000269|PubMed:24474694"
FT   MOD_RES         3
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         7
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         8
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         12
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         23
FT                   /note="Cysteine sulfonic acid (-SO3H); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P63159"
FT   MOD_RES         28
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         29
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         30
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         35
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         43
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P63158"
FT   MOD_RES         45
FT                   /note="Cysteine sulfonic acid (-SO3H); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P63159"
FT   MOD_RES         90
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P63158"
FT   MOD_RES         100
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         106
FT                   /note="Cysteine sulfonic acid (-SO3H)"
FT                   /evidence="ECO:0000250|UniProtKB:P63159"
FT   MOD_RES         127
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         128
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         141
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P63158"
FT   MOD_RES         172
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         173
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         177
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         180
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         181
FT                   /note="ADP-ribosylserine"
FT                   /evidence="ECO:0000269|PubMed:28190768"
FT   MOD_RES         182
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         183
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         184
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   MOD_RES         185
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10103"
FT   DISULFID        23..45
FT                   /note="In disulfide HMGB1; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P63159"
FT   CROSSLNK        28
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   CROSSLNK        43
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   CROSSLNK        44
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   CROSSLNK        68
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   CROSSLNK        180
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   CROSSLNK        182
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   CROSSLNK        183
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   CROSSLNK        184
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-?)"
FT                   /evidence="ECO:0000269|PubMed:29618516"
FT   VARIANT         11
FT                   /note="G -> R (in gastric-carcinoma cell line)"
FT                   /evidence="ECO:0000269|PubMed:9036861"
FT                   /id="VAR_046451"
FT   VARIANT         149
FT                   /note="A -> E (in gastric-carcinoma cell line)"
FT                   /evidence="ECO:0000269|PubMed:9036861"
FT                   /id="VAR_046452"
FT   VARIANT         156
FT                   /note="E -> Q"
FT                   /evidence="ECO:0000269|Ref.10"
FT                   /id="VAR_046453"
FT   VARIANT         190
FT                   /note="D -> G (in gastric-carcinoma cell line)"
FT                   /evidence="ECO:0000269|PubMed:9036861"
FT                   /id="VAR_046454"
FT   MUTAGEN         35
FT                   /note="S->A: Greatly reduces phosphorylation, nuclear
FT                   localization; when associated with A-39; A-42; A-46; A-53
FT                   and A-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         35
FT                   /note="S->E: Cytoplasmic localization (phosphorylation
FT                   mimicking); when associated with E-39; E-42; E-46; E-53 and
FT                   E-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         39
FT                   /note="S->A: Greatly reduces phosphorylation, nuclear
FT                   localization; when associated with A-35; A-42; A-46; A-53
FT                   and A-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         39
FT                   /note="S->E: Cytoplasmic localization (phosphorylation
FT                   mimicking); when associated with E-35; E-42; E-46; E-53 and
FT                   E-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         42
FT                   /note="S->A: Greatly reduces phosphorylation, nuclear
FT                   localization; when associated with A-35; A-39; A-46; A-53
FT                   and A-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         42
FT                   /note="S->E: Cytoplasmic localization (phosphorylation
FT                   mimicking); when associated with E-35; E-39; E-46; E-53 and
FT                   E-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         46
FT                   /note="S->A: Greatly reduces phosphorylation, nuclear
FT                   localization; when associated with A-35; A-39; A-42; A-53
FT                   and A-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         46
FT                   /note="S->E: Cytoplasmic localization (phosphorylation
FT                   mimicking); when associated with E-35; E-39; E-42; E-53 and
FT                   E-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         53
FT                   /note="S->A: Greatly reduces phosphorylation, nuclear
FT                   localization; when associated with A-35; A-39; A-42; A-46
FT                   and A-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         53
FT                   /note="S->E: Cytoplasmic localization (phosphorylation
FT                   mimicking); when associated with E-35; E-39; E-42; E-46 and
FT                   E-181."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         67
FT                   /note="D->A: Abolishes cleavage by CASP1 and impairs
FT                   ability to antagonize apoptosis-induced immune tolerance."
FT                   /evidence="ECO:0000269|PubMed:24474694"
FT   MUTAGEN         106
FT                   /note="C->S: Inhibits oxidation-dependent inactivation of
FT                   immunostimmulatory activity in apoptotic cells."
FT                   /evidence="ECO:0000269|PubMed:18631454"
FT   MUTAGEN         181
FT                   /note="S->A: Greatly reduces phosphorylation, nuclear
FT                   localization; when associated with A-35; A-39; A-42; A-46
FT                   and A-53."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   MUTAGEN         181
FT                   /note="S->E: Cytoplasmic localization (phosphorylation
FT                   mimicking); when associated with E-35; E-39; E-42; E-46 and
FT                   E-53."
FT                   /evidence="ECO:0000269|PubMed:17114460"
FT   CONFLICT        143
FT                   /note="P -> H (in Ref. 13; AAI41845)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        215
FT                   /note="E -> D (in Ref. 8; CAG33144)"
FT                   /evidence="ECO:0000305"
FT   STRAND          1..3
FT                   /evidence="ECO:0007829|PDB:2YRQ"
FT   STRAND          6..8
FT                   /evidence="ECO:0007829|PDB:2YRQ"
FT   HELIX           20..30
FT                   /evidence="ECO:0007829|PDB:6CIK"
FT   STRAND          31..33
FT                   /evidence="ECO:0007829|PDB:6CIK"
FT   HELIX           38..47
FT                   /evidence="ECO:0007829|PDB:6CIK"
FT   HELIX           54..76
FT                   /evidence="ECO:0007829|PDB:2LY4"
FT   STRAND          92..94
FT                   /evidence="ECO:0007829|PDB:2YRQ"
FT   HELIX           101..116
FT                   /evidence="ECO:0007829|PDB:6CIK"
FT   STRAND          118..120
FT                   /evidence="ECO:0007829|PDB:2YRQ"
FT   HELIX           122..135
FT                   /evidence="ECO:0007829|PDB:6CIK"
FT   HELIX           138..140
FT                   /evidence="ECO:0007829|PDB:2YRQ"
FT   HELIX           142..157
FT                   /evidence="ECO:0007829|PDB:6CIK"
SQ   SEQUENCE   215 AA;  24894 MW;  8A868CF277D417B5 CRC64;
     MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKKCSERWK TMSAKEKGKF
     EDMAKADKAR YEREMKTYIP PKGETKKKFK DPNAPKRPPS AFFLFCSEYR PKIKGEHPGL
     SIGDVAKKLG EMWNNTAADD KQPYEKKAAK LKEKYEKDIA AYRAKGKPDA AKKGVVKAEK
     SKKKKEEEED EEDEEDEEEE EDEEDEDEEE DDDDE
//
ID   HUNIN_HUMAN             Reviewed;          24 AA.
AC   Q8IVG9;
DT   27-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2003, sequence version 1.
DT   28-JAN-2026, entry version 127.
DE   RecName: Full=Humanin {ECO:0000303|PubMed:11371646};
DE   AltName: Full=Humanin mitochondrial {ECO:0000303|PubMed:19477263};
DE            Short=HNM {ECO:0000303|PubMed:19477263};
GN   Name=MT-RNR2 {ECO:0000312|HGNC:HGNC:7471};
GN   Synonyms=HN {ECO:0000303|PubMed:11371646};
OS   Homo sapiens (Human).
OG   Mitochondrion.
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, AND MUTAGENESIS OF LEU-9.
RC   TISSUE=Brain;
RX   PubMed=11371646; DOI=10.1073/pnas.101133498;
RA   Hashimoto Y., Niikura T., Tajima H., Yasukawa T., Sudo H., Ito Y., Kita Y.,
RA   Kawasumi M., Kouyama K., Doyu M., Sobue G., Koide T., Tsuji S., Lang J.,
RA   Kurokawa K., Nashimoto I.;
RT   "A rescue factor abolishing neuronal cell death by a wide spectrum of
RT   familial Alzheimer's disease genes and Abeta.";
RL   Proc. Natl. Acad. Sci. U.S.A. 98:6336-6341(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH IGFBP3, AND
RP   MUTAGENESIS OF PHE-6.
RX   PubMed=14561895; DOI=10.1073/pnas.2135111100;
RA   Ikonen M., Liu B., Hashimoto Y., Ma L., Lee K.W., Niikura T., Nishimoto I.,
RA   Cohen P.;
RT   "Interaction between the Alzheimer's survival peptide humanin and insulin-
RT   like growth factor-binding protein 3 regulates cell survival and
RT   apoptosis.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:13042-13047(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   FUNCTION, AND MUTAGENESIS OF 1-MET-ALA-2; 1-MET--PRO-3; PRO-3;
RP   4-ARG--MET-6; CYS-8; LEU-9; LEU-12; THR-13; SER-14; PRO-19; 19-PRO--ALA-24
RP   AND 20-VAL--ALA-24.
RX   PubMed=11717357; DOI=10.1523/jneurosci.21-23-09235.2001;
RA   Hashimoto Y., Niikura T., Ito Y., Sudo H., Hata M., Arakawa E., Abe Y.,
RA   Kita Y., Nishimoto I.;
RT   "Detailed characterization of neuroprotection by a rescue factor humanin
RT   against various Alzheimer's disease-relevant insults.";
RL   J. Neurosci. 21:9235-9245(2001).
RN   [5]
RP   FUNCTION.
RX   PubMed=12154011; DOI=10.1096/fj.02-0018fje;
RA   Caricasole A., Bruno V., Cappuccio I., Melchiorri D., Copani A.,
RA   Nicoletti F.;
RT   "A novel rat gene encoding a Humanin-like peptide endowed with broad
RT   neuroprotective activity.";
RL   FASEB J. 16:1331-1333(2002).
RN   [6]
RP   EVIDENCE OF IN VIVO EXPRESSION, AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=12009529; DOI=10.1016/s0304-3940(02)00199-4;
RA   Tajima H., Niikura T., Hashimoto Y., Ito Y., Kita Y., Terashita K.,
RA   Yamazaki K., Koto A., Aiso S., Nishimoto I.;
RT   "Evidence for in vivo production of Humanin peptide, a neuroprotective
RT   factor against Alzheimer's disease-related insults.";
RL   Neurosci. Lett. 324:227-231(2002).
RN   [7]
RP   INTERACTION WITH TRIM11, AND SUBCELLULAR LOCATION.
RX   PubMed=12670303; DOI=10.1046/j.1460-9568.2003.02553.x;
RA   Niikura T., Hashimoto Y., Tajima H., Ishizaka M., Yamagishi Y.,
RA   Kawasumi M., Nawa M., Terashita K., Aiso S., Nishimoto I.;
RT   "A tripartite motif protein TRIM11 binds and destabilizes Humanin, a
RT   neuroprotective peptide against Alzheimer's disease-relevant insults.";
RL   Eur. J. Neurosci. 17:1150-1158(2003).
RN   [8]
RP   FUNCTION, SUBUNIT, AND MUTAGENESIS OF SER-7 AND SER-14.
RX   PubMed=12787071; DOI=10.1046/j.1471-4159.2003.01797.x;
RA   Terashita K., Hashimoto Y., Niikura T., Tajima H., Yamagishi Y.,
RA   Ishizaka M., Kawasumi M., Chiba T., Kanekura K., Yamada M., Nawa M.,
RA   Kita Y., Aiso S., Nishimoto I.;
RT   "Two serine residues distinctly regulate the rescue function of Humanin, an
RT   inhibiting factor of Alzheimer's disease-related neurotoxicity: functional
RT   potentiation by isomerization and dimerization.";
RL   J. Neurochem. 85:1521-1538(2003).
RN   [9]
RP   FUNCTION, INTERACTION WITH BAX, AND MUTAGENESIS OF 1-MET--PHE-6;
RP   18-LEU--ALA-24; CYS-8 AND LEU-9.
RX   PubMed=12732850; DOI=10.1038/nature01627;
RA   Guo B., Zhai D., Cabezas E., Welsh K., Nouraini S., Satterthwait A.C.,
RA   Reed J.C.;
RT   "Humanin peptide suppresses apoptosis by interfering with Bax activation.";
RL   Nature 423:456-461(2003).
RN   [10]
RP   FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND MUTAGENESIS OF PRO-3; SER-7;
RP   CYS-8; LEU-9; LEU-10; LEU-11; LEU-12; THR-13; SER-14; PRO-19 AND VAL-20.
RX   PubMed=12860203; DOI=10.1016/s0196-9781(03)00106-2;
RA   Yamagishi Y., Hashimoto Y., Niikura T., Nishimoto I.;
RT   "Identification of essential amino acids in Humanin, a neuroprotective
RT   factor against Alzheimer's disease-relevant insults.";
RL   Peptides 24:585-595(2003).
RN   [11]
RP   FUNCTION, AND MUTAGENESIS OF SER-14.
RX   PubMed=15465011; DOI=10.1016/j.bbrc.2004.09.046;
RA   Harada M., Habata Y., Hosoya M., Nishi K., Fujii R., Kobayashi M.,
RA   Hinuma S.;
RT   "N-Formylated humanin activates both formyl peptide receptor-like 1 and
RT   2.";
RL   Biochem. Biophys. Res. Commun. 324:255-261(2004).
RN   [12]
RP   FUNCTION.
RX   PubMed=15153530; DOI=10.4049/jimmunol.172.11.7078;
RA   Ying G., Iribarren P., Zhou Y., Gong W., Zhang N., Yu Z.-X., Le Y., Cui Y.,
RA   Wang J.M.;
RT   "Humanin, a newly identified neuroprotective factor, uses the G protein-
RT   coupled formylpeptide receptor-like-1 as a functional receptor.";
RL   J. Immunol. 172:7078-7085(2004).
RN   [13]
RP   FUNCTION, INTERACTION WITH BID, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP   CYS-8 AND SER-14.
RX   PubMed=15661737; DOI=10.1074/jbc.m411902200;
RA   Zhai D., Luciano F., Zhu X., Guo B., Satterthwait A.C., Reed J.C.;
RT   "Humanin binds and nullifies Bid activity by blocking its activation of Bax
RT   and Bak.";
RL   J. Biol. Chem. 280:15815-15824(2005).
RN   [14]
RP   FUNCTION, INTERACTION WITH BIM, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP   CYS-8.
RX   PubMed=15661735; DOI=10.1074/jbc.m413062200;
RA   Luciano F., Zhai D., Zhu X., Bailly-Maitre B., Ricci J.E.,
RA   Satterthwait A.C., Reed J.C.;
RT   "Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax
RT   family protein BimEL.";
RL   J. Biol. Chem. 280:15825-15835(2005).
RN   [15]
RP   TISSUE SPECIFICITY, AND INDUCTION.
RX   PubMed=19477263; DOI=10.1016/j.ygeno.2009.05.006;
RA   Bodzioch M., Lapicka-Bodzioch K., Zapala B., Kamysz W., Kiec-Wilk B.,
RA   Dembinska-Kiec A.;
RT   "Evidence for potential functionality of nuclearly-encoded humanin
RT   isoforms.";
RL   Genomics 94:247-256(2009).
RN   [16]
RP   FUNCTION.
RX   PubMed=19386761; DOI=10.1091/mbc.e09-02-0168;
RA   Hashimoto Y., Kurita M., Aiso S., Nishimoto I., Matsuoka M.;
RT   "Humanin inhibits neuronal cell death by interacting with a cytokine
RT   receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130.";
RL   Mol. Biol. Cell 20:2864-2873(2009).
RN   [17]
RP   FUNCTION, INTERACTION WITH IGFBP3, SUBCELLULAR LOCATION, DEVELOPMENTAL
RP   STAGE, AND MUTAGENESIS OF PHE-6 AND SER-7.
RX   PubMed=19623253; DOI=10.1371/journal.pone.0006334;
RA   Muzumdar R.H., Huffman D.M., Atzmon G., Buettner C., Cobb L.J., Fishman S.,
RA   Budagov T., Cui L., Einstein F.H., Poduval A., Hwang D., Barzilai N.,
RA   Cohen P.;
RT   "Humanin: a novel central regulator of peripheral insulin action.";
RL   PLoS ONE 4:e6334-e6334(2009).
RN   [18]
RP   FUNCTION.
RX   PubMed=19952275; DOI=10.1210/en.2009-0577;
RA   Lue Y., Swerdloff R., Liu Q., Mehta H., Hikim A.S., Lee K.W., Jia Y.,
RA   Hwang D., Cobb L.J., Cohen P., Wang C.;
RT   "Opposing roles of insulin-like growth factor binding protein 3 and humanin
RT   in the regulation of testicular germ cell apoptosis.";
RL   Endocrinology 151:350-357(2010).
RN   [19]
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=20542501; DOI=10.1016/j.fertnstert.2010.04.075;
RA   Moretti E., Giannerini V., Rossini L., Matsuoka M., Trabalzini L.,
RA   Collodel G.;
RT   "Immunolocalization of humanin in human sperm and testis.";
RL   Fertil. Steril. 94:2888-2890(2010).
RN   [20]
RP   INTERACTION WITH MPP8.
RX   PubMed=23532874; DOI=10.1002/psc.2500;
RA   Maximov V.V., Martynenko A.V., Arman I.P., Tarantul V.Z.;
RT   "Humanin binds MPP8: mapping interaction sites of the peptide and
RT   protein.";
RL   J. Pept. Sci. 19:301-307(2013).
RN   [21]
RP   FUNCTION.
RX   PubMed=23277413; DOI=10.1007/s11064-012-0951-6;
RA   Zhao S.T., Zhao L., Li J.H.;
RT   "Neuroprotective Peptide humanin inhibits inflammatory response in
RT   astrocytes induced by lipopolysaccharide.";
RL   Neurochem. Res. 38:581-588(2013).
RN   [22]
RP   FUNCTION.
RX   PubMed=25138702; DOI=10.1007/s11010-014-2182-4;
RA   Hashimoto Y., Takeshita Y., Naito M., Uchino H., Matsuoka M.;
RT   "Apollon/Bruce is upregulated by Humanin.";
RL   Mol. Cell. Biochem. 397:147-155(2014).
RN   [23]
RP   FUNCTION, AND INTERACTION WITH IGFBP3.
RX   PubMed=26216267; DOI=10.2174/0929866522666150728114955;
RA   Njomen E., Evans H.G., Gedara S.H., Heyl D.L.;
RT   "Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3
RT   (IGFBP3) and Regulates Its Interaction with Importin-beta.";
RL   Protein Pept. Lett. 22:869-876(2015).
RN   [24]
RP   FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=26990160; DOI=10.1167/iovs.15-17053;
RA   Sreekumar P.G., Ishikawa K., Spee C., Mehta H.H., Wan J., Yen K., Cohen P.,
RA   Kannan R., Hinton D.R.;
RT   "The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From
RT   Oxidative Stress, Senescence, and Mitochondrial Dysfunction.";
RL   Invest. Ophthalmol. Vis. Sci. 57:1238-1253(2016).
RN   [25]
RP   FUNCTION.
RX   PubMed=27783653; DOI=10.1371/journal.pone.0165150;
RA   Matsunaga D., Sreekumar P.G., Ishikawa K., Terasaki H., Barron E.,
RA   Cohen P., Kannan R., Hinton D.R.;
RT   "Humanin Protects RPE Cells from Endoplasmic Reticulum Stress-Induced
RT   Apoptosis by Upregulation of Mitochondrial Glutathione.";
RL   PLoS ONE 11:e0165150-e0165150(2016).
RN   [26]
RP   FUNCTION, INTERACTION WITH AMYLOID-BETA PROTEIN 42, MASS SPECTROMETRY, AND
RP   MUTAGENESIS OF SER-14.
RX   PubMed=28282805; DOI=10.3233/jad-160951;
RA   Romeo M., Stravalaci M., Beeg M., Rossi A., Fiordaliso F., Corbelli A.,
RA   Salmona M., Gobbi M., Cagnotto A., Diomede L.;
RT   "Humanin Specifically Interacts with Amyloid-beta Oligomers and Counteracts
RT   Their in vivo Toxicity.";
RL   J. Alzheimers Dis. 57:857-871(2017).
RN   [27]
RP   FUNCTION.
RX   PubMed=29432738; DOI=10.1016/j.bbrc.2018.02.071;
RA   Qin Q., Jin J., He F., Zheng Y., Li T., Zhang Y., He J.;
RT   "Humanin promotes mitochondrial biogenesis in pancreatic MIN6 beta-cells.";
RL   Biochem. Biophys. Res. Commun. 497:292-297(2018).
RN   [28]
RP   FUNCTION.
RX   PubMed=30029058; DOI=10.1016/j.molimm.2018.07.008;
RA   Wang X., Wu Z., He Y., Zhang H., Tian L., Zheng C., Shang T., Zhu Q.,
RA   Li D., He Y.;
RT   "Humanin prevents high glucose-induced monocyte adhesion to endothelial
RT   cells by targeting KLF2.";
RL   Mol. Immunol. 101:245-250(2018).
RN   [29]
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=30920769; DOI=10.1111/andr.12614;
RA   Rao M., Wu Z., Wen Y., Wang R., Zhao S., Tang L.;
RT   "Humanin levels in human seminal plasma and spermatozoa are related to
RT   sperm quality.";
RL   Andrology 7:859-866(2019).
RN   [30]
RP   FUNCTION, AND MUTAGENESIS OF CYS-8 AND SER-14.
RX   PubMed=31690630; DOI=10.1074/jbc.ra119.011297;
RA   Morris D.L., Kastner D.W., Johnson S., Strub M.P., He Y., Bleck C.K.E.,
RA   Lee D.Y., Tjandra N.;
RT   "Humanin induces conformational changes in the apoptosis regulator BAX and
RT   sequesters it into fibers, preventing mitochondrial outer-membrane
RT   permeabilization.";
RL   J. Biol. Chem. 294:19055-19065(2019).
RN   [31]
RP   FUNCTION.
RX   PubMed=32923762; DOI=10.1021/acsomega.0c01778;
RA   Li W., Zhang D., Yuan W., Wang C., Huang Q., Luo J.;
RT   "Humanin Ameliorates Free Fatty Acid-Induced Endothelial Inflammation by
RT   Suppressing the NLRP3 Inflammasome.";
RL   ACS Omega 5:22039-22045(2020).
RN   [32]
RP   FUNCTION, AND MUTAGENESIS OF CYS-8 AND SER-14.
RX   PubMed=33106313; DOI=10.1074/jbc.ra120.013023;
RA   Morris D.L., Johnson S., Bleck C.K.E., Lee D.Y., Tjandra N.;
RT   "Humanin selectively prevents the activation of pro-apoptotic protein BID
RT   by sequestering it into fibers.";
RL   J. Biol. Chem. 295:18226-18238(2020).
RN   [33]
RP   STRUCTURE BY NMR, AND DOMAIN.
RX   PubMed=15721287; DOI=10.1016/j.bbrc.2005.01.100;
RA   Benaki D., Zikos C., Evangelou A., Livaniou E., Vlassi M., Mikros E.,
RA   Pelecanou M.;
RT   "Solution structure of humanin, a peptide against Alzheimer's disease-
RT   related neurotoxicity.";
RL   Biochem. Biophys. Res. Commun. 329:152-160(2005).
RN   [34]
RP   STRUCTURE BY NMR OF MUTANT GLY-14.
RX   PubMed=16945331; DOI=10.1016/j.bbrc.2006.08.087;
RA   Benaki D., Zikos C., Evangelou A., Livaniou E., Vlassi M., Mikros E.,
RA   Pelecanou M.;
RT   "Solution structure of Ser14Gly-humanin, a potent rescue factor against
RT   neuronal cell death in Alzheimer's disease.";
RL   Biochem. Biophys. Res. Commun. 349:634-642(2006).
RN   [35] {ECO:0007744|PDB:5GIW}
RP   STRUCTURE BY NMR WITH D-SER-14, FUNCTION, AND MUTAGENESIS OF SER-14.
RX   PubMed=27349871; DOI=10.1016/j.bbrc.2016.06.114;
RA   Alsanousi N., Sugiki T., Furuita K., So M., Lee Y.H., Fujiwara T.,
RA   Kojima C.;
RT   "Solution NMR structure and inhibitory effect against amyloid-beta
RT   fibrillation of Humanin containing a d-isomerized serine residue.";
RL   Biochem. Biophys. Res. Commun. 477:647-653(2016).
CC   -!- FUNCTION: Plays a role as a neuroprotective factor (PubMed:11371646,
CC       PubMed:11717357, PubMed:12154011, PubMed:12787071, PubMed:12860203,
CC       PubMed:19386761). Protects against neuronal cell death induced by
CC       multiple different familial Alzheimer disease genes and amyloid-beta
CC       proteins in Alzheimer disease (PubMed:11371646, PubMed:11717357,
CC       PubMed:12154011, PubMed:12787071, PubMed:12860203, PubMed:19386761).
CC       Mediates its neuroprotective effect by interacting with a receptor
CC       complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR
CC       (PubMed:19386761). Also acts as a ligand for G-protein coupled
CC       receptors FPR2/FPRL1 and FPR3/FPRL2 (PubMed:15465011). Inhibits
CC       amyloid-beta protein 40 fibril formation (PubMed:27349871). Also
CC       inhibits amyloid-beta protein 42 fibril formation (PubMed:28282805).
CC       Suppresses apoptosis by binding to BAX and preventing the translocation
CC       of BAX from the cytosol to mitochondria (PubMed:12732850,
CC       PubMed:26990160). Also suppresses apoptosis by binding to BID and
CC       inhibiting the interaction of BID with BAX and BAK which prevents
CC       oligomerization of BAX and BAK and suppresses release of apoptogenic
CC       proteins from mitochondria (PubMed:15661737). Forms fibers with BAX and
CC       also with BID, inducing BAX and BID conformational changes and
CC       sequestering them into the fibers which prevents their activation
CC       (PubMed:31690630, PubMed:33106313). Can also suppress apoptosis by
CC       interacting with BIM isoform BimEL, inhibiting BimEL-induced activation
CC       of BAX, blocking oligomerization of BAX and BAK, and preventing release
CC       of apoptogenic proteins from mitochondria (PubMed:15661735). Plays a
CC       role in up-regulation of anti-apoptotic protein BIRC6/APOLLON, leading
CC       to inhibition of neuronal cell death (PubMed:25138702). Binds to IGFBP3
CC       and specifically blocks IGFBP3-induced cell death (PubMed:14561895,
CC       PubMed:26216267). Competes with importin KPNB1 for binding to IGFBP3
CC       which is likely to block IGFBP3 nuclear import (PubMed:26216267).
CC       Induces chemotaxis of mononuclear phagocytes via FPR2/FPRL1
CC       (PubMed:15153530). Reduces aggregation and fibrillary formation by
CC       suppressing the effect of APP on mononuclear phagocytes and acts by
CC       competitively inhibiting the access of FPR2 to APP (PubMed:15153530).
CC       Protects retinal pigment epithelium (RPE) cells against oxidative
CC       stress-induced and endoplasmic reticulum (ER) stress-induced apoptosis
CC       (PubMed:26990160, PubMed:27783653). Promotes mitochondrial biogenesis
CC       in RPE cells following oxidative stress and promotes STAT3
CC       phosphorylation which leads to inhibition of CASP3 release
CC       (PubMed:26990160). Also reduces CASP4 levels in RPE cells, suppresses
CC       ER stress-induced mitochondrial superoxide production and plays a role
CC       in up-regulation of mitochondrial glutathione (PubMed:27783653).
CC       Reduces testicular hormone deprivation-induced apoptosis of germ cells
CC       at the nonandrogen-sensitive stages of the seminiferous epithelium
CC       cycle (PubMed:19952275). Protects endothelial cells against free fatty
CC       acid-induced inflammation by suppressing oxidative stress, reducing
CC       expression of TXNIP and inhibiting activation of the NLRP3 inflammasome
CC       which inhibits expression of pro-inflammatory cytokines IL1B and IL18
CC       (PubMed:32923762). Protects against high glucose-induced endothelial
CC       cell dysfunction by mediating activation of ERK5 which leads to
CC       increased expression of transcription factor KLF2 and prevents monocyte
CC       adhesion to endothelial cells (PubMed:30029058). Inhibits the
CC       inflammatory response in astrocytes (PubMed:23277413). Increases the
CC       expression of PPARGC1A/PGC1A in pancreatic beta cells which promotes
CC       mitochondrial biogenesis (PubMed:29432738). Increases insulin
CC       sensitivity (PubMed:19623253). {ECO:0000269|PubMed:11371646,
CC       ECO:0000269|PubMed:11717357, ECO:0000269|PubMed:12154011,
CC       ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:12787071,
CC       ECO:0000269|PubMed:12860203, ECO:0000269|PubMed:14561895,
CC       ECO:0000269|PubMed:15153530, ECO:0000269|PubMed:15465011,
CC       ECO:0000269|PubMed:15661735, ECO:0000269|PubMed:15661737,
CC       ECO:0000269|PubMed:19386761, ECO:0000269|PubMed:19623253,
CC       ECO:0000269|PubMed:19952275, ECO:0000269|PubMed:23277413,
CC       ECO:0000269|PubMed:25138702, ECO:0000269|PubMed:26216267,
CC       ECO:0000269|PubMed:26990160, ECO:0000269|PubMed:27349871,
CC       ECO:0000269|PubMed:27783653, ECO:0000269|PubMed:28282805,
CC       ECO:0000269|PubMed:29432738, ECO:0000269|PubMed:30029058,
CC       ECO:0000269|PubMed:31690630, ECO:0000269|PubMed:32923762,
CC       ECO:0000269|PubMed:33106313}.
CC   -!- SUBUNIT: Homodimer (PubMed:12787071, PubMed:12860203). Interacts with
CC       amyloid-beta protein 42 (Abeta42); the interaction prevents Abeta42
CC       fibril formation (PubMed:28282805). Interacts with BAX; forms fibers
CC       with BAX which results in BAX conformational changes and sequestering
CC       of BAX into the fibers, preventing BAX activation (PubMed:12732850,
CC       PubMed:31690630). Interacts with both full-length BID and cleaved BID
CC       p15; forms fibers with BID which results in BID conformational changes
CC       and sequestering of BID into the fibers, preventing BID activation
CC       (PubMed:15661737, PubMed:33106313). Interacts with BIM isoform BimEL
CC       but not with BIM isoforms BimL or BimS; the interaction prevents BIM-
CC       induced apoptosis (PubMed:15661735). Interacts with IGFBP3; competes
CC       with importin KPNB1 for binding to IGFBP3, blocking IGFBP3 nuclear
CC       import (PubMed:14561895, PubMed:19623253, PubMed:26216267). Interacts
CC       with TRIM11 (PubMed:12670303). Interacts with MPP8 (PubMed:23532874).
CC       {ECO:0000269|PubMed:12670303, ECO:0000269|PubMed:12732850,
CC       ECO:0000269|PubMed:12787071, ECO:0000269|PubMed:12860203,
CC       ECO:0000269|PubMed:14561895, ECO:0000269|PubMed:15661735,
CC       ECO:0000269|PubMed:15661737, ECO:0000269|PubMed:19623253,
CC       ECO:0000269|PubMed:23532874, ECO:0000269|PubMed:26216267,
CC       ECO:0000269|PubMed:28282805, ECO:0000269|PubMed:31690630,
CC       ECO:0000269|PubMed:33106313}.
CC   -!- INTERACTION:
CC       Q8IVG9; PRO_0000000092 [P05067]: APP; NbExp=4; IntAct=EBI-8643752, EBI-821758;
CC       Q8IVG9; Q07812: BAX; NbExp=5; IntAct=EBI-8643752, EBI-516580;
CC       Q8IVG9; P17936: IGFBP3; NbExp=7; IntAct=EBI-8643752, EBI-715709;
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11371646,
CC       ECO:0000269|PubMed:12860203, ECO:0000269|PubMed:19623253,
CC       ECO:0000269|PubMed:26990160}. Cytoplasm {ECO:0000269|PubMed:11371646,
CC       ECO:0000269|PubMed:12670303, ECO:0000269|PubMed:15661737,
CC       ECO:0000269|PubMed:20542501, ECO:0000269|PubMed:26990160}. Cell
CC       projection, cilium, flagellum {ECO:0000269|PubMed:20542501,
CC       ECO:0000269|PubMed:30920769}. Nucleus {ECO:0000269|PubMed:20542501}.
CC       Mitochondrion {ECO:0000269|PubMed:20542501,
CC       ECO:0000269|PubMed:26990160}. Note=Localizes to the sperm flagellum
CC       where it is highly concentrated in the midpiece (PubMed:20542501,
CC       PubMed:30920769). Detected in the cytoplasm and nucleus of
CC       spermatocytes and spermatids (PubMed:20542501). Also detected in sperm
CC       mitochondria (PubMed:20542501). In retinal pigment epithelium cells,
CC       detected in cytoplasm and mitochondria (PubMed:26990160).
CC       {ECO:0000269|PubMed:20542501, ECO:0000269|PubMed:26990160,
CC       ECO:0000269|PubMed:30920769}.
CC   -!- TISSUE SPECIFICITY: Expressed in testis, seminal plasma and sperm (at
CC       protein level) (PubMed:20542501, PubMed:30920769). Higher seminal
CC       plasma levels are associated with normospermia than with oligospermia,
CC       asthenospermia or oligoasthenospermia (at protein level)
CC       (PubMed:30920769). Higher sperm levels are associated with normospermia
CC       than with asthenospermia (at protein level) (PubMed:30920769).
CC       Expressed in retinal epithelial cells (at protein level)
CC       (PubMed:26990160). Expressed in the heart, skeletal muscle, kidney and
CC       liver. Lesser but significant expression is observed in the brain and
CC       the gastrointestinal tract. Expressed in the AD brain, where it is
CC       found in some of the large intact neurons of the occipital lobes and
CC       small and round reactive glial cells in the hippocampus.
CC       {ECO:0000269|PubMed:11371646, ECO:0000269|PubMed:12009529,
CC       ECO:0000269|PubMed:19477263, ECO:0000269|PubMed:20542501,
CC       ECO:0000269|PubMed:26990160, ECO:0000269|PubMed:30920769}.
CC   -!- DEVELOPMENTAL STAGE: Levels decline with increasing age.
CC       {ECO:0000269|PubMed:19623253}.
CC   -!- INDUCTION: Release is regulated by intracellular mechanism. The
CC       intracellular level is regulated by TRIM11 through proteasome-mediated
CC       degradation. {ECO:0000269|PubMed:19477263}.
CC   -!- DOMAIN: Largely unstructured in aqueous solution.
CC       {ECO:0000269|PubMed:15721287}.
CC   -!- MASS SPECTROMETRY: Mass=2686.78; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:28282805};
CC   -!- SIMILARITY: Belongs to the humanin family. {ECO:0000305}.
CC   -!- CAUTION: The humanin peptide described here has been shown to be
CC       biologically active but is the product of a mitochondrial gene, MT-RNR2
CC       (PubMed:12009529). If translation of the mRNA occurs in the
CC       mitochondrion rather than in the cytoplasm, then the usage of the
CC       mitochondrial genetic code would lead to the production of a shorter
CC       peptide lacking the last three C-terminal residues. The mechanisms
CC       allowing the production and the secretion of humanin remain unclear.
CC       The possibility exists that the physiologically active humanin peptide
CC       is encoded by one of the related genes present in the nuclear genome
CC       (PubMed:19477263). {ECO:0000305|PubMed:12009529,
CC       ECO:0000305|PubMed:19477263}.
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DR   EMBL; AY029066; AAK50430.1; -; mRNA.
DR   EMBL; BE899497; -; NOT_ANNOTATED_CDS; mRNA.
DR   PDB; 1Y32; NMR; -; A=1-24.
DR   PDB; 2GD3; NMR; -; A=1-24.
DR   PDB; 5GIW; NMR; -; X=1-24.
DR   PDB; 7WVX; EM; 2.80 A; L=1-24.
DR   PDBsum; 1Y32; -.
DR   PDBsum; 2GD3; -.
DR   PDBsum; 5GIW; -.
DR   PDBsum; 7WVX; -.
DR   AlphaFoldDB; Q8IVG9; -.
DR   BMRB; Q8IVG9; -.
DR   EMDB; EMD-32861; -.
DR   SMR; Q8IVG9; -.
DR   FunCoup; Q8IVG9; 5.
DR   IntAct; Q8IVG9; 3.
DR   MINT; Q8IVG9; -.
DR   iPTMnet; Q8IVG9; -.
DR   PhosphoSitePlus; Q8IVG9; -.
DR   BioMuta; HGNC:7471; -.
DR   AGR; HGNC:7471; -.
DR   GeneCards; MT-RNR2; -.
DR   HGNC; HGNC:7471; MT-RNR2.
DR   MalaCards; MT-RNR2; -.
DR   MIM; 561010; gene.
DR   InParanoid; Q8IVG9; -.
DR   PAN-GO; Q8IVG9; 2 GO annotations based on evolutionary models.
DR   PhylomeDB; Q8IVG9; -.
DR   PathwayCommons; Q8IVG9; -.
DR   Reactome; R-HSA-416476; G alpha (q) signalling events.
DR   Reactome; R-HSA-418594; G alpha (i) signalling events.
DR   Reactome; R-HSA-444473; Formyl peptide receptors bind formyl peptides and many other ligands.
DR   SignaLink; Q8IVG9; -.
DR   ChiTaRS; MT-RNR2; human.
DR   EvolutionaryTrace; Q8IVG9; -.
DR   Pharos; Q8IVG9; Tdark.
DR   PRO; PR:Q8IVG9; -.
DR   Proteomes; UP000005640; Mitochondrion MT.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR   GO; GO:0036126; C:sperm flagellum; IDA:UniProtKB.
DR   GO; GO:0097225; C:sperm midpiece; IDA:UniProtKB.
DR   GO; GO:0001664; F:G protein-coupled receptor binding; IPI:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR   GO; GO:0048019; F:receptor antagonist activity; IDA:UniProtKB.
DR   GO; GO:0005102; F:signaling receptor binding; TAS:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0007267; P:cell-cell signaling; IDA:UniProtKB.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProtKB.
DR   GO; GO:0006879; P:intracellular iron ion homeostasis; NAS:UniProtKB.
DR   GO; GO:0030595; P:leukocyte chemotaxis; IDA:UniProtKB.
DR   GO; GO:0007005; P:mitochondrion organization; IDA:UniProtKB.
DR   GO; GO:1905907; P:negative regulation of amyloid fibril formation; IDA:UniProtKB.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:1900118; P:negative regulation of execution phase of apoptosis; IBA:GO_Central.
DR   GO; GO:0050728; P:negative regulation of inflammatory response; IDA:UniProtKB.
DR   GO; GO:0032692; P:negative regulation of interleukin-1 production; IDA:UniProtKB.
DR   GO; GO:0032701; P:negative regulation of interleukin-18 production; IDA:UniProtKB.
DR   GO; GO:0150079; P:negative regulation of neuroinflammatory response; IDA:UniProtKB.
DR   GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:UniProtKB.
DR   GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IDA:UniProtKB.
DR   GO; GO:1902883; P:negative regulation of response to oxidative stress; IDA:UniProtKB.
DR   GO; GO:0097435; P:supramolecular fiber organization; IDA:UniProtKB.
DR   CDD; cd20245; humanin; 1.
DR   DisProt; DP02267; -.
DR   InterPro; IPR028139; Humanin.
DR   PANTHER; PTHR33895; HUMANIN-LIKE 4; 1.
DR   PANTHER; PTHR33895:SF15; HUMANIN-RELATED; 1.
DR   Pfam; PF15040; Humanin; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Apoptosis; Cell projection; Cilium; Cytoplasm; Flagellum;
KW   Mitochondrion; Nucleus; Reference proteome; Secreted.
FT   CHAIN           1..24
FT                   /note="Humanin"
FT                   /id="PRO_0000044146"
FT   REGION          1..12
FT                   /note="Sufficient to interact with BID and BIM and to
FT                   suppress BID and BIM activity"
FT                   /evidence="ECO:0000269|PubMed:15661735,
FT                   ECO:0000269|PubMed:15661737"
FT   REGION          3..19
FT                   /note="Sufficient for neuroprotective activity"
FT   REGION          5..12
FT                   /note="Sufficient to interact with MPP8"
FT                   /evidence="ECO:0000269|PubMed:23532874"
FT   REGION          9..11
FT                   /note="Required for secretion"
FT                   /evidence="ECO:0000269|PubMed:12860203"
FT   REGION          19..20
FT                   /note="Required for secretion"
FT                   /evidence="ECO:0000269|PubMed:12860203"
FT   MUTAGEN         1..6
FT                   /note="Missing: No effect on binding to BAX."
FT                   /evidence="ECO:0000269|PubMed:12732850"
FT   MUTAGEN         1..3
FT                   /note="Missing: Abolishes neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357"
FT   MUTAGEN         1..2
FT                   /note="Missing: No effect on neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357"
FT   MUTAGEN         3
FT                   /note="P->A: Abolishes neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12860203"
FT   MUTAGEN         4..6
FT                   /note="RGF->AGA: Potentiates neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357"
FT   MUTAGEN         6
FT                   /note="F->A: Abolishes binding to IGFBP3 and increases
FT                   insulin sensitivity."
FT                   /evidence="ECO:0000269|PubMed:14561895,
FT                   ECO:0000269|PubMed:19623253"
FT   MUTAGEN         7
FT                   /note="S->A: Abolishes neuroprotective activity and
FT                   dimerization. No effect on insulin sensitivity."
FT                   /evidence="ECO:0000269|PubMed:12787071,
FT                   ECO:0000269|PubMed:12860203, ECO:0000269|PubMed:19623253"
FT   MUTAGEN         8
FT                   /note="C->A: Abolishes neuroprotective activity. Formation
FT                   of short irregularly shaped fibers with BAX with fibers
FT                   showing non-uniform diameters. Formation of thin
FT                   irregularly kinked fibers with BID."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:12860203,
FT                   ECO:0000269|PubMed:31690630, ECO:0000269|PubMed:33106313"
FT   MUTAGEN         8
FT                   /note="C->D,E,F,G,I,L,M,N,Q,S,T,V,W,Y: Abolishes
FT                   neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12732850"
FT   MUTAGEN         8
FT                   /note="C->H: Significantly reduces neuroprotective
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12732850"
FT   MUTAGEN         8
FT                   /note="C->K,R: No effect on neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12732850"
FT   MUTAGEN         8
FT                   /note="C->P: Abolishes neuroprotective activity and
FT                   interaction with BAX and BID. Abolishes BID-induced caspase
FT                   activation and mitochondrial release of SMAC. Greatly
FT                   reduced interaction with BIM. Abolishes BIM-induced caspase
FT                   activation and apoptosis."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:15661735,
FT                   ECO:0000269|PubMed:15661737"
FT   MUTAGEN         9
FT                   /note="L->A: Abolishes neuroprotective activity and
FT                   dimerization."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12732850, ECO:0000269|PubMed:12860203"
FT   MUTAGEN         9
FT                   /note="L->R: Abolishes binding to BAX. Abolishes
FT                   secretion."
FT                   /evidence="ECO:0000269|PubMed:11371646,
FT                   ECO:0000269|PubMed:11717357, ECO:0000269|PubMed:12732850,
FT                   ECO:0000269|PubMed:12860203"
FT   MUTAGEN         10
FT                   /note="L->D: Abolishes secretion."
FT                   /evidence="ECO:0000269|PubMed:12860203"
FT   MUTAGEN         10
FT                   /note="L->R: Abolishes secretion."
FT                   /evidence="ECO:0000269|PubMed:12860203"
FT   MUTAGEN         11
FT                   /note="L->R: Abolishes secretion."
FT                   /evidence="ECO:0000269|PubMed:12860203"
FT   MUTAGEN         12
FT                   /note="L->A: Abolishes neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12860203"
FT   MUTAGEN         13
FT                   /note="T->A: Abolishes neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12860203"
FT   MUTAGEN         14
FT                   /note="S->A,R,W,E,P: Abolishes neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12787071, ECO:0000269|PubMed:12860203"
FT   MUTAGEN         14
FT                   /note="S->G: Potentiates neuroprotective activity.
FT                   Increased inhibition of amyloid-beta protein 40 fibril
FT                   formation. Reduced levels of amyloid-beta 42 protein.
FT                   Affects fiber formation with BAX with fewer fibers running
FT                   in parallel. Affects fiber formation with BID with
FT                   formation of shorter fibers. No effect on binding to BID or
FT                   on BID-induced caspase activation and mitochondrial release
FT                   of SMAC. Does not affect interaction with FPR2 or FPR3."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:15465011, ECO:0000269|PubMed:15661737,
FT                   ECO:0000269|PubMed:27349871, ECO:0000269|PubMed:28282805,
FT                   ECO:0000269|PubMed:31690630, ECO:0000269|PubMed:33106313"
FT   MUTAGEN         19..24
FT                   /note="Missing: Abolishes neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357"
FT   MUTAGEN         19
FT                   /note="P->A: Abolishes neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357,
FT                   ECO:0000269|PubMed:12860203"
FT   MUTAGEN         19
FT                   /note="P->R: Abolishes secretion."
FT                   /evidence="ECO:0000269|PubMed:12860203"
FT   MUTAGEN         20..24
FT                   /note="Missing: No effect on neuroprotective activity."
FT                   /evidence="ECO:0000269|PubMed:11717357"
FT   MUTAGEN         20
FT                   /note="V->R: Abolishes secretion."
FT                   /evidence="ECO:0000269|PubMed:12860203"
FT   STRAND          5..10
FT                   /evidence="ECO:0007829|PDB:7WVX"
FT   STRAND          14..17
FT                   /evidence="ECO:0007829|PDB:2GD3"
FT   STRAND          18..21
FT                   /evidence="ECO:0007829|PDB:1Y32"
SQ   SEQUENCE   24 AA;  2687 MW;  08B9A778EC13B971 CRC64;
     MAPRGFSCLL LLTSEIDLPV KRRA
//
ID   NAT8B_HUMAN             Reviewed;         227 AA.
AC   Q9UHF3; Q0VAD9; Q6NT18;
DT   17-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   28-JAN-2026, entry version 130.
DE   RecName: Full=N-acetyltransferase 8B;
DE            EC=2.3.1.- {ECO:0000269|PubMed:19011241, ECO:0000269|PubMed:22267734, ECO:0000269|PubMed:24556617, ECO:0000269|PubMed:31945187};
DE   AltName: Full=Acetyltransferase 1;
DE            Short=ATase1 {ECO:0000303|PubMed:19011241, ECO:0000303|PubMed:24556617};
DE   AltName: Full=Camello-like protein 2;
DE   AltName: Full=Protein-lysine N6-acetyltransferase 8B {ECO:0000305};
GN   Name=NAT8B {ECO:0000312|HGNC:HGNC:30235};
GN   Synonyms=CML2 {ECO:0000303|PubMed:16395595, ECO:0000312|EMBL:AAF22299.1};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Colon tumor {ECO:0000312|EMBL:AAF22299.1};
RX   PubMed=11397015; DOI=10.1006/dbio.2001.0261;
RA   Popsueva A.E., Luchinskaya N.N., Ludwig A.V., Zinovjeva O.Y.,
RA   Poteryaev D.A., Feigelman M.M., Ponomarev M.B., Berekelya L.,
RA   Belyavsky A.V.;
RT   "Overexpression of camello, a member of a novel protein family, reduces
RT   blastomere adhesion and inhibits gastrulation in Xenopus laevis.";
RL   Dev. Biol. 234:483-496(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS 16-SER--LEU-227
RP   DEL AND 168-GLN--LEU-227 DEL.
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [3]
RP   POLYMORPHISM.
RX   PubMed=16395595; DOI=10.1007/s00439-005-0125-6;
RA   Hahn Y., Lee B.;
RT   "Human-specific nonsense mutations identified by genome sequence
RT   comparisons.";
RL   Hum. Genet. 119:169-178(2006).
RN   [4]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INDUCTION BY CERAMIDES,
RP   AND TOPOLOGY.
RX   PubMed=19011241; DOI=10.1074/jbc.m804901200;
RA   Ko M.H., Puglielli L.;
RT   "Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based
RT   lysine acetyltransferases post-translationally regulate BACE1 levels.";
RL   J. Biol. Chem. 284:2482-2492(2009).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, AND INDUCTION.
RX   PubMed=22267734; DOI=10.1074/jbc.m111.310136;
RA   Ding Y., Ko M.H., Pehar M., Kotch F., Peters N.R., Luo Y., Salamat S.M.,
RA   Puglielli L.;
RT   "Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces
RT   beta-secretase (BACE1) levels and Abeta generation.";
RL   J. Biol. Chem. 287:8424-8433(2012).
RN   [6]
RP   FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=24556617; DOI=10.1016/j.jmb.2014.02.012;
RA   Mak A.B., Pehar M., Nixon A.M., Williams R.A., Uetrecht A.C., Puglielli L.,
RA   Moffat J.;
RT   "Post-translational regulation of CD133 by ATase1/ATase2-mediated lysine
RT   acetylation.";
RL   J. Mol. Biol. 426:2175-2182(2014).
RN   [7]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, ACETYLATION AT LYS-99,
RP   AND MUTAGENESIS OF LYS-99; ARG-149; SER-183 AND SER-190.
RX   PubMed=31945187; DOI=10.1111/jnc.14958;
RA   Rigby M.J., Ding Y., Farrugia M.A., Feig M., Cortese G.P., Mitchell H.,
RA   Burger C., Puglielli L.;
RT   "The endoplasmic reticulum acetyltransferases ATase1/NAT8B and ATase2/NAT8
RT   are differentially regulated to adjust engagement of the secretory
RT   pathway.";
RL   J. Neurochem. 154:404-423(2020).
CC   -!- FUNCTION: Endoplasmic reticulum (ER)-membrane-bound lysine N-
CC       acetyltransferase catalyzing the N6-acetylation of lysine residues in
CC       the lumen of the ER in various proteins, including PROM1 and BACE1,
CC       using acetyl-CoA as acetyl donor (PubMed:19011241, PubMed:22267734,
CC       PubMed:24556617, PubMed:31945187). Thereby, may regulate apoptosis
CC       through the acetylation and the regulation of the expression of PROM1
CC       (PubMed:24556617). Acetylates and stabilizes BACE1 immature protein,
CC       leading to increased steady-state levels in neurons. By acting on BACE1
CC       expression, may regulate amyloid beta-peptide formation
CC       (PubMed:19011241, PubMed:22267734). N(6)-lysine acetylation in ER
CC       maintains protein homeostasis and regulates reticulophagy (By
CC       similarity). {ECO:0000250|UniProtKB:E0CYC6,
CC       ECO:0000269|PubMed:19011241, ECO:0000269|PubMed:22267734,
CC       ECO:0000269|PubMed:24556617, ECO:0000269|PubMed:31945187}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-lysyl-[protein] + acetyl-CoA = N(6)-acetyl-L-lysyl-[protein]
CC         + CoA + H(+); Xref=Rhea:RHEA:45948, Rhea:RHEA-COMP:9752, Rhea:RHEA-
CC         COMP:10731, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57288, ChEBI:CHEBI:61930;
CC         Evidence={ECO:0000269|PubMed:19011241, ECO:0000269|PubMed:22267734,
CC         ECO:0000269|PubMed:24556617, ECO:0000269|PubMed:31945187};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45949;
CC         Evidence={ECO:0000305|PubMed:19011241};
CC   -!- ACTIVITY REGULATION: Allosterically regulated by acetylation at residue
CC       Lys-99. {ECO:0000269|PubMed:31945187}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate
CC       compartment membrane {ECO:0000269|PubMed:19011241,
CC       ECO:0000269|PubMed:24556617}; Single-pass type II membrane protein
CC       {ECO:0000305|PubMed:19011241}. Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:19011241}; Single-pass type II membrane protein
CC       {ECO:0000305|PubMed:19011241}. Note=Enriched in the endoplasmic
CC       reticulum-Golgi intermediate compartment (ERGIC).
CC       {ECO:0000269|PubMed:19011241, ECO:0000269|PubMed:24556617}.
CC   -!- INDUCTION: Up-regulated by ceramides (PubMed:19011241). Up-regulated in
CC       the brain of Alzheimer's disease patients (PubMed:22267734).
CC       {ECO:0000269|PubMed:19011241, ECO:0000269|PubMed:22267734}.
CC   -!- PTM: Acetylation on Lys-99 modulates enzymatic activity.
CC       {ECO:0000269|PubMed:31945187}.
CC   -!- POLYMORPHISM: The sequence shown in this entry differs from the
CC       translation of the reference genome assembly (GRCh38/hg38) due to two
CC       nonsense variants creating stop codons at positions 16 and 168 in the
CC       reference genome. Both nonsense variants would abolish catalytic
CC       activity. The sequence shown in this entry is that of the double
CC       variant p.[Ter16Ser;Ter168Gln]. The variant p.Ter16Ser may be extremely
CC       rare and is not reported in the Genome Aggregation Database (gnomAD
CC       v3.1.2). The variant p.Ter168Gln is common in the human population with
CC       a frequency of 75%. Although the existence of the double variant
CC       p.[Ter16Ser;Ter168Gln] has not been proven in normal tissues, several
CC       lines of evidence support its existence in certain tumors or cell
CC       lines. It has been cloned from a colon tumor and has also been detected
CC       at the mRNA level in H4 neuroglioma cell line, as well as in the
CC       neuroblastoma cell line SH-SY5Y (PubMed:11397015, PubMed:19011241). In
CC       H4 and SH-SY5Y cells, its mRNA level can be up-regulated by ceramides.
CC       In H4 cells, the silencing of NAT8B double variant often leads to cell
CC       death, suggesting a function in these cells (PubMed:19011241).
CC       Functional assays show that NAT8B possesses robust N-acetyltransferase
CC       activity in a similar, but not identical way to its paralog NAT8
CC       (PubMed:19011241, PubMed:24556617). {ECO:0000269|PubMed:11397015,
CC       ECO:0000269|PubMed:19011241, ECO:0000269|PubMed:24556617}.
CC   -!- SIMILARITY: Belongs to the NAT8 family. {ECO:0000305}.
CC   -!- CAUTION: The sequence shown in this entry differs from the translation
CC       of the reference genome assembly (GRCh38/hg38) due to two nonsense
CC       variants creating stop codons at positions 16 and 168 in the reference
CC       genome. {ECO:0000305}.
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DR   EMBL; AF185571; AAF22299.1; -; mRNA.
DR   EMBL; AC092653; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   AlphaFoldDB; Q9UHF3; -.
DR   SMR; Q9UHF3; -.
DR   BioGRID; 119557; 21.
DR   FunCoup; Q9UHF3; 43.
DR   IntAct; Q9UHF3; 20.
DR   iPTMnet; Q9UHF3; -.
DR   PhosphoSitePlus; Q9UHF3; -.
DR   BioMuta; NAT8B; -.
DR   MassIVE; Q9UHF3; -.
DR   PeptideAtlas; Q9UHF3; -.
DR   ProteomicsDB; 84340; -.
DR   DNASU; 51471; -.
DR   AGR; HGNC:30235; -.
DR   ClinPGx; PA162396978; -.
DR   DisGeNET; 51471; -.
DR   GeneCards; NAT8B; -.
DR   HGNC; HGNC:30235; NAT8B.
DR   MIM; 608190; gene.
DR   InParanoid; Q9UHF3; -.
DR   OrthoDB; 41532at2759; -.
DR   PAN-GO; Q9UHF3; 1 GO annotation based on evolutionary models.
DR   PhylomeDB; Q9UHF3; -.
DR   BRENDA; 2.3.1.32; 2681.
DR   PathwayCommons; Q9UHF3; -.
DR   Reactome; R-HSA-977225; Amyloid fiber formation.
DR   SignaLink; Q9UHF3; -.
DR   BioGRID-ORCS; 51471; 9 hits in 243 CRISPR screens.
DR   GenomeRNAi; 51471; -.
DR   Pharos; Q9UHF3; Tbio.
DR   PRO; PR:Q9UHF3; -.
DR   Proteomes; UP000005640; Unplaced.
DR   RNAct; Q9UHF3; protein.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR   GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR   GO; GO:0004468; F:L-lysine N-acetyltransferase activity, acting on acetyl phosphate as donor; TAS:Reactome.
DR   GO; GO:0008080; F:N-acetyltransferase activity; IBA:GO_Central.
DR   GO; GO:0061733; F:protein-lysine-acetyltransferase activity; IDA:UniProtKB.
DR   GO; GO:1990000; P:amyloid fibril formation; TAS:Reactome.
DR   GO; GO:0050435; P:amyloid-beta metabolic process; IMP:UniProtKB.
DR   GO; GO:0001702; P:gastrulation with mouth forming second; NAS:UniProtKB.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:0018003; P:peptidyl-lysine N6-acetylation; IDA:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; ISS:UniProtKB.
DR   GO; GO:0140500; P:regulation of reticulophagy; ISS:UniProtKB.
DR   CDD; cd04301; NAT_SF; 1.
DR   FunFam; 3.40.630.30:FF:000118; N-acetyltransferase family 8 member 3; 1.
DR   Gene3D; 3.40.630.30; -; 1.
DR   InterPro; IPR016181; Acyl_CoA_acyltransferase.
DR   InterPro; IPR000182; GNAT_dom.
DR   InterPro; IPR050769; NAT_camello-type.
DR   PANTHER; PTHR13947; GNAT FAMILY N-ACETYLTRANSFERASE; 1.
DR   PANTHER; PTHR13947:SF48; N-ACETYLTRANSFERASE 8-RELATED; 1.
DR   Pfam; PF00583; Acetyltransf_1; 1.
DR   SUPFAM; SSF55729; Acyl-CoA N-acyltransferases (Nat); 1.
DR   PROSITE; PS51186; GNAT; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Acyltransferase; Endoplasmic reticulum; Membrane;
KW   Proteomics identification; Reference proteome; Signal-anchor; Transferase;
KW   Transmembrane; Transmembrane helix.
FT   CHAIN           1..227
FT                   /note="N-acetyltransferase 8B"
FT                   /id="PRO_0000284685"
FT   TOPO_DOM        1..42
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255, ECO:0000269|PubMed:19011241"
FT   TRANSMEM        43..63
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000305|PubMed:19011241"
FT   TOPO_DOM        64..227
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255, ECO:0000269|PubMed:19011241"
FT   DOMAIN          61..214
FT                   /note="N-acetyltransferase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00532"
FT   MOD_RES         99
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:31945187"
FT   VARIANT         16..227
FT                   /note="Missing"
FT                   /evidence="ECO:0000269|PubMed:15815621,
FT                   ECO:0000269|PubMed:16395595"
FT                   /id="VAR_088065"
FT   VARIANT         168..227
FT                   /note="Missing (in dbSNP:rs4852974)"
FT                   /evidence="ECO:0000269|PubMed:15815621,
FT                   ECO:0000269|PubMed:16395595"
FT                   /id="VAR_088066"
FT   MUTAGEN         99
FT                   /note="K->E,R: Diminishes protein-lysine N6-
FT                   acetyltransferase activity."
FT                   /evidence="ECO:0000269|PubMed:31945187"
FT   MUTAGEN         149
FT                   /note="R->A: Exhibits reduced protein-lysine N6-
FT                   acetyltransferase activity; when associated with A-183 and
FT                   A-190."
FT                   /evidence="ECO:0000269|PubMed:31945187"
FT   MUTAGEN         183
FT                   /note="S->A: Exhibits reduced protein-lysine N6-
FT                   acetyltransferase activity; when associated with A-149 and
FT                   A-190."
FT                   /evidence="ECO:0000269|PubMed:31945187"
FT   MUTAGEN         190
FT                   /note="S->A: Exhibits reduced protein-lysine N6-
FT                   acetyltransferase activity; when associated with A-149 and
FT                   A-183."
FT                   /evidence="ECO:0000269|PubMed:31945187"
SQ   SEQUENCE   227 AA;  25366 MW;  E45FBA89E1E03CB0 CRC64;
     MAPYHIRKYQ ESDRKSVVGL LSGGMAEHAP ATFRRLLKLP RTLILLLGGA LALLLVSGSW
     ILALVFSLSL LPALWFLAKK PWTRYVDIAL RTDMSDITKS YLSECGSCFW VAESEEKVVG
     TVGALPVDDP TLREKRLQLF HLSVDNEHRG QGIAKALVRT VLQFARDQGY SEVVLDTSNI
     QLSAMGLYQS LGFKKTGQSF FHVWARLVDL HTVHFIYHLP SAQAGRL
//
ID   OGT1_HUMAN              Reviewed;        1046 AA.
AC   O15294; Q7Z3K0; Q8WWM8; Q96CC1; Q9UG57;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   21-JUN-2005, sequence version 3.
DT   28-JAN-2026, entry version 249.
DE   RecName: Full=UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit;
DE            EC=2.4.1.255 {ECO:0000269|PubMed:15361863, ECO:0000269|PubMed:21240259, ECO:0000269|PubMed:21285374, ECO:0000269|PubMed:30699359, ECO:0000269|PubMed:37541260, ECO:0000305|PubMed:26369908, ECO:0000305|PubMed:26678539};
DE   AltName: Full=O-GlcNAc transferase subunit p110;
DE   AltName: Full=O-linked N-acetylglucosamine transferase 110 kDa subunit;
DE            Short=OGT;
GN   Name=OGT {ECO:0000303|PubMed:11773972, ECO:0000312|HGNC:HGNC:8127};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), PROTEIN SEQUENCE OF 227-236 AND
RP   955-971, AND TISSUE SPECIFICITY.
RC   TISSUE=Liver;
RX   PubMed=9083068; DOI=10.1074/jbc.272.14.9316;
RA   Lubas W.A., Frank D.W., Krause M., Hanover J.A.;
RT   "O-linked GlcNAc transferase is a conserved nucleocytoplasmic protein
RT   containing tetratricopeptide repeats.";
RL   J. Biol. Chem. 272:9316-9324(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 2 AND 3).
RX   PubMed=11773972; DOI=10.1007/s00335-001-2108-9;
RA   Nolte D., Muller U.;
RT   "Human O-GlcNAc transferase (OGT): genomic structure, analysis of splice
RT   variants, fine mapping in Xq13.1.";
RL   Mamm. Genome 13:62-64(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RC   TISSUE=Endometrium, Fetal brain, and Spinal cord;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC   TISSUE=Colon, and Pancreas;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   PROTEIN SEQUENCE OF 2-17; 31-42; 161-168; 244-250; 339-348; 734-752;
RP   868-877 AND 1002-1010, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT
RP   ALA-2, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   TISSUE=Hepatoma;
RA   Bienvenut W.V., Dhillon A.S., Kolch W.;
RL   Submitted (FEB-2008) to UniProtKB.
RN   [6]
RP   FUNCTION, AND INTERACTION WITH SIN3A.
RX   PubMed=12150998; DOI=10.1016/s0092-8674(02)00810-3;
RA   Yang X., Zhang F., Kudlow J.E.;
RT   "Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A:
RT   coupling protein O-GlcNAcylation to transcriptional repression.";
RL   Cell 110:69-80(2002).
RN   [7]
RP   INTERACTION WITH HCFC1.
RX   PubMed=12670868; DOI=10.1101/gad.252103;
RA   Wysocka J., Myers M.P., Laherty C.D., Eisenman R.N., Herr W.;
RT   "Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4
RT   methyltransferase are tethered together selectively by the cell-
RT   proliferation factor HCF-1.";
RL   Genes Dev. 17:896-911(2003).
RN   [8]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [9]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [10]
RP   FUNCTION, AND ASSOCIATION WITH ALZHEIMER DISEASE.
RX   PubMed=19451179; DOI=10.1093/brain/awp099;
RA   Liu F., Shi J., Tanimukai H., Gu J., Gu J., Grundke-Iqbal I., Iqbal K.,
RA   Gong C.X.;
RT   "Reduced O-GlcNAcylation links lower brain glucose metabolism and tau
RT   pathology in Alzheimer's disease.";
RL   Brain 132:1820-1832(2009).
RN   [11]
RP   INDUCTION.
RX   PubMed=19073609; DOI=10.1074/jbc.m803198200;
RA   Taylor R.P., Geisler T.S., Chambers J.H., McClain D.A.;
RT   "Up-regulation of O-GlcNAc transferase with glucose deprivation in HepG2
RT   cells is mediated by decreased hexosamine pathway flux.";
RL   J. Biol. Chem. 284:3425-3432(2009).
RN   [12]
RP   RETRACTED PAPER.
RX   PubMed=19377461; DOI=10.1038/nature07954;
RA   Fujiki R., Chikanishi T., Hashiba W., Ito H., Takada I., Roeder R.G.,
RA   Kitagawa H., Kato S.;
RT   "GlcNAcylation of a histone methyltransferase in retinoic-acid-induced
RT   granulopoiesis.";
RL   Nature 459:455-459(2009).
RN   [13]
RP   RETRACTION NOTICE OF PUBMED:19377461.
RX   PubMed=24336203; DOI=10.1038/nature12896;
RA   Fujiki R., Chikanishi T., Hashiba W., Ito H., Takada I., Roeder R.G.,
RA   Kitagawa H., Kato S.;
RT   "Retraction: GlcNAcylation of a histone methyltransferase in retinoic-acid-
RT   induced granulopoiesis.";
RL   Nature 505:574-574(2014).
RN   [14]
RP   FUNCTION IN HISTONE H4 ACETYLATION, IDENTIFICATION IN NSL COMPLEX, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=20018852; DOI=10.1074/jbc.c109.087981;
RA   Cai Y., Jin J., Swanson S.K., Cole M.D., Choi S.H., Florens L.,
RA   Washburn M.P., Conaway J.W., Conaway R.C.;
RT   "Subunit composition and substrate specificity of a MOF-containing histone
RT   acetyltransferase distinct from the male-specific lethal (MSL) complex.";
RL   J. Biol. Chem. 285:4268-4272(2010).
RN   [15]
RP   FUNCTION, AND POSSIBLE ASSOCIATION WITH DIABETES.
RX   PubMed=20018868; DOI=10.1074/jbc.m109.077818;
RA   Whelan S.A., Dias W.B., Thiruneelakantapillai L., Lane M.D., Hart G.W.;
RT   "Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated
RT   insulin signaling by O-Linked beta-N-acetylglucosamine in 3T3-L1
RT   adipocytes.";
RL   J. Biol. Chem. 285:5204-5211(2010).
RN   [16]
RP   IDENTIFICATION BY MASS SPECTROMETRY IN A THAP1/THAP3-HCFC1-OGT COMPLEX,
RP   INTERACTION WITH THAP1 AND THAP3, AND FUNCTION.
RX   PubMed=20200153; DOI=10.1074/jbc.m109.072579;
RA   Mazars R., Gonzalez-de-Peredo A., Cayrol C., Lavigne A.C., Vogel J.L.,
RA   Ortega N., Lacroix C., Gautier V., Huet G., Ray A., Monsarrat B.,
RA   Kristie T.M., Girard J.P.;
RT   "The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and
RT   O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias.";
RL   J. Biol. Chem. 285:13364-13371(2010).
RN   [17]
RP   FUNCTION (ISOFORM 2), AND SUBCELLULAR LOCATION (ISOFORM 2).
RX   PubMed=20824293; DOI=10.1007/s00726-010-0719-8;
RA   Shin S.H., Love D.C., Hanover J.A.;
RT   "Elevated O-GlcNAc-dependent signaling through inducible mOGT expression
RT   selectively triggers apoptosis.";
RL   Amino Acids 40:885-893(2011).
RN   [18]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [19]
RP   FUNCTION.
RX   PubMed=22121020; DOI=10.1038/nature10656;
RA   Fujiki R., Hashiba W., Sekine H., Yokoyama A., Chikanishi T., Ito S.,
RA   Imai Y., Kim J., He H.H., Igarashi K., Kanno J., Ohtake F., Kitagawa H.,
RA   Roeder R.G., Brown M., Kato S.;
RT   "GlcNAcylation of histone H2B facilitates its monoubiquitination.";
RL   Nature 480:557-560(2011).
RN   [20]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND UBIQUITINATION.
RX   PubMed=21285374; DOI=10.1073/pnas.1013822108;
RA   Daou S., Mashtalir N., Hammond-Martel I., Pak H., Yu H., Sui G.,
RA   Vogel J.L., Kristie T.M., Affar E.B.;
RT   "Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the
RT   host cell factor-1 maturation pathway.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:2747-2752(2011).
RN   [21]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [22]
RP   FUNCTION.
RX   PubMed=22923583; DOI=10.1126/science.1222278;
RA   Yi W., Clark P.M., Mason D.E., Keenan M.C., Hill C., Goddard W.A. III,
RA   Peters E.C., Driggers E.M., Hsieh-Wilson L.C.;
RT   "Phosphofructokinase 1 glycosylation regulates cell growth and
RT   metabolism.";
RL   Science 337:975-980(2012).
RN   [23]
RP   FUNCTION, AND INTERACTION WITH TET2 AND TET3.
RX   PubMed=23353889; DOI=10.1038/emboj.2012.357;
RA   Deplus R., Delatte B., Schwinn M.K., Defrance M., Mendez J., Murphy N.,
RA   Dawson M.A., Volkmar M., Putmans P., Calonne E., Shih A.H., Levine R.L.,
RA   Bernard O., Mercher T., Solary E., Urh M., Daniels D.L., Fuks F.;
RT   "TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and
RT   SET1/COMPASS.";
RL   EMBO J. 32:645-655(2013).
RN   [24]
RP   INTERACTION WITH KMT2E.
RX   PubMed=23629655; DOI=10.1074/jbc.m112.439729;
RA   Zhou P., Wang Z., Yuan X., Zhou C., Liu L., Wan X., Zhang F., Ding X.,
RA   Wang C., Xiong S., Wang Z., Yuan J., Li Q., Zhang Y.;
RT   "Mixed lineage leukemia 5 (MLL5) protein regulates cell cycle progression
RT   and E2F1-responsive gene expression via association with host cell factor-1
RT   (HCF-1).";
RL   J. Biol. Chem. 288:17532-17543(2013).
RN   [25]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [26]
RP   FUNCTION, AND INTERACTION WITH TET2 AND TET3.
RX   PubMed=23222540; DOI=10.1038/nature11742;
RA   Chen Q., Chen Y., Bian C., Fujiki R., Yu X.;
RT   "TET2 promotes histone O-GlcNAcylation during gene transcription.";
RL   Nature 493:561-564(2013).
RN   [27]
RP   INTERACTION WITH KIF5B; RHOT1; RHOT2 AND TRAK1.
RX   PubMed=24995978; DOI=10.1016/j.cell.2014.06.007;
RA   Pekkurnaz G., Trinidad J.C., Wang X., Kong D., Schwarz T.L.;
RT   "Glucose regulates mitochondrial motility via Milton modification by O-
RT   GlcNAc transferase.";
RL   Cell 158:54-68(2014).
RN   [28]
RP   FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT THR-454, AND MUTAGENESIS
RP   OF THR-454.
RX   PubMed=24563466; DOI=10.1074/jbc.m113.523068;
RA   Bullen J.W., Balsbaugh J.L., Chanda D., Shabanowitz J., Hunt D.F.,
RA   Neumann D., Hart G.W.;
RT   "Cross-talk between two essential nutrient-sensitive enzymes: O-GlcNAc
RT   transferase (OGT) and AMP-activated protein kinase (AMPK).";
RL   J. Biol. Chem. 289:10592-10606(2014).
RN   [29]
RP   FUNCTION.
RX   PubMed=24474760; DOI=10.1073/pnas.1323226111;
RA   Chu C.S., Lo P.W., Yeh Y.H., Hsu P.H., Peng S.H., Teng Y.C., Kang M.L.,
RA   Wong C.H., Juan L.J.;
RT   "O-GlcNAcylation regulates EZH2 protein stability and function.";
RL   Proc. Natl. Acad. Sci. U.S.A. 111:1355-1360(2014).
RN   [30]
RP   FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN A COMPLEX WITH KMT2E AND
RP   USP7, INTERACTION WITH KMT2E AND USP7, SUBCELLULAR LOCATION, ACTIVE SITE,
RP   AND MUTAGENESIS OF HIS-508 AND HIS-568.
RX   PubMed=26678539; DOI=10.1371/journal.pone.0145023;
RA   Ding X., Jiang W., Zhou P., Liu L., Wan X., Yuan X., Wang X., Chen M.,
RA   Chen J., Yang J., Kong C., Li B., Peng C., Wong C.C., Hou F., Zhang Y.;
RT   "Mixed lineage leukemia 5 (MLL5) protein stability is cooperatively
RT   regulated by O-GlcNac transferase (OGT) and ubiquitin specific protease 7
RT   (USP7).";
RL   PLoS ONE 10:E0145023-E0145023(2015).
RN   [31]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=26369908; DOI=10.1093/glycob/cwv076;
RA   Hou C.W., Mohanan V., Zachara N.E., Grimes C.L.;
RT   "Identification and biological consequences of the O-GlcNAc modification of
RT   the human innate immune receptor, Nod2.";
RL   Glycobiology 26:13-18(2016).
RN   [32]
RP   FUNCTION.
RX   PubMed=27527864; DOI=10.18632/oncotarget.11083;
RA   Jo Y.K., Park N.Y., Park S.J., Kim B.G., Shin J.H., Jo D.S., Bae D.J.,
RA   Suh Y.A., Chang J.H., Lee E.K., Kim S.Y., Kim J.C., Cho D.H.;
RT   "O-GlcNAcylation of ATG4B positively regulates autophagy by increasing its
RT   hydroxylase activity.";
RL   Oncotarget 7:57186-57196(2016).
RN   [33]
RP   FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, GLYCOSYLATION
RP   AT SER-399, AND MUTAGENESIS OF 208-TRP--ILE-211; SER-391; THR-393; SER-399
RP   AND THR-404.
RX   PubMed=27713473; DOI=10.1038/srep34614;
RA   Seo H.G., Kim H.B., Kang M.J., Ryum J.H., Yi E.C., Cho J.W.;
RT   "Identification of the nuclear localisation signal of O-GlcNAc transferase
RT   and its nuclear import regulation.";
RL   Sci. Rep. 6:34614-34614(2016).
RN   [34]
RP   INTERACTION WITH HUMAN T-CELL LEUKEMIA VIRUS 1/HTLV-1 PROTEIN TAX.
RX   PubMed=28742148; DOI=10.1371/journal.ppat.1006518;
RA   Groussaud D., Khair M., Tollenaere A.I., Waast L., Kuo M.S., Mangeney M.,
RA   Martella C., Fardini Y., Coste S., Souidi M., Benit L., Pique C., Issad T.;
RT   "Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein
RT   facilitates viral transcription.";
RL   PLoS Pathog. 13:E1006518-E1006518(2017).
RN   [35]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=30699359; DOI=10.1016/j.celrep.2019.01.018;
RA   Sager R.A., Woodford M.R., Backe S.J., Makedon A.M., Baker-Williams A.J.,
RA   DiGregorio B.T., Loiselle D.R., Haystead T.A., Zachara N.E., Prodromou C.,
RA   Bourboulia D., Schmidt L.S., Linehan W.M., Bratslavsky G., Mollapour M.;
RT   "Post-translational regulation of FNIP1 creates a rheostat for the
RT   molecular chaperone Hsp90.";
RL   Cell Rep. 26:1344-1356(2019).
RN   [36]
RP   FUNCTION (ISOFORM 4), CATALYTIC ACTIVITY (ISOFORM 4), GLYCOSYLATION AT
RP   SER-10; THR-12; SER-18; THR-38; SER-52 AND SER-56 (ISOFORM 4), AND
RP   MUTAGENESIS OF SER-10; THR-12; SER-18; THR-38; SER-52; SER-56 AND HIS-127
RP   (ISOFORM 4).
RX   PubMed=31527085; DOI=10.1074/jbc.ra119.009085;
RA   Liu L., Li L., Ma C., Shi Y., Liu C., Xiao Z., Zhang Y., Tian F., Gao Y.,
RA   Zhang J., Ying W., Wang P.G., Zhang L.;
RT   "O-GlcNAcylation of Thr12/Ser56 in short-form O-GlcNAc transferase (sOGT)
RT   regulates its substrate selectivity.";
RL   J. Biol. Chem. 294:16620-16633(2019).
RN   [37]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=34074792; DOI=10.1073/pnas.2104897118;
RA   Kim T.H., Payliss B.J., Nosella M.L., Lee I.T.W., Toyama Y.,
RA   Forman-Kay J.D., Kay L.E.;
RT   "Interaction hot spots for phase separation revealed by NMR studies of a
RT   CAPRIN1 condensed phase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021).
RN   [38]
RP   FUNCTION, AND INTERACTION WITH PROSER1.
RX   PubMed=34667079; DOI=10.26508/lsa.202101228;
RA   Wang X., Rosikiewicz W., Sedkov Y., Martinez T., Hansen B.S., Schreiner P.,
RA   Christensen J., Xu B., Pruett-Miller S.M., Helin K., Herz H.M.;
RT   "PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on
RT   UTX-dependent enhancers and CpG islands.";
RL   Life. Sci Alliance 5:0-0(2022).
RN   [39]
RP   FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBUNIT, PHOSPHORYLATION AT THR-454,
RP   AND MUTAGENESIS OF THR-454 AND 461-ASP--PRO-463.
RX   PubMed=37541260; DOI=10.1016/j.molcel.2023.07.011;
RA   Xu C., Pan X., Wang D., Guan Y., Yang W., Chen X., Liu Y.;
RT   "O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.";
RL   Mol. Cell 0:0-0(2023).
RN   [40]
RP   FUNCTION.
RX   PubMed=37962578; DOI=10.1007/s00011-023-01812-1;
RA   Yu F., Zhang Z., Leng Y., Chen A.F.;
RT   "O-GlcNAc modification of GSDMD attenuates LPS-induced endothelial cells
RT   pyroptosis.";
RL   Inflamm. Res. 73:5-17(2024).
RN   [41]
RP   UBIQUITINATION.
RX   PubMed=39894887; DOI=10.1038/s41467-025-56633-z;
RA   Zhang N., Meng Y., Mao S., Ni H., Huang C., Shen L., Fu K., Lv L., Yu C.,
RA   Meekrathok P., Kuang C., Chen F., Zhang Y., Yuan K.;
RT   "FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation
RT   homeostasis to restrain endometrial malignancy.";
RL   Nat. Commun. 16:1274-1274(2025).
RN   [42]
RP   X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 26-400, FUNCTION, CATALYTIC
RP   ACTIVITY, DOMAIN, AND MUTAGENESIS OF TRP-208 AND ILE-211.
RX   PubMed=15361863; DOI=10.1038/nsmb833;
RA   Jinek M., Rehwinkel J., Lazarus B.D., Izaurralde E., Hanover J.A.,
RA   Conti E.;
RT   "The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits
RT   structural similarities to importin alpha.";
RL   Nat. Struct. Mol. Biol. 11:1001-1007(2004).
RN   [43]
RP   X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 323-1041 IN COMPLEXES WITH UDP
RP   AND PEPTIDE SUBSTRATE, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP   BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, ACTIVE SITE, AND MUTAGENESIS OF
RP   HIS-508; HIS-568 AND HIS-911.
RX   PubMed=21240259; DOI=10.1038/nature09638;
RA   Lazarus M.B., Nam Y., Jiang J., Sliz P., Walker S.;
RT   "Structure of human O-GlcNAc transferase and its complex with a peptide
RT   substrate.";
RL   Nature 469:564-567(2011).
RN   [44] {ECO:0007744|PDB:4GYW, ECO:0007744|PDB:4GYY, ECO:0007744|PDB:4GZ3, ECO:0007744|PDB:4GZ5, ECO:0007744|PDB:4GZ6}
RP   X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 323-1041 IN COMPLEXES WITH UDP;
RP   PEPTIDE SUBSTRATE; SUBSTRATE ANALOGS; PRODUCT AND PRODUCT ANALOG, FUNCTION,
RP   CATALYTIC ACTIVITY, PATHWAY, SUBSTRATE SPECIFICITY, AND REACTION MECHANISM.
RX   PubMed=23103939; DOI=10.1038/nchembio.1109;
RA   Lazarus M.B., Jiang J., Gloster T.M., Zandberg W.F., Whitworth G.E.,
RA   Vocadlo D.J., Walker S.;
RT   "Structural snapshots of the reaction coordinate for O-GlcNAc
RT   transferase.";
RL   Nat. Chem. Biol. 8:966-968(2012).
RN   [45] {ECO:0007744|PDB:4XI9, ECO:0007744|PDB:4XIF, ECO:0007744|PDB:5BNW, ECO:0007744|PDB:5C1D}
RP   X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 323-1041 IN COMPLEX WITH PEPTIDE
RP   SUBSTRATES, FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=26237509; DOI=10.1038/nsmb.3063;
RA   Pathak S., Alonso J., Schimpl M., Rafie K., Blair D.E., Borodkin V.S.,
RA   Albarbarawi O., van Aalten D.M.F.;
RT   "The active site of O-GlcNAc transferase imposes constraints on substrate
RT   sequence.";
RL   Nat. Struct. Mol. Biol. 22:744-750(2015).
RN   [46]
RP   VARIANT XLID106 THR-319.
RX   PubMed=26273451; DOI=10.1002/ccr3.301;
RA   Bouazzi H., Lesca G., Trujillo C., Alwasiyah M.K., Munnich A.;
RT   "Nonsyndromic X-linked intellectual deficiency in three brothers with a
RT   novel MED12 missense mutation [c.5922G>T (p.Glu1974His)].";
RL   Clin. Case Rep. 3:604-609(2015).
RN   [47]
RP   VARIANT XLID106 PHE-254, CHARACTERIZATION OF VARIANT XLID106 PHE-254, AND
RP   FUNCTION.
RX   PubMed=28302723; DOI=10.1074/jbc.m116.771030;
RA   Vaidyanathan K., Niranjan T., Selvan N., Teo C.F., May M., Patel S.,
RA   Weatherly B., Skinner C., Opitz J., Carey J., Viskochil D., Gecz J.,
RA   Shaw M., Peng Y., Alexov E., Wang T., Schwartz C., Wells L.;
RT   "Identification and characterization of a missense mutation in the O-linked
RT   beta-N-acetylglucosamine (O-GlcNAc) transferase gene that segregates with
RT   X-linked intellectual disability.";
RL   J. Biol. Chem. 292:8948-8963(2017).
RN   [48]
RP   VARIANT XLID106 PRO-284, CHARACTERIZATION OF VARIANT XLID106 PRO-284, AND
RP   FUNCTION.
RX   PubMed=28584052; DOI=10.1074/jbc.m117.790097;
RA   Willems A.P., Gundogdu M., Kempers M.J.E., Giltay J.C., Pfundt R.,
RA   Elferink M., Loza B.F., Fuijkschot J., Ferenbach A.T., van Gassen K.L.I.,
RA   van Aalten D.M.F., Lefeber D.J.;
RT   "Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients with
RT   X-linked intellectual disability.";
RL   J. Biol. Chem. 292:12621-12631(2017).
CC   -!- FUNCTION: Catalyzes the transfer of a single N-acetylglucosamine from
CC       UDP-GlcNAc to a serine or threonine residue in cytoplasmic and nuclear
CC       proteins resulting in their modification with a beta-linked N-
CC       acetylglucosamine (O-GlcNAc) (PubMed:12150998, PubMed:15361863,
CC       PubMed:19451179, PubMed:20018868, PubMed:21240259, PubMed:21285374,
CC       PubMed:23103939, PubMed:26237509, PubMed:26369908, PubMed:26678539,
CC       PubMed:27713473, PubMed:37541260, PubMed:37962578). Glycosylates a
CC       large and diverse number of proteins including histone H2B, AKT1, AMPK,
CC       ATG4B, CAPRIN1, EZH2, FNIP1, GSDMD, KRT7, LMNA, LMNB1, LMNB2, RPTOR,
CC       HOXA1, PFKL, KMT2E/MLL5, MAPT/TAU, TET2, RBL2, RET, NOD2 and HCFC1
CC       (PubMed:19451179, PubMed:20200153, PubMed:21285374, PubMed:22923583,
CC       PubMed:23353889, PubMed:24474760, PubMed:26237509, PubMed:26369908,
CC       PubMed:26678539, PubMed:27527864, PubMed:30699359, PubMed:34074792,
CC       PubMed:34667079, PubMed:37541260, PubMed:37962578). Can regulate their
CC       cellular processes via cross-talk between glycosylation and
CC       phosphorylation or by affecting proteolytic processing
CC       (PubMed:21285374). Involved in insulin resistance in muscle and
CC       adipocyte cells via glycosylating insulin signaling components and
CC       inhibiting the 'Thr-308' phosphorylation of AKT1, enhancing IRS1
CC       phosphorylation and attenuating insulin signaling (By similarity).
CC       Involved in glycolysis regulation by mediating glycosylation of 6-
CC       phosphofructokinase PFKL, inhibiting its activity (PubMed:22923583).
CC       Plays a key role in chromatin structure by mediating O-GlcNAcylation of
CC       'Ser-112' of histone H2B: recruited to CpG-rich transcription start
CC       sites of active genes via its interaction with TET proteins (TET1, TET2
CC       or TET3) (PubMed:22121020, PubMed:23353889). As part of the NSL complex
CC       indirectly involved in acetylation of nucleosomal histone H4 on several
CC       lysine residues (PubMed:20018852). O-GlcNAcylation of 'Ser-75' of EZH2
CC       increases its stability, and facilitating the formation of H3K27me3 by
CC       the PRC2/EED-EZH2 complex (PubMed:24474760). Stabilizes KMT2E/MLL5 by
CC       mediating its glycosylation, thereby preventing KMT2E/MLL5
CC       ubiquitination (PubMed:26678539). Regulates circadian oscillation of
CC       the clock genes and glucose homeostasis in the liver (By similarity).
CC       Stabilizes clock proteins BMAL1 and CLOCK through O-glycosylation,
CC       which prevents their ubiquitination and subsequent degradation (By
CC       similarity). Promotes the CLOCK-BMAL1-mediated transcription of genes
CC       in the negative loop of the circadian clock such as PER1/2 and CRY1/2.
CC       O-glycosylates HCFC1 and regulates its proteolytic processing and
CC       transcriptional activity (PubMed:21285374, PubMed:28302723,
CC       PubMed:28584052). Component of a THAP1/THAP3-HCFC1-OGT complex that is
CC       required for the regulation of the transcriptional activity of RRM1
CC       (PubMed:20200153). Regulates mitochondrial motility in neurons by
CC       mediating glycosylation of TRAK1 (By similarity). Promotes autophagy by
CC       mediating O-glycosylation of ATG4B (PubMed:27527864). Acts as a
CC       regulator of mTORC1 signaling by mediating O-glycosylation of RPTOR and
CC       FNIP1: O-GlcNAcylation of RPTOR in response to glucose sufficiency
CC       promotes activation of the mTORC1 complex (PubMed:30699359,
CC       PubMed:37541260). {ECO:0000250|UniProtKB:P56558,
CC       ECO:0000250|UniProtKB:Q8CGY8, ECO:0000269|PubMed:12150998,
CC       ECO:0000269|PubMed:15361863, ECO:0000269|PubMed:19451179,
CC       ECO:0000269|PubMed:20018852, ECO:0000269|PubMed:20018868,
CC       ECO:0000269|PubMed:20200153, ECO:0000269|PubMed:21240259,
CC       ECO:0000269|PubMed:21285374, ECO:0000269|PubMed:22121020,
CC       ECO:0000269|PubMed:22923583, ECO:0000269|PubMed:23103939,
CC       ECO:0000269|PubMed:23353889, ECO:0000269|PubMed:24474760,
CC       ECO:0000269|PubMed:24563466, ECO:0000269|PubMed:26237509,
CC       ECO:0000269|PubMed:26369908, ECO:0000269|PubMed:26678539,
CC       ECO:0000269|PubMed:27527864, ECO:0000269|PubMed:28302723,
CC       ECO:0000269|PubMed:28584052, ECO:0000269|PubMed:30699359,
CC       ECO:0000269|PubMed:34074792, ECO:0000269|PubMed:34667079,
CC       ECO:0000269|PubMed:37541260, ECO:0000269|PubMed:37962578}.
CC   -!- FUNCTION: [Isoform 2]: The mitochondrial isoform (mOGT) is cytotoxic
CC       and triggers apoptosis in several cell types including INS1, an
CC       insulinoma cell line. {ECO:0000269|PubMed:20824293}.
CC   -!- FUNCTION: [Isoform 4]: Has N-acetylglucosaminyltransferase activity:
CC       glycosylates proteins, such as HNRNPU, NEUROD1, NUP62 and PDCD6IP
CC       (PubMed:31527085). Displays specific substrate selectivity compared to
CC       other isoforms (PubMed:31527085). {ECO:0000269|PubMed:31527085}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-(N-
CC         acetyl-beta-D-glucosaminyl)-L-seryl-[protein] + UDP + H(+);
CC         Xref=Rhea:RHEA:48904, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:12251,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:57705,
CC         ChEBI:CHEBI:58223, ChEBI:CHEBI:90838; EC=2.4.1.255;
CC         Evidence={ECO:0000269|PubMed:15361863, ECO:0000269|PubMed:21240259,
CC         ECO:0000269|PubMed:21285374, ECO:0000269|PubMed:23103939,
CC         ECO:0000269|PubMed:24563466, ECO:0000269|PubMed:26237509,
CC         ECO:0000269|PubMed:27713473, ECO:0000269|PubMed:30699359,
CC         ECO:0000269|PubMed:34074792, ECO:0000305|PubMed:26369908,
CC         ECO:0000305|PubMed:26678539};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48905;
CC         Evidence={ECO:0000269|PubMed:24563466, ECO:0000269|PubMed:26237509,
CC         ECO:0000269|PubMed:27713473, ECO:0000269|PubMed:30699359,
CC         ECO:0000269|PubMed:34074792};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-
CC         (N-acetyl-beta-D-glucosaminyl)-L-threonyl-[protein] + UDP + H(+);
CC         Xref=Rhea:RHEA:48908, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:12252,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:57705,
CC         ChEBI:CHEBI:58223, ChEBI:CHEBI:90840; EC=2.4.1.255;
CC         Evidence={ECO:0000269|PubMed:15361863, ECO:0000269|PubMed:21240259,
CC         ECO:0000269|PubMed:21285374, ECO:0000269|PubMed:24563466,
CC         ECO:0000269|PubMed:26237509, ECO:0000269|PubMed:37541260,
CC         ECO:0000305|PubMed:26678539};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48909;
CC         Evidence={ECO:0000269|PubMed:24563466, ECO:0000269|PubMed:26237509,
CC         ECO:0000269|PubMed:27713473, ECO:0000269|PubMed:37541260};
CC   -!- CATALYTIC ACTIVITY: [Isoform 4]:
CC       Reaction=L-seryl-[protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-(N-
CC         acetyl-beta-D-glucosaminyl)-L-seryl-[protein] + UDP + H(+);
CC         Xref=Rhea:RHEA:48904, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:12251,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:57705,
CC         ChEBI:CHEBI:58223, ChEBI:CHEBI:90838; EC=2.4.1.255;
CC         Evidence={ECO:0000269|PubMed:31527085};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48905;
CC         Evidence={ECO:0000269|PubMed:31527085};
CC   -!- CATALYTIC ACTIVITY: [Isoform 4]:
CC       Reaction=L-threonyl-[protein] + UDP-N-acetyl-alpha-D-glucosamine = 3-O-
CC         (N-acetyl-beta-D-glucosaminyl)-L-threonyl-[protein] + UDP + H(+);
CC         Xref=Rhea:RHEA:48908, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:12252,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:57705,
CC         ChEBI:CHEBI:58223, ChEBI:CHEBI:90840; EC=2.4.1.255;
CC         Evidence={ECO:0000269|PubMed:31527085};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48909;
CC         Evidence={ECO:0000269|PubMed:31527085};
CC   -!- ACTIVITY REGULATION: Subject to product inhibition by UDP.
CC       {ECO:0000269|PubMed:21240259}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=1.8 uM for UDP-N-acetyl-D-glucosamine
CC         {ECO:0000269|PubMed:21240259};
CC   -!- PATHWAY: Protein modification; protein glycosylation.
CC       {ECO:0000269|PubMed:15361863, ECO:0000269|PubMed:21240259,
CC       ECO:0000269|PubMed:21285374, ECO:0000269|PubMed:23103939,
CC       ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:27713473,
CC       ECO:0000269|PubMed:31527085, ECO:0000269|PubMed:37541260}.
CC   -!- SUBUNIT: Monomer; may exist in different oligomerization states in
CC       cells (PubMed:21240259, PubMed:27713473). Homotrimer, oligomerizes via
CC       TPR repeats 6 and 7. Trimerization is not necessary for activity in
CC       vitro, however it increases affinity for UDP-GlcNAc (By similarity).
CC       Component of a THAP1/THAP3-HCFC1-OGT complex (PubMed:12670868,
CC       PubMed:20200153). Component of the NSL complex at least composed of
CC       MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and
CC       HCFC1 (PubMed:20018852). Found in a complex with KIF5B, RHOT1, RHOT2
CC       and TRAK1 (PubMed:24995978). Found in a complex composed of at least
CC       SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Component of a
CC       complex composed of KMT2E/MLL5 (isoform 3), OGT (isoform 1) and USP7;
CC       the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination
CC       and proteasomal-mediated degradation (PubMed:23629655,
CC       PubMed:26678539). Interacts (via TPRs 1-6) with SIN3A; the interaction
CC       mediates transcriptional repression in parallel with histone
CC       deacetylase (PubMed:12150998). Interacts (via TPR 5-6) with TET1, TET2
CC       and TET3 (PubMed:23222540, PubMed:23353889). Interacts (via TPR repeats
CC       6 and 7) with ATXN10 (By similarity). Interacts with NSD2 (By
CC       similarity). Interacts with PROSER1; this interaction mediates TET2 O-
CC       GlcNAcylation and stability by promoting the interaction between OGT
CC       and TET2 (PubMed:34667079). {ECO:0000250|UniProtKB:P56558,
CC       ECO:0000250|UniProtKB:Q8CGY8, ECO:0000269|PubMed:12150998,
CC       ECO:0000269|PubMed:20018852, ECO:0000269|PubMed:20200153,
CC       ECO:0000269|PubMed:21240259, ECO:0000269|PubMed:23222540,
CC       ECO:0000269|PubMed:23353889, ECO:0000269|PubMed:23629655,
CC       ECO:0000269|PubMed:24995978, ECO:0000269|PubMed:26678539,
CC       ECO:0000269|PubMed:34667079}.
CC   -!- SUBUNIT: [Isoform 1]: Interacts with USP7.
CC       {ECO:0000269|PubMed:26678539}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with human T-cell leukemia
CC       virus 1/HTLV-1 protein Tax; this interaction increases Tax interacting
CC       partner CREB1 O-GlcNAcylation. {ECO:0000269|PubMed:28742148}.
CC   -!- INTERACTION:
CC       O15294; Q9BTC0: DIDO1; NbExp=4; IntAct=EBI-539828, EBI-739985;
CC       O15294; P51610: HCFC1; NbExp=10; IntAct=EBI-539828, EBI-396176;
CC       O15294; O95644: NFATC1; NbExp=2; IntAct=EBI-539828, EBI-6907210;
CC       O15294; Q9H1M0: NUP62CL; NbExp=7; IntAct=EBI-539828, EBI-751933;
CC       O15294; Q8NDX5: PHC3; NbExp=3; IntAct=EBI-539828, EBI-1223801;
CC       O15294; P36873: PPP1CC; NbExp=11; IntAct=EBI-539828, EBI-356283;
CC       O15294; P11464: PSG1; NbExp=3; IntAct=EBI-539828, EBI-716740;
CC       O15294; Q04206: RELA; NbExp=2; IntAct=EBI-539828, EBI-73886;
CC       O15294; O95721: SNAP29; NbExp=2; IntAct=EBI-539828, EBI-490676;
CC       O15294; Q15750: TAB1; NbExp=3; IntAct=EBI-539828, EBI-358643;
CC       O15294; E7EQS8: TET2; NbExp=3; IntAct=EBI-539828, EBI-10177000;
CC       O15294; Q6N021: TET2; NbExp=7; IntAct=EBI-539828, EBI-310727;
CC       O15294; Q6N021-1: TET2; NbExp=5; IntAct=EBI-539828, EBI-20717492;
CC       O15294; O43151: TET3; NbExp=7; IntAct=EBI-539828, EBI-2831148;
CC       O15294; Q9UPV9: TRAK1; NbExp=3; IntAct=EBI-539828, EBI-1105048;
CC       O15294; O94763: URI1; NbExp=10; IntAct=EBI-539828, EBI-357067;
CC       O15294; O94763-1: URI1; NbExp=3; IntAct=EBI-539828, EBI-12590720;
CC       O15294; P09022: Hoxa1; Xeno; NbExp=3; IntAct=EBI-539828, EBI-3957603;
CC       O15294; P63088: Ppp1cc; Xeno; NbExp=3; IntAct=EBI-539828, EBI-80049;
CC       O15294; Q8BG87: Tet3; Xeno; NbExp=2; IntAct=EBI-539828, EBI-9031997;
CC       O15294-3; A0A0S2Z5B5: NUP62CL; NbExp=3; IntAct=EBI-11536584, EBI-16439000;
CC       O15294-3; Q9H1M0: NUP62CL; NbExp=3; IntAct=EBI-11536584, EBI-751933;
CC       O15294-3; Q9UHR5: SAP30BP; NbExp=3; IntAct=EBI-11536584, EBI-751683;
CC       O15294-3; Q8N9R8: SCAI; NbExp=3; IntAct=EBI-11536584, EBI-4395514;
CC       O15294-3; Q15973: ZNF124; NbExp=3; IntAct=EBI-11536584, EBI-2555767;
CC       O15294-3; Q12140: BSC1; Xeno; NbExp=3; IntAct=EBI-11536584, EBI-36401;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26678539,
CC       ECO:0000269|PubMed:27713473}. Cytoplasm {ECO:0000269|PubMed:26678539,
CC       ECO:0000269|PubMed:27713473}. Note=Predominantly localizes to the
CC       nucleus (PubMed:26678539). Translocates into the nucleus via
CC       association with importin KPNA1 (PubMed:27713473).
CC       {ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:27713473}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion
CC       {ECO:0000269|PubMed:20824293}. Membrane {ECO:0000269|PubMed:20824293}.
CC       Note=Associates with the mitochondrial inner membrane.
CC       {ECO:0000269|PubMed:20824293}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm
CC       {ECO:0000269|PubMed:21285374}. Nucleus {ECO:0000269|PubMed:20018852,
CC       ECO:0000269|PubMed:21285374}. Cell membrane
CC       {ECO:0000250|UniProtKB:P56558}. Mitochondrion membrane
CC       {ECO:0000250|UniProtKB:P56558}. Cell projection
CC       {ECO:0000250|UniProtKB:P56558}. Note=Mostly in the nucleus. Retained in
CC       the nucleus via interaction with HCFC1 (PubMed:21285374). After insulin
CC       induction, translocated from the nucleus to the cell membrane via
CC       phosphatidylinositide binding. Colocalizes with AKT1 at the plasma
CC       membrane. TRAK1 recruits this protein to mitochondria. In the absence
CC       of TRAK1, localizes in cytosol and nucleus (By similarity).
CC       {ECO:0000250|UniProtKB:P56558, ECO:0000269|PubMed:21285374}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm
CC       {ECO:0000303|PubMed:31527085}. Nucleus {ECO:0000303|PubMed:31527085}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=4;
CC       Name=3; Synonyms=Nucleocytoplasmic isoform
CC       {ECO:0000303|PubMed:31527085}, ncOGT {ECO:0000303|PubMed:31527085};
CC         IsoId=O15294-1; Sequence=Displayed;
CC       Name=2; Synonyms=Mitochondrial isoform {ECO:0000303|PubMed:20824293},
CC       mOGT {ECO:0000303|PubMed:20824293};
CC         IsoId=O15294-2; Sequence=VSP_006553;
CC       Name=1;
CC         IsoId=O15294-3; Sequence=VSP_014164;
CC       Name=4; Synonyms=Short isoform {ECO:0000303|PubMed:31527085}, sOGT
CC       {ECO:0000303|PubMed:31527085};
CC         IsoId=O15294-4; Sequence=VSP_040764;
CC   -!- TISSUE SPECIFICITY: Highly expressed in pancreas and to a lesser extent
CC       in skeletal muscle, heart, brain and placenta. Present in trace amounts
CC       in lung and liver. {ECO:0000269|PubMed:9083068}.
CC   -!- INDUCTION: [Isoform 3]: Induction of the nucleocytoplasmic OGT (ncOGT)
CC       isoform in the liver on glucose deprivation is mediated by the
CC       decreased hexosamine biosynthesis pathway (HBP) flux.
CC       {ECO:0000269|PubMed:19073609}.
CC   -!- DOMAIN: The TPR repeat domain is required for substrate binding and
CC       oligomerization. {ECO:0000269|PubMed:15361863}.
CC   -!- PTM: Ubiquitinated by the SCF(FBXO31) complex, leading to its
CC       proteasomal degradation. {ECO:0000269|PubMed:21285374,
CC       ECO:0000269|PubMed:39894887}.
CC   -!- PTM: Phosphorylation on Ser-3 or Ser-4 by GSK3-beta positively
CC       regulates its activity (By similarity). Phosphorylation at Thr-454 by
CC       AMPK promotes nuclear localization (PubMed:24563466).
CC       {ECO:0000250|UniProtKB:Q8CGY8, ECO:0000269|PubMed:24563466}.
CC   -!- PTM: Glycosylated via autocatalysis; O-GlcNAcylation at Ser-399
CC       promotes nuclear localization. {ECO:0000269|PubMed:27713473}.
CC   -!- PTM: [Isoform 4]: Glycosylated via autocatalysis; does not affect the
CC       enzyme activity but regulates substrate selectivity.
CC       {ECO:0000269|PubMed:31527085}.
CC   -!- DISEASE: Note=Regulation of OGT activity and altered O-GlcNAcylations
CC       are implicated in diabetes and Alzheimer disease. O-GlcNAcylation of
CC       AKT1 affects insulin signaling and, possibly diabetes. Reduced O-
CC       GlcNAcylations and resulting increased phosphorylations of MAPT/TAU are
CC       observed in Alzheimer disease (AD) brain cerebrum.
CC       {ECO:0000269|PubMed:19451179}.
CC   -!- DISEASE: Intellectual developmental disorder, X-linked 106 (XLID106)
CC       [MIM:300997]: A form of intellectual disability, a disorder
CC       characterized by significantly below average general intellectual
CC       functioning associated with impairments in adaptive behavior and
CC       manifested during the developmental period. Intellectual deficiency is
CC       the only primary symptom of non-syndromic X-linked forms, while
CC       syndromic forms present with associated physical, neurological and/or
CC       psychiatric manifestations. {ECO:0000269|PubMed:26273451,
CC       ECO:0000269|PubMed:28302723, ECO:0000269|PubMed:28584052}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the glycosyltransferase 41 family. O-GlcNAc
CC       transferase subfamily. {ECO:0000305}.
CC   -!- CAUTION: Was originally thought to be part of the MLL5-L complex, at
CC       least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and
CC       OGT (PubMed:19377461). However, the corresponding article has been
CC       retracted (PubMed:24336203). {ECO:0000269|PubMed:19377461,
CC       ECO:0000269|PubMed:24336203}.
CC   -!- WEB RESOURCE: Name=Functional Glycomics Gateway - GTase; Note=UDP-N-
CC       acetylglucosamine--peptide N-acetylglucosaminyltransferase 110kDa
CC       subunit;
CC       URL="http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_hum_554";
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DR   EMBL; U77413; AAB63466.1; -; mRNA.
DR   EMBL; AJ315767; CAC86127.1; -; Genomic_DNA.
DR   EMBL; AJ315767; CAC86128.1; -; Genomic_DNA.
DR   EMBL; AJ315767; CAC86129.1; -; Genomic_DNA.
DR   EMBL; AL050366; CAB62528.1; -; mRNA.
DR   EMBL; AL833085; CAD89970.1; -; mRNA.
DR   EMBL; BX537844; CAD97853.1; -; mRNA.
DR   EMBL; BC014434; AAH14434.1; -; mRNA.
DR   EMBL; BC038180; AAH38180.1; -; mRNA.
DR   CCDS; CCDS14414.1; -. [O15294-1]
DR   CCDS; CCDS35502.1; -. [O15294-3]
DR   RefSeq; NP_858058.1; NM_181672.3. [O15294-1]
DR   RefSeq; NP_858059.1; NM_181673.3. [O15294-3]
DR   PDB; 1W3B; X-ray; 2.85 A; A/B=26-410.
DR   PDB; 3PE3; X-ray; 2.78 A; A/B/C/D=323-1041.
DR   PDB; 3PE4; X-ray; 1.95 A; A/C=323-1041.
DR   PDB; 3TAX; X-ray; 1.88 A; A/C=323-1041.
DR   PDB; 4AY5; X-ray; 3.15 A; A/B/C/D=323-1041.
DR   PDB; 4AY6; X-ray; 3.30 A; A/B/C/D=323-1041.
DR   PDB; 4CDR; X-ray; 3.15 A; A/B/C/D=323-1041.
DR   PDB; 4GYW; X-ray; 1.70 A; A/C=323-1041.
DR   PDB; 4GYY; X-ray; 1.85 A; A/C=323-1041.
DR   PDB; 4GZ3; X-ray; 1.90 A; A/C=323-1041.
DR   PDB; 4GZ5; X-ray; 3.08 A; A/B/C/D=323-1041.
DR   PDB; 4GZ6; X-ray; 2.98 A; A/B/C/D=323-1041.
DR   PDB; 4N39; X-ray; 1.76 A; A=323-1041.
DR   PDB; 4N3A; X-ray; 1.88 A; A=323-1041.
DR   PDB; 4N3B; X-ray; 2.17 A; A=323-1041.
DR   PDB; 4N3C; X-ray; 2.55 A; A=323-1041.
DR   PDB; 4XI9; X-ray; 3.10 A; A/B/C/D=323-1041.
DR   PDB; 4XIF; X-ray; 3.20 A; A/B/C/D=323-1041.
DR   PDB; 5BNW; X-ray; 2.40 A; A=323-1041.
DR   PDB; 5C1D; X-ray; 2.05 A; A=323-1041.
DR   PDB; 5HGV; X-ray; 2.05 A; A/C=323-1041.
DR   PDB; 5LVV; X-ray; 2.54 A; A=325-1046.
DR   PDB; 5LWV; X-ray; 1.90 A; A=325-1046.
DR   PDB; 5NPR; X-ray; 1.85 A; A=325-1041.
DR   PDB; 5NPS; X-ray; 1.68 A; A=324-1041.
DR   PDB; 5VIE; X-ray; 2.60 A; A/C=323-1041.
DR   PDB; 5VIF; X-ray; 2.25 A; A=323-1041.
DR   PDB; 6E37; X-ray; 2.53 A; A=323-1041.
DR   PDB; 6EOU; X-ray; 1.75 A; A=26-410.
DR   PDB; 6IBO; X-ray; 2.17 A; A=323-1041.
DR   PDB; 6MA1; X-ray; 2.75 A; A=323-1041.
DR   PDB; 6MA2; X-ray; 2.10 A; A=323-1041.
DR   PDB; 6MA3; X-ray; 2.00 A; A=323-1041.
DR   PDB; 6MA4; X-ray; 2.00 A; A=323-1041.
DR   PDB; 6MA5; X-ray; 2.00 A; A=323-1041.
DR   PDB; 6Q4M; X-ray; 2.20 A; A=323-1041.
DR   PDB; 6TKA; X-ray; 1.91 A; AAA=323-1046.
DR   PDB; 7NTF; EM; 5.32 A; A/B=2-1046.
DR   PDB; 7YEA; EM; 3.82 A; A/B=1-1046.
DR   PDB; 7YEH; EM; 3.92 A; A/B=1-1046.
DR   PDB; 8CM9; X-ray; 2.80 A; A/B/C/D=323-1041.
DR   PDB; 8FE6; X-ray; 3.06 A; A/C/E/G=323-1041.
DR   PDB; 8FE7; X-ray; 2.98 A; A/C/E/G=323-1041.
DR   PDB; 8FUF; X-ray; 3.69 A; A/C/E/G=323-1041.
DR   PDBsum; 1W3B; -.
DR   PDBsum; 3PE3; -.
DR   PDBsum; 3PE4; -.
DR   PDBsum; 3TAX; -.
DR   PDBsum; 4AY5; -.
DR   PDBsum; 4AY6; -.
DR   PDBsum; 4CDR; -.
DR   PDBsum; 4GYW; -.
DR   PDBsum; 4GYY; -.
DR   PDBsum; 4GZ3; -.
DR   PDBsum; 4GZ5; -.
DR   PDBsum; 4GZ6; -.
DR   PDBsum; 4N39; -.
DR   PDBsum; 4N3A; -.
DR   PDBsum; 4N3B; -.
DR   PDBsum; 4N3C; -.
DR   PDBsum; 4XI9; -.
DR   PDBsum; 4XIF; -.
DR   PDBsum; 5BNW; -.
DR   PDBsum; 5C1D; -.
DR   PDBsum; 5HGV; -.
DR   PDBsum; 5LVV; -.
DR   PDBsum; 5LWV; -.
DR   PDBsum; 5NPR; -.
DR   PDBsum; 5NPS; -.
DR   PDBsum; 5VIE; -.
DR   PDBsum; 5VIF; -.
DR   PDBsum; 6E37; -.
DR   PDBsum; 6EOU; -.
DR   PDBsum; 6IBO; -.
DR   PDBsum; 6MA1; -.
DR   PDBsum; 6MA2; -.
DR   PDBsum; 6MA3; -.
DR   PDBsum; 6MA4; -.
DR   PDBsum; 6MA5; -.
DR   PDBsum; 6Q4M; -.
DR   PDBsum; 6TKA; -.
DR   PDBsum; 7NTF; -.
DR   PDBsum; 7YEA; -.
DR   PDBsum; 7YEH; -.
DR   PDBsum; 8CM9; -.
DR   PDBsum; 8FE6; -.
DR   PDBsum; 8FE7; -.
DR   PDBsum; 8FUF; -.
DR   AlphaFoldDB; O15294; -.
DR   EMDB; EMD-12588; -.
DR   EMDB; EMD-33768; -.
DR   EMDB; EMD-33773; -.
DR   SMR; O15294; -.
DR   BioGRID; 114049; 980.
DR   ComplexPortal; CPX-3323; SIN3A histone deacetylase complex, ES cell-specific variant.
DR   ComplexPortal; CPX-809; NSL histone acetyltransferase complex.
DR   CORUM; O15294; -.
DR   DIP; DIP-33491N; -.
DR   FunCoup; O15294; 2502.
DR   IntAct; O15294; 188.
DR   MINT; O15294; -.
DR   STRING; 9606.ENSP00000362824; -.
DR   BindingDB; O15294; -.
DR   ChEMBL; CHEMBL5955; -.
DR   CAZy; GT41; Glycosyltransferase Family 41.
DR   GlyCosmos; O15294; 7 sites, 1 glycan.
DR   GlyGen; O15294; 12 sites, 1 O-linked glycan (7 sites).
DR   iPTMnet; O15294; -.
DR   MetOSite; O15294; -.
DR   PhosphoSitePlus; O15294; -.
DR   SwissPalm; O15294; -.
DR   BioMuta; OGT; -.
DR   CPTAC; CPTAC-1261; -.
DR   CPTAC; CPTAC-1262; -.
DR   jPOST; O15294; -.
DR   MassIVE; O15294; -.
DR   PaxDb; 9606-ENSP00000362824; -.
DR   PeptideAtlas; O15294; -.
DR   ProteomicsDB; 48562; -. [O15294-1]
DR   ProteomicsDB; 48563; -. [O15294-2]
DR   ProteomicsDB; 48564; -. [O15294-3]
DR   ProteomicsDB; 48565; -. [O15294-4]
DR   Pumba; O15294; -.
DR   Antibodypedia; 27791; 461 antibodies from 44 providers.
DR   DNASU; 8473; -.
DR   Ensembl; ENST00000373701.7; ENSP00000362805.3; ENSG00000147162.16. [O15294-3]
DR   Ensembl; ENST00000373719.8; ENSP00000362824.3; ENSG00000147162.16. [O15294-1]
DR   GeneID; 8473; -.
DR   KEGG; hsa:8473; -.
DR   MANE-Select; ENST00000373719.8; ENSP00000362824.3; NM_181672.3; NP_858058.1.
DR   UCSC; uc004eaa.3; human. [O15294-1]
DR   AGR; HGNC:8127; -.
DR   ClinPGx; PA31914; -.
DR   CTD; 8473; -.
DR   DisGeNET; 8473; -.
DR   GeneCards; OGT; -.
DR   HGNC; HGNC:8127; OGT.
DR   HPA; ENSG00000147162; Low tissue specificity.
DR   MalaCards; OGT; -.
DR   MIM; 300255; gene.
DR   MIM; 300997; phenotype.
DR   OpenTargets; ENSG00000147162; -.
DR   VEuPathDB; HostDB:ENSG00000147162; -.
DR   eggNOG; KOG1124; Eukaryota.
DR   eggNOG; KOG4626; Eukaryota.
DR   GeneTree; ENSGT00940000155085; -.
DR   HOGENOM; CLU_001721_1_0_1; -.
DR   InParanoid; O15294; -.
DR   OMA; MNESEHF; -.
DR   OrthoDB; 9991317at2759; -.
DR   PAN-GO; O15294; 2 GO annotations based on evolutionary models.
DR   PhylomeDB; O15294; -.
DR   BioCyc; MetaCyc:ENSG00000147162-MONOMER; -.
DR   BRENDA; 2.4.1.255; 2681.
DR   PathwayCommons; O15294; -.
DR   Reactome; R-HSA-3214847; HATs acetylate histones.
DR   Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis.
DR   Reactome; R-HSA-5675482; Regulation of necroptotic cell death.
DR   Reactome; R-HSA-5689603; UCH proteinases.
DR   Reactome; R-HSA-9772755; Formation of WDR5-containing histone-modifying complexes.
DR   SABIO-RK; O15294; -.
DR   SignaLink; O15294; -.
DR   SIGNOR; O15294; -.
DR   UniPathway; UPA00378; -.
DR   Agora; ENSG00000147162; -.
DR   BioGRID-ORCS; 8473; 407 hits in 784 CRISPR screens.
DR   ChiTaRS; OGT; human.
DR   EvolutionaryTrace; O15294; -.
DR   GeneWiki; OGT_(gene); -.
DR   GenomeRNAi; 8473; -.
DR   Pharos; O15294; Tchem.
DR   PRO; PR:O15294; -.
DR   Proteomes; UP000005640; Chromosome X.
DR   RNAct; O15294; protein.
DR   Bgee; ENSG00000147162; Expressed in middle temporal gyrus and 214 other cell types or tissues.
DR   ExpressionAtlas; O15294; baseline and differential.
DR   GO; GO:0042995; C:cell projection; IEA:UniProtKB-SubCell.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0000123; C:histone acetyltransferase complex; IDA:UniProtKB.
DR   GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0044545; C:NSL complex; IDA:ComplexPortal.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0017122; C:protein N-acetylglucosaminyltransferase complex; IDA:UniProtKB.
DR   GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR   GO; GO:0070822; C:Sin3-type complex; NAS:ComplexPortal.
DR   GO; GO:0008375; F:acetylglucosaminyltransferase activity; TAS:ProtInc.
DR   GO; GO:0031490; F:chromatin DNA binding; IEA:Ensembl.
DR   GO; GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; IDA:UniProtKB.
DR   GO; GO:0097363; F:protein O-acetylglucosaminyltransferase activity; IDA:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IDA:UniProtKB.
DR   GO; GO:0071333; P:cellular response to glucose stimulus; IDA:UniProtKB.
DR   GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR   GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR   GO; GO:0030097; P:hemopoiesis; ISS:ARUK-UCL.
DR   GO; GO:0000423; P:mitophagy; ISS:ARUK-UCL.
DR   GO; GO:0030336; P:negative regulation of cell migration; NAS:ComplexPortal.
DR   GO; GO:0160076; P:negative regulation of non-canonical inflammasome complex assembly; IDA:UniProtKB.
DR   GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; IMP:UniProtKB.
DR   GO; GO:1902455; P:negative regulation of stem cell population maintenance; NAS:ComplexPortal.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; NAS:ComplexPortal.
DR   GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; NAS:ComplexPortal.
DR   GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; NAS:ComplexPortal.
DR   GO; GO:0046889; P:positive regulation of lipid biosynthetic process; IEA:Ensembl.
DR   GO; GO:0045862; P:positive regulation of proteolysis; IDA:UniProtKB.
DR   GO; GO:1902459; P:positive regulation of stem cell population maintenance; NAS:ComplexPortal.
DR   GO; GO:1904263; P:positive regulation of TORC1 signaling; IDA:UniProtKB.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0000432; P:positive regulation of transcription from RNA polymerase II promoter by glucose; IEA:Ensembl.
DR   GO; GO:0045727; P:positive regulation of translation; IDA:UniProt.
DR   GO; GO:0006493; P:protein O-linked glycosylation; IDA:UniProtKB.
DR   GO; GO:0016485; P:protein processing; IMP:UniProtKB.
DR   GO; GO:0006111; P:regulation of gluconeogenesis; ISS:UniProtKB.
DR   GO; GO:0006110; P:regulation of glycolytic process; IDA:UniProtKB.
DR   GO; GO:0046626; P:regulation of insulin receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0060544; P:regulation of necroptotic process; TAS:Reactome.
DR   GO; GO:0098696; P:regulation of neurotransmitter receptor localization to postsynaptic specialization membrane; IEA:Ensembl.
DR   GO; GO:0035020; P:regulation of Rac protein signal transduction; IDA:UniProtKB.
DR   GO; GO:0051963; P:regulation of synapse assembly; IEA:Ensembl.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IMP:UniProtKB.
DR   GO; GO:0032868; P:response to insulin; IDA:UniProtKB.
DR   GO; GO:0007584; P:response to nutrient; TAS:ProtInc.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   DisProt; DP03891; -.
DR   DisProt; DP03949; -. [O15294-3]
DR   FunFam; 1.25.40.10:FF:000013; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit; 1.
DR   FunFam; 1.25.40.10:FF:000019; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit; 1.
DR   FunFam; 3.30.720.150:FF:000001; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit; 1.
DR   FunFam; 3.40.50.11380:FF:000001; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit; 1.
DR   FunFam; 3.40.50.2000:FF:000012; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit; 1.
DR   Gene3D; 3.30.720.150; -; 1.
DR   Gene3D; 3.40.50.11380; -; 1.
DR   Gene3D; 3.40.50.2000; Glycogen Phosphorylase B; 1.
DR   Gene3D; 1.25.40.10; Tetratricopeptide repeat domain; 2.
DR   InterPro; IPR037919; OGT.
DR   InterPro; IPR029489; OGT/SEC/SPY_C.
DR   InterPro; IPR011990; TPR-like_helical_dom_sf.
DR   InterPro; IPR019734; TPR_rpt.
DR   PANTHER; PTHR44366; UDP-N-ACETYLGLUCOSAMINE--PEPTIDE N-ACETYLGLUCOSAMINYLTRANSFERASE 110 KDA SUBUNIT; 1.
DR   PANTHER; PTHR44366:SF1; UDP-N-ACETYLGLUCOSAMINE--PEPTIDE N-ACETYLGLUCOSAMINYLTRANSFERASE 110 KDA SUBUNIT; 1.
DR   Pfam; PF13844; Glyco_transf_41; 1.
DR   Pfam; PF00515; TPR_1; 2.
DR   Pfam; PF13414; TPR_11; 3.
DR   Pfam; PF13424; TPR_12; 1.
DR   Pfam; PF13181; TPR_8; 2.
DR   SMART; SM00028; TPR; 12.
DR   SUPFAM; SSF48452; TPR-like; 2.
DR   PROSITE; PS50005; TPR; 12.
DR   PROSITE; PS50293; TPR_REGION; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Apoptosis;
KW   Biological rhythms; Cell membrane; Cell projection; Chromatin regulator;
KW   Cytoplasm; Direct protein sequencing; Disease variant; Glycoprotein;
KW   Glycosyltransferase; Host-virus interaction; Intellectual disability;
KW   Lipid-binding; Membrane; Mitochondrion; Nucleus; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Repeat; TPR repeat;
KW   Transferase; Ubl conjugation; Ubl conjugation pathway.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|Ref.5, ECO:0007744|PubMed:19413330,
FT                   ECO:0007744|PubMed:22814378"
FT   CHAIN           2..1046
FT                   /note="UDP-N-acetylglucosamine--peptide N-
FT                   acetylglucosaminyltransferase 110 kDa subunit"
FT                   /id="PRO_0000191772"
FT   REPEAT          21..54
FT                   /note="TPR 1"
FT   REPEAT          89..122
FT                   /note="TPR 2"
FT   REPEAT          123..156
FT                   /note="TPR 3"
FT   REPEAT          157..190
FT                   /note="TPR 4"
FT   REPEAT          191..224
FT                   /note="TPR 5"
FT   REPEAT          225..258
FT                   /note="TPR 6"
FT   REPEAT          259..292
FT                   /note="TPR 7"
FT   REPEAT          293..326
FT                   /note="TPR 8"
FT   REPEAT          327..360
FT                   /note="TPR 9"
FT   REPEAT          361..394
FT                   /note="TPR 10"
FT   REPEAT          395..428
FT                   /note="TPR 11"
FT   REPEAT          429..462
FT                   /note="TPR 12"
FT   REPEAT          463..473
FT                   /note="TPR 13; truncated"
FT   REGION          991..1010
FT                   /note="Required for phosphatidylinositol 3,4,5-triphosphate
FT                   binding"
FT                   /evidence="ECO:0000250|UniProtKB:P56558"
FT   MOTIF           464..466
FT                   /note="DFP motif"
FT                   /evidence="ECO:0000269|PubMed:27713473"
FT   MOTIF           487..503
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        508
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000305|PubMed:21240259,
FT                   ECO:0000305|PubMed:26678539"
FT   BINDING         849
FT                   /ligand="UDP"
FT                   /ligand_id="ChEBI:CHEBI:58223"
FT                   /evidence="ECO:0000269|PubMed:23103939,
FT                   ECO:0007744|PDB:4GYW"
FT   BINDING         852
FT                   /ligand="UDP"
FT                   /ligand_id="ChEBI:CHEBI:58223"
FT                   /evidence="ECO:0000269|PubMed:23103939,
FT                   ECO:0007744|PDB:4GYW"
FT   BINDING         906..908
FT                   /ligand="UDP"
FT                   /ligand_id="ChEBI:CHEBI:58223"
FT                   /evidence="ECO:0000269|PubMed:23103939,
FT                   ECO:0007744|PDB:4GYW"
FT   BINDING         911..914
FT                   /ligand="UDP"
FT                   /ligand_id="ChEBI:CHEBI:58223"
FT                   /evidence="ECO:0000269|PubMed:23103939,
FT                   ECO:0007744|PDB:4GYW"
FT   BINDING         930..932
FT                   /ligand="UDP"
FT                   /ligand_id="ChEBI:CHEBI:58223"
FT                   /evidence="ECO:0000269|PubMed:23103939,
FT                   ECO:0007744|PDB:4GYW"
FT   BINDING         935
FT                   /ligand="UDP"
FT                   /ligand_id="ChEBI:CHEBI:58223"
FT                   /evidence="ECO:0000269|PubMed:23103939,
FT                   ECO:0007744|PDB:4GYW"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0000269|Ref.5, ECO:0007744|PubMed:19413330,
FT                   ECO:0007744|PubMed:22814378"
FT   MOD_RES         3
FT                   /note="Phosphoserine; by GSK3-beta; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q8CGY8"
FT   MOD_RES         4
FT                   /note="Phosphoserine; by GSK3-beta; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q8CGY8"
FT   MOD_RES         20
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         454
FT                   /note="Phosphothreonine; by AMPK"
FT                   /evidence="ECO:0000269|PubMed:24563466,
FT                   ECO:0000269|PubMed:37541260"
FT   MOD_RES         989
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P56558"
FT   CARBOHYD        3
FT                   /note="O-linked (GlcNAc) serine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q8CGY8"
FT   CARBOHYD        4
FT                   /note="O-linked (GlcNAc) serine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q8CGY8"
FT   CARBOHYD        399
FT                   /note="O-linked (GlcNAc) serine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:27713473"
FT   VAR_SEQ         1..381
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:17974005"
FT                   /id="VSP_040764"
FT   VAR_SEQ         1..176
FT                   /note="MASSVGNVADSTEPTKRMLSFQGLAELAHREYQAGDFEAAERHCMQLWRQEP
FT                   DNTGVLLLLSSIHFQCRRLDRSAHFSTLAIKQNPLLAEAYSNLGNVYKERGQLQEAIEH
FT                   YRHALRLKPDFIDGYINLAAALVAAGDMEGAVQAYVSALQYNPDLYCVRSDLGNLLKAL
FT                   GRLEEA -> MLQGHFWLVREGIMISPSSPPPPNLFFFPLQIFPFPFTSFPSHLLSLTP
FT                   P (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:9083068"
FT                   /id="VSP_006553"
FT   VAR_SEQ         13..22
FT                   /note="Missing (in isoform 1)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:17974005"
FT                   /id="VSP_014164"
FT   VARIANT         254
FT                   /note="L -> F (in XLID106; decreased protein abundance;
FT                   reduced protein stability; dbSNP:rs1131692155)"
FT                   /evidence="ECO:0000269|PubMed:28302723"
FT                   /id="VAR_079254"
FT   VARIANT         284
FT                   /note="R -> P (in XLID106; decreased protein abundance;
FT                   decreased enzyme activity; reduced protein stability;
FT                   dbSNP:rs1114167891)"
FT                   /evidence="ECO:0000269|PubMed:28584052"
FT                   /id="VAR_079183"
FT   VARIANT         319
FT                   /note="A -> T (in XLID106; uncertain significance;
FT                   dbSNP:rs1602147851)"
FT                   /evidence="ECO:0000269|PubMed:26273451"
FT                   /id="VAR_074019"
FT   VARIANT         538
FT                   /note="L -> P (found in a renal cell carcinoma sample;
FT                   somatic mutation)"
FT                   /id="VAR_064736"
FT   MUTAGEN         208..211
FT                   /note="WLAI->ELAD: Abolished homooligomerization."
FT                   /evidence="ECO:0000269|PubMed:27713473"
FT   MUTAGEN         208
FT                   /note="W->E: Abolishes homodimerization of the TPR domain.
FT                   Slightly reduced enzyme activity; when associated with D-
FT                   211."
FT                   /evidence="ECO:0000269|PubMed:15361863"
FT   MUTAGEN         211
FT                   /note="I->D: Abolishes homodimerization of the TPR domain.
FT                   Slightly reduced enzyme activity; when associated with E-
FT                   208."
FT                   /evidence="ECO:0000269|PubMed:15361863"
FT   MUTAGEN         391
FT                   /note="S->A: Reduced autoglycosylation."
FT                   /evidence="ECO:0000269|PubMed:27713473"
FT   MUTAGEN         393
FT                   /note="T->V: Reduced autoglycosylation."
FT                   /evidence="ECO:0000269|PubMed:27713473"
FT   MUTAGEN         399
FT                   /note="S->A: Reduced autoglycosylation. Reduced
FT                   localization to the nucleus."
FT                   /evidence="ECO:0000269|PubMed:27713473"
FT   MUTAGEN         404
FT                   /note="T->V: Reduced autoglycosylation."
FT                   /evidence="ECO:0000269|PubMed:27713473"
FT   MUTAGEN         454
FT                   /note="T->A: Abolished phosphorylation by AMPK. Does not
FT                   affect ability to regulate mTORC1."
FT                   /evidence="ECO:0000269|PubMed:24563466,
FT                   ECO:0000269|PubMed:37541260"
FT   MUTAGEN         454
FT                   /note="T->E: Affects substrate selectivity. Mimics
FT                   phosphorylation; does not affect ability to regulate
FT                   mTORC1."
FT                   /evidence="ECO:0000269|PubMed:24563466,
FT                   ECO:0000269|PubMed:37541260"
FT   MUTAGEN         461..463
FT                   /note="DFP->AAA: Impaired localization to the nucleus."
FT                   /evidence="ECO:0000269|PubMed:37541260"
FT   MUTAGEN         508
FT                   /note="H->A: Loss of enzyme activity. Moderate increase in
FT                   KMT2E ubiquitination. Moderate increase in KMT2E
FT                   ubiquitination; when associated with A-508."
FT                   /evidence="ECO:0000269|PubMed:21240259,
FT                   ECO:0000269|PubMed:26678539"
FT   MUTAGEN         568
FT                   /note="H->A: Reduces enzyme activity by about 95%. Moderate
FT                   increase in KMT2E ubiquitination; when associated with A-
FT                   508."
FT                   /evidence="ECO:0000269|PubMed:21240259,
FT                   ECO:0000269|PubMed:26678539"
FT   MUTAGEN         911
FT                   /note="H->A: Reduces enzyme activity by over 90%."
FT                   /evidence="ECO:0000269|PubMed:21240259"
FT   CONFLICT        308
FT                   /note="S -> Q (in Ref. 3; CAB62528)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        663
FT                   /note="L -> P (in Ref. 3; CAD97853)"
FT                   /evidence="ECO:0000305"
FT   HELIX           27..34
FT                   /evidence="ECO:0007829|PDB:1W3B"
FT   HELIX           37..50
FT                   /evidence="ECO:0007829|PDB:1W3B"
FT   HELIX           60..67
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           71..83
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           89..101
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           105..118
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           123..135
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           139..152
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           157..169
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           173..186
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           191..203
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           207..220
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           225..237
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           241..254
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           259..271
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           275..288
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           293..306
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           309..322
FT                   /evidence="ECO:0007829|PDB:6EOU"
FT   HELIX           325..340
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           343..356
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           361..373
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           377..390
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           395..407
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           411..424
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           429..442
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           445..458
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           463..475
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           482..498
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   TURN            507..509
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           510..512
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           517..535
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           536..538
FT                   /evidence="ECO:0007829|PDB:4GYY"
FT   STRAND          547..549
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   TURN            550..554
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          556..563
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          565..568
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           569..574
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           577..580
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   TURN            583..585
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          586..594
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           600..608
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          609..614
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           615..617
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           621..631
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          634..639
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          641..643
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           649..652
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          656..664
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          671..673
FT                   /evidence="ECO:0007829|PDB:8FE6"
FT   STRAND          676..679
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   TURN            681..683
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           686..691
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          693..698
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           708..711
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           713..715
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          719..722
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          724..727
FT                   /evidence="ECO:0007829|PDB:8CM9"
FT   STRAND          731..737
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           741..746
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          748..750
FT                   /evidence="ECO:0007829|PDB:4GYW"
FT   STRAND          752..755
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          773..780
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           781..792
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          795..799
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          802..806
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           807..809
FT                   /evidence="ECO:0007829|PDB:4GYY"
FT   HELIX           810..813
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           815..818
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          820..822
FT                   /evidence="ECO:0007829|PDB:4AY5"
FT   STRAND          825..831
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           832..835
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          839..841
FT                   /evidence="ECO:0007829|PDB:6MA5"
FT   STRAND          843..845
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           850..852
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           855..867
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          872..877
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           880..882
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           883..892
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           897..899
FT                   /evidence="ECO:0007829|PDB:4GYW"
FT   STRAND          900..904
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           908..914
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           915..917
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          919..922
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          925..927
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           931..938
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   STRAND          943..945
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           951..953
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           955..963
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           966..968
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           973..985
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           987..1003
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   HELIX           1005..1007
FT                   /evidence="ECO:0007829|PDB:6MA4"
FT   HELIX           1009..1028
FT                   /evidence="ECO:0007829|PDB:5NPS"
FT   CARBOHYD        O15294-4:10
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   CARBOHYD        O15294-4:12
FT                   /note="O-linked (GlcNAc) threonine"
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   CARBOHYD        O15294-4:18
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   CARBOHYD        O15294-4:38
FT                   /note="O-linked (GlcNAc) threonine"
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   CARBOHYD        O15294-4:52
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   CARBOHYD        O15294-4:56
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   MUTAGEN         O15294-4:10
FT                   /note="S->A: Does not affect global auto-O-GlcNAcylation."
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   MUTAGEN         O15294-4:12
FT                   /note="T->A: Decreased auto-O-GlcNAcylation."
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   MUTAGEN         O15294-4:18
FT                   /note="S->A: Does not affect global auto-O-GlcNAcylation."
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   MUTAGEN         O15294-4:38
FT                   /note="T->A: Does not affect global auto-O-GlcNAcylation."
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   MUTAGEN         O15294-4:52
FT                   /note="S->A: Does not affect global auto-O-GlcNAcylation."
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   MUTAGEN         O15294-4:56
FT                   /note="S->A: Increased auto-O-GlcNAcylation."
FT                   /evidence="ECO:0000269|PubMed:31527085"
FT   MUTAGEN         O15294-4:127
FT                   /note="H->A: Loss of enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:31527085"
SQ   SEQUENCE   1046 AA;  116925 MW;  852ED68BDDE63363 CRC64;
     MASSVGNVAD STEPTKRMLS FQGLAELAHR EYQAGDFEAA ERHCMQLWRQ EPDNTGVLLL
     LSSIHFQCRR LDRSAHFSTL AIKQNPLLAE AYSNLGNVYK ERGQLQEAIE HYRHALRLKP
     DFIDGYINLA AALVAAGDME GAVQAYVSAL QYNPDLYCVR SDLGNLLKAL GRLEEAKACY
     LKAIETQPNF AVAWSNLGCV FNAQGEIWLA IHHFEKAVTL DPNFLDAYIN LGNVLKEARI
     FDRAVAAYLR ALSLSPNHAV VHGNLACVYY EQGLIDLAID TYRRAIELQP HFPDAYCNLA
     NALKEKGSVA EAEDCYNTAL RLCPTHADSL NNLANIKREQ GNIEEAVRLY RKALEVFPEF
     AAAHSNLASV LQQQGKLQEA LMHYKEAIRI SPTFADAYSN MGNTLKEMQD VQGALQCYTR
     AIQINPAFAD AHSNLASIHK DSGNIPEAIA SYRTALKLKP DFPDAYCNLA HCLQIVCDWT
     DYDERMKKLV SIVADQLEKN RLPSVHPHHS MLYPLSHGFR KAIAERHGNL CLDKINVLHK
     PPYEHPKDLK LSDGRLRVGY VSSDFGNHPT SHLMQSIPGM HNPDKFEVFC YALSPDDGTN
     FRVKVMAEAN HFIDLSQIPC NGKAADRIHQ DGIHILVNMN GYTKGARNEL FALRPAPIQA
     MWLGYPGTSG ALFMDYIITD QETSPAEVAE QYSEKLAYMP HTFFIGDHAN MFPHLKKKAV
     IDFKSNGHIY DNRIVLNGID LKAFLDSLPD VKIVKMKCPD GGDNADSSNT ALNMPVIPMN
     TIAEAVIEMI NRGQIQITIN GFSISNGLAT TQINNKAATG EEVPRTIIVT TRSQYGLPED
     AIVYCNFNQL YKIDPSTLQM WANILKRVPN SVLWLLRFPA VGEPNIQQYA QNMGLPQNRI
     IFSPVAPKEE HVRRGQLADV CLDTPLCNGH TTGMDVLWAG TPMVTMPGET LASRVAASQL
     TCLGCLELIA KNRQEYEDIA VKLGTDLEYL KKVRGKVWKQ RISSPLFNTK QYTMELERLY
     LQMWEHYAAG NKPDHMIKPV EVTESA
//
ID   OLR1_HUMAN              Reviewed;         273 AA.
AC   P78380; A8K7V9; B4DI48; G3V1I4; Q2PP00; Q7Z484;
DT   16-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1997, sequence version 1.
DT   28-JAN-2026, entry version 215.
DE   RecName: Full=Oxidized low-density lipoprotein receptor 1;
DE            Short=Ox-LDL receptor 1;
DE   AltName: Full=C-type lectin domain family 8 member A;
DE   AltName: Full=Lectin-like oxidized LDL receptor 1;
DE            Short=LOX-1;
DE            Short=Lectin-like oxLDL receptor 1;
DE            Short=hLOX-1;
DE   AltName: Full=Lectin-type oxidized LDL receptor 1;
DE   Contains:
DE     RecName: Full=Oxidized low-density lipoprotein receptor 1, soluble form;
GN   Name=OLR1; Synonyms=CLEC8A, LOX1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC   TISSUE=Lung;
RX   PubMed=9052782; DOI=10.1038/386073a0;
RA   Sawamura T., Kume N., Aoyama T., Moriwaki H., Hoshikawa H., Aiba Y.,
RA   Tanaka T., Miwa S., Katsura Y., Kita T., Masaki T.;
RT   "An endothelial receptor for oxidized low-density lipoprotein.";
RL   Nature 386:73-77(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=9763655; DOI=10.1159/000015059;
RA   Li X., Bouzyk M.M., Wang X.;
RT   "Assignment of the human oxidized low-density lipoprotein receptor gene
RT   (OLR1) to chromosome 12p13.1-->p12.3, and identification of a polymorphic
RT   CA-repeat marker in the OLR1 gene.";
RL   Cytogenet. Cell Genet. 82:34-36(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DOMAIN, DISULFIDE BONDS,
RP   GLYCOSYLATION, AND MUTAGENESIS OF CYS-144; CYS-155; CYS-172; ASN-183;
RP   209-ARG-ASN-210; HIS-226; ARG-229; ARG-231; 235-SER-GLN-236; SER-240;
RP   CYS-243; CYS-256; CYS-264 AND 267-LYS--GLN-273.
RX   PubMed=11256994; DOI=10.1242/jcs.114.7.1273;
RA   Shi X., Niimi S., Ohtani T., Machida S.;
RT   "Characterization of residues and sequences of the carbohydrate recognition
RT   domain required for cell surface localization and ligand binding of human
RT   lectin-like oxidized LDL receptor.";
RL   J. Cell Sci. 114:1273-1282(2001).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY, AND INDUCTION.
RX   PubMed=9828121; DOI=10.1006/geno.1998.5561;
RA   Yamanaka S., Zhang X.-Y., Miura K., Kim S., Iwao H.;
RT   "The human gene encoding the lectin-type oxidized LDL receptor (OLR1) is a
RT   novel member of the natural killer gene complex with a unique expression
RT   profile.";
RL   Genomics 54:191-199(1998).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INVOLVEMENT IN MYOCARDIAL
RP   INFARCTION, AND VARIANT ASN-167.
RX   PubMed=12646194; DOI=10.1016/s0006-291x(03)00326-7;
RA   Tatsuguchi M., Furutani M., Hinagata J., Tanaka T., Furutani Y.,
RA   Imamura S., Kawana M., Masaki T., Kasanuki H., Sawamura T., Matsuoka R.;
RT   "Oxidized LDL receptor gene (OLR1) is associated with the risk of
RT   myocardial infarction.";
RL   Biochem. Biophys. Res. Commun. 303:247-250(2003).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Millar D.S.;
RL   Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC   TISSUE=Placenta;
RA   Li W.B., Gruber C., Jessee J., Polayes D.;
RT   "Full-length cDNA libraries and normalization.";
RL   Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP   ASN-167.
RC   TISSUE=Corpus callosum, and Synovial cell;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   NHLBI resequencing and genotyping service (RS&G);
RL   Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16541075; DOI=10.1038/nature04569;
RA   Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA   Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA   Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA   Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA   Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA   Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA   Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA   Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA   Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA   Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA   Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA   Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA   Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA   Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA   Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA   Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA   Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA   David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA   D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA   Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA   Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA   Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA   LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA   Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA   Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA   Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA   Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA   Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA   Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA   Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA   Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA   Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA   Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA   Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA   Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA   Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA   Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA   Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA   Gibbs R.A.;
RT   "The finished DNA sequence of human chromosome 12.";
RL   Nature 440:346-351(2006).
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [12]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Placenta;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [13]
RP   FUNCTION.
RX   PubMed=11821063; DOI=10.1016/s0014-5793(01)03297-5;
RA   Hayashida K., Kume N., Minami M., Kita T.;
RT   "Lectin-like oxidized LDL receptor-1 (LOX-1) supports adhesion of
RT   mononuclear leukocytes and a monocyte-like cell line THP-1 cells under
RT   static and flow conditions.";
RL   FEBS Lett. 511:133-138(2002).
RN   [14]
RP   FUNCTION, AND TISSUE SPECIFICITY.
RX   PubMed=12354387; DOI=10.1016/s1074-7613(02)00388-6;
RA   Delneste Y., Magistrelli G., Gauchat J.-F., Haeuw J.-P., Aubry J.-F.,
RA   Nakamura K., Kawakami-Honda N., Goetsch L., Sawamura T., Bonnefoy J.-Y.,
RA   Jeannin P.;
RT   "Involvement of LOX-1 in dendritic cell-mediated antigen cross-
RT   presentation.";
RL   Immunity 17:353-362(2002).
RN   [15]
RP   INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=12384789; DOI=10.1007/s00439-002-0802-7;
RA   Luedecking-Zimmer E., DeKosky S.T., Chen Q., Barmada M.M., Kamboh M.I.;
RT   "Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for
RT   Alzheimer's disease on chromosome 12.";
RL   Hum. Genet. 111:443-451(2002).
RN   [16]
RP   INDUCTION.
RX   PubMed=12878212; DOI=10.1016/s0006-291x(03)01295-6;
RA   Hu B., Li D., Sawamura T., Mehta J.L.;
RT   "Oxidized LDL through LOX-1 modulates LDL-receptor expression in human
RT   coronary artery endothelial cells.";
RL   Biochem. Biophys. Res. Commun. 307:1008-1012(2003).
RN   [17]
RP   INVOLVEMENT IN MYOCARDIAL INFARCTION.
RX   PubMed=12810610; DOI=10.1161/01.cir.0000074207.85796.36;
RA   Chen Q., Reis S.E., Kammerer C., Craig W.Y., LaPierre S.E., Zimmer E.L.,
RA   McNamara D.M., Pauly D.F., Sharaf B., Holubkov R., Bairey Merz C.N.,
RA   Sopko G., Bontempo F., Kamboh M.I.;
RT   "Genetic variation in lectin-like oxidized low-density lipoprotein receptor
RT   1 (LOX1) gene and the risk of coronary artery disease.";
RL   Circulation 107:3146-3151(2003).
RN   [18]
RP   INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=12807963; DOI=10.1136/jmg.40.6.424;
RA   Lambert J.-C., Luedecking-Zimmer E., Merrot S., Hayes A., Thaker U.,
RA   Desai P., Houzet A., Hermant X., Cottel D., Pritchard A., Iwatsubo T.,
RA   Pasquier F., Frigard B., Conneally P.M., Chartier-Harlin M.-C.,
RA   DeKosky S.T., Lendon C., Mann D., Kamboh M.I., Amouyel P.;
RT   "Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1)
RT   gene with Alzheimer's disease.";
RL   J. Med. Genet. 40:424-430(2003).
RN   [19]
RP   HOMODIMERIZATION, INTERCHAIN DISULFIDE BOND, AND MUTAGENESIS OF CYS-140.
RX   PubMed=15000751; DOI=10.1089/104454904322759920;
RA   Xie Q., Matsunaga S., Niimi S., Ogawa S., Tokuyasu K., Sakakibara Y.,
RA   Machida S.;
RT   "Human lectin-like oxidized low-density lipoprotein receptor-1 functions as
RT   a dimer in living cells.";
RL   DNA Cell Biol. 23:111-117(2004).
RN   [20]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=15060104; DOI=10.1136/jmg.2003.016980;
RA   Bertram L., Parkinson M., Mullin K., Menon R., Blacker D., Tanzi R.E.;
RT   "No association between a previously reported OLR1 3' UTR polymorphism and
RT   Alzheimer's disease in a large family sample.";
RL   J. Med. Genet. 41:286-288(2004).
RN   [21]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=15276231; DOI=10.1016/j.neulet.2004.05.023;
RA   Pritchard A., St Clair D., Lemmon H., Mann D.M.A., Lendon C.;
RT   "No association between polymorphisms in the lectin-like oxidised low
RT   density lipoprotein receptor (ORL1) gene on chromosome 12 and Alzheimer's
RT   disease in a UK cohort.";
RL   Neurosci. Lett. 366:126-129(2004).
RN   [22]
RP   INVOLVEMENT IN MYOCARDIAL INFARCTION.
RX   PubMed=15976314; DOI=10.1161/01.res.0000174563.62625.8e;
RA   Mango R., Biocca S., del Vecchio F., Clementi F., Sangiuolo F., Amati F.,
RA   Filareto A., Grelli S., Spitalieri P., Filesi I., Favalli C., Lauro R.,
RA   Mehta J.L., Romeo F., Novelli G.;
RT   "In vivo and in vitro studies support that a new splicing isoform of OLR1
RT   gene is protective against acute myocardial infarction.";
RL   Circ. Res. 97:152-158(2005).
RN   [23]
RP   INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=15860461; DOI=10.1093/gerona/60.3.280;
RA   D'Introno A., Solfrizzi V., Colacicco A.M., Capurso C., Torres F.,
RA   Capurso S.A., Capurso A., Panza F.;
RT   "Polymorphisms in the oxidized low-density lipoprotein receptor-1 gene and
RT   risk of Alzheimer's disease.";
RL   J. Gerontol. 60:280-284(2005).
RN   [24]
RP   DOMAIN, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 22-LYS--LYS-25 AND GLU-70.
RX   PubMed=15935375; DOI=10.1016/j.yjmcc.2005.05.001;
RA   Chen M., Sawamura T.;
RT   "Essential role of cytoplasmic sequences for cell-surface sorting of the
RT   lectin-like oxidized LDL receptor-1 (LOX-1).";
RL   J. Mol. Cell. Cardiol. 39:553-561(2005).
RN   [25]
RP   GLYCOSYLATION AT ASN-139.
RX   PubMed=22688517; DOI=10.1007/s10719-012-9408-z;
RA   Qian Y., Zhang X., Zhou L., Yun X., Xie J., Xu J., Ruan Y., Ren S.;
RT   "Site-specific N-glycosylation identification of recombinant human lectin-
RT   like oxidized low density lipoprotein receptor-1 (LOX-1).";
RL   Glycoconj. J. 29:399-409(2012).
RN   [26]
RP   PALMITOYLATION AT CYS-36 AND CYS-46, AND SUBCELLULAR LOCATION.
RX   PubMed=23583401; DOI=10.1016/j.bbrc.2013.03.120;
RA   Kumano-Kuramochi M., Xie Q., Kajiwara S., Komba S., Minowa T., Machida S.;
RT   "Lectin-like oxidized LDL receptor-1 is palmitoylated and internalizes
RT   ligands via caveolae/raft-dependent endocytosis.";
RL   Biochem. Biophys. Res. Commun. 434:594-599(2013).
RN   [27]
RP   FUNCTION (MICROBIAL INFECTION), AND INTERACTION WITH N.MENINGITIDIS ADHESIN
RP   A (MICROBIAL INFECTION).
RX   PubMed=27302108; DOI=10.1038/srep27996;
RA   Scietti L., Sampieri K., Pinzuti I., Bartolini E., Benucci B., Liguori A.,
RA   Haag A.F., Lo Surdo P., Pansegrau W., Nardi-Dei V., Santini L., Arora S.,
RA   Leber X., Rindi S., Savino S., Costantino P., Maione D., Merola M.,
RA   Speziale P., Bottomley M.J., Bagnoli F., Masignani V., Pizza M.,
RA   Scharenberg M., Schlaeppi J.M., Nissum M., Liberatori S.;
RT   "Exploring host-pathogen interactions through genome wide protein
RT   microarray analysis.";
RL   Sci. Rep. 6:27996-27996(2016).
RN   [28]
RP   INTERACTION WITH N.MENINGITIDIS ADHESIN A (MICROBIAL INFECTION).
RX   PubMed=30327444; DOI=10.1128/mbio.01914-18;
RA   Liguori A., Dello Iacono L., Maruggi G., Benucci B., Merola M.,
RA   Lo Surdo P., Lopez-Sagaseta J., Pizza M., Malito E., Bottomley M.J.;
RT   "NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions
RT   Competed by Meningococcus B Vaccine-Elicited Human Antibodies.";
RL   MBio 9:0-0(2018).
RN   [29]
RP   X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 136-270, SUBUNIT, AND DISULFIDE
RP   BONDS.
RX   PubMed=15695803; DOI=10.1074/jbc.m500768200;
RA   Park H., Adsit F.G., Boyington J.C.;
RT   "The 1.4 angstrom crystal structure of the human oxidized low density
RT   lipoprotein receptor lox-1.";
RL   J. Biol. Chem. 280:13593-13599(2005).
RN   [30]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 143-271, SUBUNIT, DISULFIDE BONDS,
RP   AND MUTAGENESIS OF TRP-150; ARG-208; ARG-209; HIS-226; ARG-229; ARG-231 AND
RP   ARG-248.
RX   PubMed=15939022; DOI=10.1016/j.str.2005.03.016;
RA   Ohki I., Ishigaki T., Oyama T., Matsunaga S., Xie Q., Ohnishi-Kameyama M.,
RA   Murata T., Tsuchiya D., Machida S., Morikawa K., Tate S.;
RT   "Crystal structure of human lectin-like, oxidized low-density lipoprotein
RT   receptor 1 ligand binding domain and its ligand recognition mode to
RT   oxLDL.";
RL   Structure 13:905-917(2005).
CC   -!- FUNCTION: Receptor that mediates the recognition, internalization and
CC       degradation of oxidatively modified low density lipoprotein (oxLDL) by
CC       vascular endothelial cells. OxLDL is a marker of atherosclerosis that
CC       induces vascular endothelial cell activation and dysfunction, resulting
CC       in pro-inflammatory responses, pro-oxidative conditions and apoptosis.
CC       Its association with oxLDL induces the activation of NF-kappa-B through
CC       an increased production of intracellular reactive oxygen and a variety
CC       of pro-atherogenic cellular responses including a reduction of nitric
CC       oxide (NO) release, monocyte adhesion and apoptosis. In addition to
CC       binding oxLDL, it acts as a receptor for the HSP70 protein involved in
CC       antigen cross-presentation to naive T-cells in dendritic cells, thereby
CC       participating in cell-mediated antigen cross-presentation. Also
CC       involved in inflammatory process, by acting as a leukocyte-adhesion
CC       molecule at the vascular interface in endotoxin-induced inflammation.
CC       Also acts as a receptor for advanced glycation end (AGE) products,
CC       activated platelets, monocytes, apoptotic cells and both Gram-negative
CC       and Gram-positive bacteria. {ECO:0000269|PubMed:11821063,
CC       ECO:0000269|PubMed:12354387, ECO:0000269|PubMed:9052782}.
CC   -!- FUNCTION: (Microbial infection) May serve as a receptor for adhesin A
CC       variant 3 (nadA) of N.meningitidis. {ECO:0000305|PubMed:27302108}.
CC   -!- SUBUNIT: Homodimer; disulfide-linked. May form a hexamer composed of 3
CC       homodimers. Interacts with HSP70. {ECO:0000269|PubMed:11256994,
CC       ECO:0000269|PubMed:15695803, ECO:0000269|PubMed:15939022}.
CC   -!- SUBUNIT: (Microbial infection) Binds to the head and beginning of the
CC       coiled stalk of N.meningitidis adhesin A (nadA) variant 3; binding can
CC       be abrogated by monoclonal antibodies against the specific regions of
CC       NadA. Binding occurs in protein microarrays, in solution and when LOX-1
CC       is expressed on the cell surface. {ECO:0000269|PubMed:27302108,
CC       ECO:0000269|PubMed:30327444}.
CC   -!- INTERACTION:
CC       P78380; P50991: CCT4; NbExp=3; IntAct=EBI-7151999, EBI-356876;
CC       P78380; P12259: F5; NbExp=2; IntAct=EBI-7151999, EBI-9640912;
CC       P78380; P78380: OLR1; NbExp=4; IntAct=EBI-7151999, EBI-7151999;
CC       P78380; Q8IW52: SLITRK4; NbExp=2; IntAct=EBI-7151999, EBI-21899250;
CC       P78380; P17987: TCP1; NbExp=5; IntAct=EBI-7151999, EBI-356553;
CC   -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor. Cell membrane;
CC       Single-pass type II membrane protein. Membrane raft. Secreted. Note=A
CC       secreted form also exists. Localization to membrane rafts requires
CC       palmitoylation.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=P78380-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P78380-2; Sequence=VSP_042555;
CC       Name=3;
CC         IsoId=P78380-3; Sequence=VSP_045277;
CC   -!- TISSUE SPECIFICITY: Expressed at high level in endothelial cells and
CC       vascular-rich organs such as placenta, lung, liver and brain, aortic
CC       intima, bone marrow, spinal cord and substantia nigra. Also expressed
CC       at the surface of dendritic cells. Widely expressed at intermediate and
CC       low level. {ECO:0000269|PubMed:12354387, ECO:0000269|PubMed:9052782,
CC       ECO:0000269|PubMed:9828121}.
CC   -!- INDUCTION: By inflammatory cytokines such as TNF, IFNG/IFN-gamma,
CC       IL6/interleukin-6 and by pathological conditions such as
CC       hyperlipidemia, hypertension and diabetes mellitus. Up-regulated in
CC       atherosclerotic lesions, by oxLDL, reactive oxygen species and fluid
CC       shear stress, suggesting that it may participate in amplification of
CC       oxLDL-induced vascular dysfunction. {ECO:0000269|PubMed:12878212,
CC       ECO:0000269|PubMed:9828121}.
CC   -!- DOMAIN: The cytoplasmic region is required for subcellular sorting on
CC       the cell surface.
CC   -!- DOMAIN: The C-type lectin domain mediates the recognition and binding
CC       of oxLDL.
CC   -!- PTM: The intrachain disulfide-bonds prevent N-glycosylation at some
CC       sites.
CC   -!- PTM: N-glycosylated.
CC   -!- DISEASE: Note=Independent association genetic studies have implicated
CC       OLR1 gene variants in myocardial infarction susceptibility.
CC   -!- DISEASE: Note=OLR1 may be involved in Alzheimer disease (AD).
CC       Involvement in AD is however unclear: according to some authors,
CC       variations in OLR1 modify the risk of AD (PubMed:12354387,
CC       PubMed:12810610, PubMed:15976314). While according to others they do
CC       not (PubMed:15000751, PubMed:15060104). {ECO:0000269|PubMed:12384789,
CC       ECO:0000269|PubMed:12807963, ECO:0000269|PubMed:15860461}.
CC   -!- WEB RESOURCE: Name=Functional Glycomics Gateway - Glycan Binding;
CC       Note=Oxidized LDL receptor;
CC       URL="http://www.functionalglycomics.org/glycomics/GBPServlet?&operationType=view&cbpId=cbp_hum_Ctlect_249";
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DR   EMBL; AB010710; BAA24580.1; -; mRNA.
DR   EMBL; AF035776; AAC82329.1; -; mRNA.
DR   EMBL; AF079167; AAC97927.1; -; Genomic_DNA.
DR   EMBL; AF079166; AAC97927.1; JOINED; Genomic_DNA.
DR   EMBL; AF079164; AAC97927.1; JOINED; Genomic_DNA.
DR   EMBL; AF079165; AAC97927.1; JOINED; Genomic_DNA.
DR   EMBL; AB102861; BAC81565.1; -; mRNA.
DR   EMBL; AJ131757; CAB38175.1; -; Genomic_DNA.
DR   EMBL; BX344276; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AK292124; BAF84813.1; -; mRNA.
DR   EMBL; AK295409; BAG58360.1; -; mRNA.
DR   EMBL; DQ314885; ABC40744.1; -; Genomic_DNA.
DR   EMBL; AC024224; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471094; EAW96157.1; -; Genomic_DNA.
DR   EMBL; CH471094; EAW96158.1; -; Genomic_DNA.
DR   EMBL; BC022295; AAH22295.1; -; mRNA.
DR   CCDS; CCDS53745.1; -. [P78380-2]
DR   CCDS; CCDS53746.1; -. [P78380-3]
DR   CCDS; CCDS8618.1; -. [P78380-1]
DR   RefSeq; NP_001166103.1; NM_001172632.2. [P78380-2]
DR   RefSeq; NP_001166104.1; NM_001172633.2. [P78380-3]
DR   RefSeq; NP_002534.1; NM_002543.4. [P78380-1]
DR   RefSeq; XP_047284863.1; XM_047428907.1. [P78380-1]
DR   PDB; 1YPO; X-ray; 3.00 A; A/B/C/D/E/F/G/H=142-272.
DR   PDB; 1YPQ; X-ray; 1.40 A; A/B=136-270.
DR   PDB; 1YPU; X-ray; 2.05 A; A/B=136-270.
DR   PDB; 1YXJ; X-ray; 1.78 A; A/B=143-271.
DR   PDB; 1YXK; X-ray; 2.40 A; A/B=136-270.
DR   PDB; 3VLG; X-ray; 2.30 A; A=133-273.
DR   PDB; 6TL7; X-ray; 1.11 A; A/B=143-273.
DR   PDB; 6TL9; X-ray; 2.73 A; A/B/C/D/E/F/G/H=143-273.
DR   PDB; 6TLA; X-ray; 2.16 A; A/B/C=129-273.
DR   PDB; 7R8U; X-ray; 1.90 A; AAA/BBB=140-271.
DR   PDB; 7W5D; X-ray; 1.14 A; A/B=136-273.
DR   PDB; 7XMP; X-ray; 1.27 A; A=136-273.
DR   PDB; 9IUD; X-ray; 1.98 A; A/B/C/D/E/F/G/H=136-273.
DR   PDBsum; 1YPO; -.
DR   PDBsum; 1YPQ; -.
DR   PDBsum; 1YPU; -.
DR   PDBsum; 1YXJ; -.
DR   PDBsum; 1YXK; -.
DR   PDBsum; 3VLG; -.
DR   PDBsum; 6TL7; -.
DR   PDBsum; 6TL9; -.
DR   PDBsum; 6TLA; -.
DR   PDBsum; 7R8U; -.
DR   PDBsum; 7W5D; -.
DR   PDBsum; 7XMP; -.
DR   PDBsum; 9IUD; -.
DR   AlphaFoldDB; P78380; -.
DR   SMR; P78380; -.
DR   BioGRID; 111021; 28.
DR   DIP; DIP-42040N; -.
DR   FunCoup; P78380; 270.
DR   IntAct; P78380; 13.
DR   MINT; P78380; -.
DR   STRING; 9606.ENSP00000309124; -.
DR   ChEMBL; CHEMBL3421522; -.
DR   GlyCosmos; P78380; 2 sites, No reported glycans.
DR   GlyGen; P78380; 2 sites.
DR   iPTMnet; P78380; -.
DR   PhosphoSitePlus; P78380; -.
DR   SwissPalm; P78380; -.
DR   BioMuta; OLR1; -.
DR   DMDM; 73621335; -.
DR   jPOST; P78380; -.
DR   MassIVE; P78380; -.
DR   PaxDb; 9606-ENSP00000309124; -.
DR   PeptideAtlas; P78380; -.
DR   ProteomicsDB; 32344; -.
DR   ProteomicsDB; 57601; -. [P78380-1]
DR   ProteomicsDB; 57602; -. [P78380-2]
DR   ABCD; P78380; 33 sequenced antibodies.
DR   Antibodypedia; 11685; 705 antibodies from 43 providers.
DR   DNASU; 4973; -.
DR   Ensembl; ENST00000309539.8; ENSP00000309124.3; ENSG00000173391.10. [P78380-1]
DR   Ensembl; ENST00000432556.6; ENSP00000405116.2; ENSG00000173391.10. [P78380-2]
DR   Ensembl; ENST00000545927.5; ENSP00000439251.1; ENSG00000173391.10. [P78380-3]
DR   GeneID; 4973; -.
DR   KEGG; hsa:4973; -.
DR   MANE-Select; ENST00000309539.8; ENSP00000309124.3; NM_002543.4; NP_002534.1.
DR   UCSC; uc001qxo.2; human. [P78380-1]
DR   AGR; HGNC:8133; -.
DR   ClinPGx; PA31920; -.
DR   CTD; 4973; -.
DR   DisGeNET; 4973; -.
DR   GeneCards; OLR1; -.
DR   HGNC; HGNC:8133; OLR1.
DR   HPA; ENSG00000173391; Tissue enhanced (lung, placenta).
DR   MalaCards; OLR1; -.
DR   MIM; 602601; gene+phenotype.
DR   OpenTargets; ENSG00000173391; -.
DR   VEuPathDB; HostDB:ENSG00000173391; -.
DR   eggNOG; KOG4297; Eukaryota.
DR   GeneTree; ENSGT00940000161941; -.
DR   InParanoid; P78380; -.
DR   OMA; NYSWLWE; -.
DR   OrthoDB; 6133475at2759; -.
DR   PAN-GO; P78380; 7 GO annotations based on evolutionary models.
DR   PhylomeDB; P78380; -.
DR   PathwayCommons; P78380; -.
DR   Reactome; R-HSA-202733; Cell surface interactions at the vascular wall.
DR   Reactome; R-HSA-6798695; Neutrophil degranulation.
DR   SignaLink; P78380; -.
DR   Agora; ENSG00000173391; -.
DR   BioGRID-ORCS; 4973; 13 hits in 1158 CRISPR screens.
DR   ChiTaRS; OLR1; human.
DR   EvolutionaryTrace; P78380; -.
DR   GeneWiki; OLR1; -.
DR   GenomeRNAi; 4973; -.
DR   Pharos; P78380; Tbio.
DR   PRO; PR:P78380; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; P78380; protein.
DR   Bgee; ENSG00000173391; Expressed in right lung and 130 other cell types or tissues.
DR   ExpressionAtlas; P78380; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; TAS:ProtInc.
DR   GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0043235; C:receptor complex; IDA:MGI.
DR   GO; GO:0035579; C:specific granule membrane; TAS:Reactome.
DR   GO; GO:0070821; C:tertiary granule membrane; TAS:Reactome.
DR   GO; GO:0030246; F:carbohydrate binding; IEA:UniProtKB-KW.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0005041; F:low-density lipoprotein particle receptor activity; IBA:GO_Central.
DR   GO; GO:0008015; P:blood circulation; TAS:ProtInc.
DR   GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR   GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR   GO; GO:0007159; P:leukocyte cell-cell adhesion; IBA:GO_Central.
DR   GO; GO:0042157; P:lipoprotein metabolic process; IBA:GO_Central.
DR   GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR   CDD; cd03593; CLECT_NK_receptors_like; 1.
DR   FunFam; 3.10.100.10:FF:000079; Oxidized low-density lipoprotein receptor 1; 1.
DR   Gene3D; 3.10.100.10; Mannose-Binding Protein A, subunit A; 1.
DR   InterPro; IPR001304; C-type_lectin-like.
DR   InterPro; IPR016186; C-type_lectin-like/link_sf.
DR   InterPro; IPR016187; CTDL_fold.
DR   InterPro; IPR033992; NKR-like_CTLD.
DR   InterPro; IPR052332; OxLDL_rcpt1-like.
DR   PANTHER; PTHR47298; OXIDIZED LOW-DENSITY LIPOPROTEIN RECEPTOR 1; 1.
DR   PANTHER; PTHR47298:SF1; OXIDIZED LOW-DENSITY LIPOPROTEIN RECEPTOR 1; 1.
DR   Pfam; PF00059; Lectin_C; 1.
DR   SMART; SM00034; CLECT; 1.
DR   SUPFAM; SSF56436; C-type lectin-like; 1.
DR   PROSITE; PS50041; C_TYPE_LECTIN_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cell adhesion; Cell membrane;
KW   Coiled coil; Disulfide bond; Glycoprotein; Immunity; Inflammatory response;
KW   Lectin; Lipoprotein; Membrane; Palmitate; Proteomics identification;
KW   Receptor; Reference proteome; Secreted; Signal-anchor; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..273
FT                   /note="Oxidized low-density lipoprotein receptor 1"
FT                   /id="PRO_0000017443"
FT   CHAIN           ?..273
FT                   /note="Oxidized low-density lipoprotein receptor 1, soluble
FT                   form"
FT                   /id="PRO_0000017444"
FT   TOPO_DOM        1..36
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        37..57
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        58..273
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          151..265
FT                   /note="C-type lectin"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00040"
FT   REGION          1..22
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          58..150
FT                   /note="Neck"
FT   COILED          64..123
FT                   /evidence="ECO:0000255"
FT   SITE            183
FT                   /note="Not glycosylated"
FT                   /evidence="ECO:0000305"
FT   LIPID           36
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:23583401"
FT   LIPID           46
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:23583401"
FT   CARBOHYD        73
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        139
FT                   /note="N-linked (GlcNAc...) (complex) asparagine"
FT                   /evidence="ECO:0000269|PubMed:22688517"
FT   DISULFID        140
FT                   /note="Interchain"
FT   DISULFID        144..155
FT   DISULFID        172..264
FT   DISULFID        243..256
FT   VAR_SEQ         142..273
FT                   /note="APCPQDWIWHGENCYLFSSGSFNWEKSQEKCLSLDAKLLKINSTADLDFIQQ
FT                   AISYSSFPFWMGLSRRNPSYPWLWEDGSPLMPHLFRVRGAVSQTYPSGTCAYIQRGAVY
FT                   AENCILAAFSICQKKANLRAQ -> GLHPASNFLFQFSILDGAVSEEPQLPMALGGRFS
FT                   FDAPLI (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_042555"
FT   VAR_SEQ         189..273
FT                   /note="DFIQQAISYSSFPFWMGLSRRNPSYPWLWEDGSPLMPHLFRVRGAVSQTYPS
FT                   GTCAYIQRGAVYAENCILAAFSICQKKANLRAQ -> I (in isoform 3)"
FT                   /evidence="ECO:0000303|Ref.7"
FT                   /id="VSP_045277"
FT   VARIANT         167
FT                   /note="K -> N (myocardial infarction susceptibility;
FT                   dbSNP:rs11053646)"
FT                   /evidence="ECO:0000269|PubMed:12646194,
FT                   ECO:0000269|PubMed:14702039"
FT                   /id="VAR_023200"
FT   MUTAGEN         22..25
FT                   /note="KKAK->EEAE: Impairs sorting into the cell surface
FT                   but retains ability to bind oxLDL. Abolishes sorting into
FT                   the cell surface; when associated with K-69."
FT                   /evidence="ECO:0000269|PubMed:15935375"
FT   MUTAGEN         70
FT                   /note="E->K: Abolishes sorting into the cell surface; when
FT                   associated with 22-E--E-25."
FT                   /evidence="ECO:0000269|PubMed:15935375"
FT   MUTAGEN         140
FT                   /note="C->S: Abolishes homodimerization."
FT                   /evidence="ECO:0000269|PubMed:15000751"
FT   MUTAGEN         144
FT                   /note="C->S: Abolishes sorting into the cell surface and
FT                   binding to acetylated LDL (AcLDL) while increasing N-
FT                   glycosylation; when associated with S-155; S-172; S-243; S-
FT                   256 and S-264."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         150
FT                   /note="W->A: Abolishes binding to acetylated LDL (AcLDL),
FT                   probably due to inappropriate homodimerization."
FT                   /evidence="ECO:0000269|PubMed:15939022"
FT   MUTAGEN         155
FT                   /note="C->S: Abolishes sorting into the cell surface and
FT                   binding to acetylated LDL (AcLDL) while increasing N-
FT                   glycosylation; when associated with S-144; S-172; S-243; S-
FT                   256 and S-264."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         172
FT                   /note="C->S: Abolishes sorting into the cell surface and
FT                   binding to acetylated LDL (AcLDL) while increasing N-
FT                   glycosylation; when associated with S-144; S-155; S-243; S-
FT                   256 and S-264."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         183
FT                   /note="N->Q: Does not affect glycosylation state."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         193
FT                   /note="Q->L: Impairs binding to acetylated LDL (AcLDL);
FT                   when associated with 198-AA-199."
FT   MUTAGEN         198..199
FT                   /note="SS->AA: Impairs binding to acetylated LDL (AcLDL);
FT                   when associated with L-193."
FT   MUTAGEN         208
FT                   /note="R->N: Does not affect subcellular location but
FT                   displays a strongly reduced affinity for acetylated LDL
FT                   (AcLDL)."
FT                   /evidence="ECO:0000269|PubMed:15939022"
FT   MUTAGEN         209..210
FT                   /note="RN->LL: Abolishes binding to acetylated LDL
FT                   (AcLDL)."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         209
FT                   /note="R->N: Does not affect binding to acetylated LDL
FT                   (AcLDL)."
FT                   /evidence="ECO:0000269|PubMed:15939022"
FT   MUTAGEN         226
FT                   /note="H->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:11256994,
FT                   ECO:0000269|PubMed:15939022"
FT   MUTAGEN         226
FT                   /note="H->Q: Abolishes binding to acetylated LDL (AcLDL);
FT                   when associated with N-229 and N-231."
FT                   /evidence="ECO:0000269|PubMed:11256994,
FT                   ECO:0000269|PubMed:15939022"
FT   MUTAGEN         229
FT                   /note="R->N: Does not affect subcellular location but
FT                   displays a reduced affinity for acetylated LDL (AcLDL).
FT                   Abolishes binding to acetylated LDL (AcLDL); when
FT                   associated with Q-226 and N-231."
FT                   /evidence="ECO:0000269|PubMed:11256994,
FT                   ECO:0000269|PubMed:15939022"
FT   MUTAGEN         231
FT                   /note="R->N: Abolishes binding to acetylated LDL (AcLDL).
FT                   Abolishes binding to AcLDL; when associated with Q-226 and
FT                   N-229."
FT                   /evidence="ECO:0000269|PubMed:11256994,
FT                   ECO:0000269|PubMed:15939022"
FT   MUTAGEN         235..236
FT                   /note="SQ->AL: Impairs binding to acetylated LDL (AcLDL);
FT                   when associated with A-240."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         240
FT                   /note="S->A: Impairs binding to acetylated LDL (AcLDL);
FT                   when associated with 235-AL-236."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         243
FT                   /note="C->S: Abolishes sorting into the cell surface and
FT                   binding to acetylated LDL (AcLDL) while increasing N-
FT                   glycosylation; when associated with S-144; S-155; S-172; S-
FT                   256 and S-264."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         248
FT                   /note="R->N: Does not affect subcellular location but
FT                   displays a reduced affinity for acetylated LDL (AcLDL)."
FT                   /evidence="ECO:0000269|PubMed:15939022"
FT   MUTAGEN         256
FT                   /note="C->S: Abolishes sorting into the cell surface and
FT                   binding to acetylated LDL (AcLDL) while increasing N-
FT                   glycosylation; when associated with S-144; S-155; S-172; S-
FT                   243 and S-264."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         264
FT                   /note="C->S: Abolishes sorting into the cell surface and
FT                   binding to acetylated LDL (AcLDL) while increasing N-
FT                   glycosylation; when associated with S-144; S-155; S-172; S-
FT                   243 and S-256."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   MUTAGEN         267..273
FT                   /note="Missing: Impairs protein folding and transport."
FT                   /evidence="ECO:0000269|PubMed:11256994"
FT   STRAND          148..151
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   STRAND          154..158
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   HELIX           165..174
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   HELIX           185..194
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   TURN            195..197
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   STRAND          202..210
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   STRAND          225..227
FT                   /evidence="ECO:0007829|PDB:1YPO"
FT   STRAND          230..233
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   STRAND          242..247
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   STRAND          250..255
FT                   /evidence="ECO:0007829|PDB:6TL7"
FT   STRAND          260..267
FT                   /evidence="ECO:0007829|PDB:6TL7"
SQ   SEQUENCE   273 AA;  30959 MW;  852DE6595DC3D361 CRC64;
     MTFDDLKIQT VKDQPDEKSN GKKAKGLQFL YSPWWCLAAA TLGVLCLGLV VTIMVLGMQL
     SQVSDLLTQE QANLTHQKKK LEGQISARQQ AEEASQESEN ELKEMIETLA RKLNEKSKEQ
     MELHHQNLNL QETLKRVANC SAPCPQDWIW HGENCYLFSS GSFNWEKSQE KCLSLDAKLL
     KINSTADLDF IQQAISYSSF PFWMGLSRRN PSYPWLWEDG SPLMPHLFRV RGAVSQTYPS
     GTCAYIQRGA VYAENCILAA FSICQKKANL RAQ
//
ID   PAWR_HUMAN              Reviewed;         340 AA.
AC   Q96IZ0; O75796; Q6FHY9; Q8N700;
DT   24-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-2001, sequence version 1.
DT   28-JAN-2026, entry version 183.
DE   RecName: Full=PRKC apoptosis WT1 regulator protein;
DE   AltName: Full=Prostate apoptosis response 4 protein;
DE            Short=Par-4;
GN   Name=PAWR; Synonyms=PAR4;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP   INTERACTION WITH WT1.
RX   PubMed=8943350; DOI=10.1128/mcb.16.12.6945;
RA   Johnstone R.W., See R.H., Sells S.F., Wang J., Muthukkumar S., Englert C.,
RA   Haber D.A., Licht J.D., Sugrue S.P., Roberts T., Rangnekar V.M., Shi Y.;
RT   "A novel repressor, par-4, modulates transcription and growth suppression
RT   functions of the Wilms' tumor suppressor WT1.";
RL   Mol. Cell. Biol. 16:6945-6956(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-78.
RA   Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-42; ARG-78; ALA-137 AND
RP   ALA-202.
RG   NIEHS SNPs program;
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Kidney;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-64.
RC   TISSUE=Blood;
RX   PubMed=12242017; DOI=10.1016/s0378-1119(02)00826-0;
RA   Hsu S.-C., Kirschenbaum F., Miller J., Cordell B., McCarthy J.V.;
RT   "Structural and functional characterization of the upstream regulatory
RT   region of the human gene encoding prostate apoptosis response factor-4.";
RL   Gene 295:109-116(2002).
RN   [6]
RP   FUNCTION IN APOPTOSIS AND TUMOR REGRESSION.
RX   PubMed=11585763;
RA   Chakraborty M., Qiu S.G., Vasudevan K.M., Rangnekar V.M.;
RT   "Par-4 drives trafficking and activation of Fas and Fasl to induce prostate
RT   cancer cell apoptosis and tumor regression.";
RL   Cancer Res. 61:7255-7263(2001).
RN   [7]
RP   INTERACTION WITH SQSTM1 AND PRKCZ.
RX   PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0;
RA   Chang S., Kim J.H., Shin J.;
RT   "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4-
RT   induced PKCzeta inhibition.";
RL   FEBS Lett. 510:57-61(2002).
RN   [8]
RP   SUBCELLULAR LOCATION, AND INTERACTION WITH THAP1.
RX   PubMed=12717420; DOI=10.1038/sj.onc.1206271;
RA   Roussigne M., Cayrol C., Clouaire T., Amalric F., Girard J.-P.;
RT   "THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-
RT   response-4 (Par-4) to PML nuclear bodies.";
RL   Oncogene 22:2432-2442(2003).
RN   [9]
RP   INTERACTION WITH AATF.
RX   PubMed=14627703; DOI=10.1074/jbc.m309811200;
RA   Guo Q., Xie J.;
RT   "AATF inhibits aberrant production of amyloid beta peptide 1-42 by
RT   interacting directly with Par-4.";
RL   J. Biol. Chem. 279:4596-4603(2004).
RN   [10]
RP   INTERACTION WITH BACE1.
RX   PubMed=15671026; DOI=10.1074/jbc.m411933200;
RA   Xie J., Guo Q.;
RT   "PAR-4 is involved in regulation of beta-secretase cleavage of the
RT   Alzheimer amyloid precursor protein.";
RL   J. Biol. Chem. 280:13824-13832(2005).
RN   [11]
RP   INTERACTION WITH SPSB1 AND SPSB2, AND MUTAGENESIS OF ASN-72.
RX   PubMed=17189197; DOI=10.1016/j.molcel.2006.11.009;
RA   Woo J.S., Suh H.Y., Park S.Y., Oh B.H.;
RT   "Structural basis for protein recognition by B30.2/SPRY domains.";
RL   Mol. Cell 24:967-976(2006).
RN   [12]
RP   REVIEW ON FUNCTION IN APOPTOSIS AND NEURODEGENERATIVE DISEASES.
RX   PubMed=12565819; DOI=10.1016/s0014-4827(02)00016-2;
RA   El-Guendy N., Rangnekar V.M.;
RT   "Apoptosis by Par-4 in cancer and neurodegenerative diseases.";
RL   Exp. Cell Res. 283:51-66(2003).
RN   [13]
RP   REVIEW.
RX   PubMed=14755681; DOI=10.1002/jcb.20000;
RA   Gurumurthy S., Rangnekar V.M.;
RT   "Par-4 inducible apoptosis in prostate cancer cells.";
RL   J. Cell. Biochem. 91:504-512(2004).
RN   [14]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [15]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [16]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [17]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [18]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-231, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [19]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [20] {ECO:0007744|PDB:2JK9}
RP   X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) OF 67-74 IN COMPLEX WITH SPSB1,
RP   INTERACTION WITH SPSB1; SPSB2 AND SPSB4, MUTAGENESIS OF ALA-66; GLU-68;
RP   LEU-69; ASN-71 AND ASN-72, AND MOTIF.
RX   PubMed=20561531; DOI=10.1016/j.jmb.2010.06.017;
RA   Filippakopoulos P., Low A., Sharpe T.D., Uppenberg J., Yao S., Kuang Z.,
RA   Savitsky P., Lewis R.S., Nicholson S.E., Norton R.S., Bullock A.N.;
RT   "Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-
RT   containing proteins SPSB1, SPSB2, and SPSB4.";
RL   J. Mol. Biol. 401:389-402(2010).
CC   -!- FUNCTION: Pro-apoptotic protein capable of selectively inducing
CC       apoptosis in cancer cells, sensitizing the cells to diverse apoptotic
CC       stimuli and causing regression of tumors in animal models. Induces
CC       apoptosis in certain cancer cells by activation of the Fas prodeath
CC       pathway and coparallel inhibition of NF-kappa-B transcriptional
CC       activity. Inhibits the transcriptional activation and augments the
CC       transcriptional repression mediated by WT1. Down-regulates the anti-
CC       apoptotic protein BCL2 via its interaction with WT1. Also seems to be a
CC       transcriptional repressor by itself. May be directly involved in
CC       regulating the amyloid precursor protein (APP) cleavage activity of
CC       BACE1. {ECO:0000269|PubMed:11585763}.
CC   -!- SUBUNIT: Homooligomer. Interacts (via the C-terminal region) with WT1
CC       (PubMed:8943350). Interacts with THAP1 (PubMed:12717420). Interacts
CC       with AATF (PubMed:14627703). Interacts with BACE1 (PubMed:15671026).
CC       Interacts with SPSB1 (via B30.2/SPRY domain); this interaction is
CC       direct and occurs in association with the Elongin BC complex
CC       (PubMed:17189197, PubMed:20561531). Interacts with SPSB2 (via
CC       B30.2/SPRY domain); this interaction occurs in association with the
CC       Elongin BC complex (PubMed:17189197, PubMed:20561531). Interacts with
CC       SPSB4 (via B30.2/SPRY domain) (PubMed:20561531); this interaction
CC       occurs in association with the Elongin BC complex (PubMed:20561531).
CC       Component of a ternary complex composed of SQSTM1 and PRKCZ
CC       (PubMed:11755531). Interacts with actin (By similarity).
CC       {ECO:0000250|UniProtKB:Q62627, ECO:0000250|UniProtKB:Q925B0,
CC       ECO:0000269|PubMed:11755531, ECO:0000269|PubMed:12717420,
CC       ECO:0000269|PubMed:14627703, ECO:0000269|PubMed:15671026,
CC       ECO:0000269|PubMed:17189197, ECO:0000269|PubMed:20561531,
CC       ECO:0000269|PubMed:8943350}.
CC   -!- INTERACTION:
CC       Q96IZ0; Q01094: E2F1; NbExp=2; IntAct=EBI-595869, EBI-448924;
CC       Q96IZ0; P11021: HSPA5; NbExp=8; IntAct=EBI-595869, EBI-354921;
CC       Q96IZ0; Q96BD6: SPSB1; NbExp=2; IntAct=EBI-595869, EBI-2659201;
CC       Q96IZ0; Q99619: SPSB2; NbExp=2; IntAct=EBI-595869, EBI-2323209;
CC       Q96IZ0; Q96A44: SPSB4; NbExp=2; IntAct=EBI-595869, EBI-2323233;
CC       Q96IZ0; P08670: VIM; NbExp=2; IntAct=EBI-595869, EBI-353844;
CC       Q96IZ0; Q9D5L7: Spsb1; Xeno; NbExp=2; IntAct=EBI-595869, EBI-8821912;
CC       Q96IZ0; O88838: Spsb2; Xeno; NbExp=6; IntAct=EBI-595869, EBI-8820410;
CC       Q96IZ0; Q8R5B6: Spsb4; Xeno; NbExp=3; IntAct=EBI-595869, EBI-8821982;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Mainly cytoplasmic in
CC       absence of apoptosis signal and in normal cells. Nuclear in most cancer
CC       cell lines. Nuclear entry seems to be essential but not sufficient for
CC       apoptosis (By similarity). Nuclear localization includes nucleoplasm
CC       and PML nuclear bodies. {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Widely expressed. Expression is elevated in various
CC       neurodegenerative diseases such as amyotrophic lateral sclerosis,
CC       Alzheimer, Parkinson and Huntington diseases and stroke. Down-regulated
CC       in several cancers. {ECO:0000269|PubMed:8943350}.
CC   -!- INDUCTION: By apoptosis.
CC   -!- DOMAIN: The leucine-zipper domain is not essential for apoptosis, but
CC       is required for sensitization of cells to exogenous apoptotic insults
CC       and for interaction with its partners. {ECO:0000250}.
CC   -!- DOMAIN: The SAC domain is a death-inducing domain selective for
CC       apoptosis induction in cancer cells. This domain is essential for
CC       nuclear entry, Fas activation, inhibition of NF-kappa-B activity and
CC       induction of apoptosis in cancer cells (By similarity). {ECO:0000250}.
CC   -!- DOMAIN: The B30.2/SPRY domain-binding motif mediates recognition by
CC       proteins containing a B30.2/SPRY domain. {ECO:0000269|PubMed:20561531}.
CC   -!- PTM: Preferentially phosphorylated at the Thr-163 by PKC in cancer
CC       cells. {ECO:0000250}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/41641/PAWR";
CC   ---------------------------------------------------------------------------
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DR   EMBL; U63809; AAC24947.1; -; mRNA.
DR   EMBL; CR536549; CAG38786.1; -; mRNA.
DR   EMBL; AY300794; AAP43693.1; -; Genomic_DNA.
DR   EMBL; BC007018; AAH07018.1; -; mRNA.
DR   EMBL; AF503628; AAM27453.1; -; Genomic_DNA.
DR   CCDS; CCDS31863.1; -.
DR   RefSeq; NP_001341661.1; NM_001354732.2.
DR   RefSeq; NP_002574.2; NM_002583.4.
DR   RefSeq; XP_047284872.1; XM_047428916.1.
DR   RefSeq; XP_054228126.1; XM_054372151.1.
DR   PDB; 2JK9; X-ray; 1.79 A; B=67-81.
DR   PDBsum; 2JK9; -.
DR   AlphaFoldDB; Q96IZ0; -.
DR   SMR; Q96IZ0; -.
DR   BioGRID; 111108; 137.
DR   CORUM; Q96IZ0; -.
DR   DIP; DIP-29003N; -.
DR   ELM; Q96IZ0; -.
DR   FunCoup; Q96IZ0; 1301.
DR   IntAct; Q96IZ0; 40.
DR   MINT; Q96IZ0; -.
DR   STRING; 9606.ENSP00000328088; -.
DR   BindingDB; Q96IZ0; -.
DR   DrugBank; DB14942; BMS-986141.
DR   GlyGen; Q96IZ0; 12 sites, 1 O-linked glycan (12 sites).
DR   iPTMnet; Q96IZ0; -.
DR   PhosphoSitePlus; Q96IZ0; -.
DR   BioMuta; PAWR; -.
DR   DMDM; 66773935; -.
DR   jPOST; Q96IZ0; -.
DR   MassIVE; Q96IZ0; -.
DR   PaxDb; 9606-ENSP00000328088; -.
DR   PeptideAtlas; Q96IZ0; -.
DR   ProteomicsDB; 76870; -.
DR   Pumba; Q96IZ0; -.
DR   TopDownProteomics; Q96IZ0; -.
DR   Antibodypedia; 1824; 392 antibodies from 41 providers.
DR   DNASU; 5074; -.
DR   Ensembl; ENST00000328827.9; ENSP00000328088.4; ENSG00000177425.12.
DR   GeneID; 5074; -.
DR   KEGG; hsa:5074; -.
DR   MANE-Select; ENST00000328827.9; ENSP00000328088.4; NM_002583.4; NP_002574.2.
DR   UCSC; uc001syx.4; human.
DR   AGR; HGNC:8614; -.
DR   ClinPGx; PA32954; -.
DR   CTD; 5074; -.
DR   DisGeNET; 5074; -.
DR   GeneCards; PAWR; -.
DR   HGNC; HGNC:8614; PAWR.
DR   HPA; ENSG00000177425; Low tissue specificity.
DR   MIM; 601936; gene.
DR   OpenTargets; ENSG00000177425; -.
DR   VEuPathDB; HostDB:ENSG00000177425; -.
DR   eggNOG; ENOG502QVUF; Eukaryota.
DR   GeneTree; ENSGT00390000000406; -.
DR   HOGENOM; CLU_076619_0_0_1; -.
DR   InParanoid; Q96IZ0; -.
DR   OMA; NCIPLAR; -.
DR   OrthoDB; 6286739at2759; -.
DR   PAN-GO; Q96IZ0; 2 GO annotations based on evolutionary models.
DR   PhylomeDB; Q96IZ0; -.
DR   PathwayCommons; Q96IZ0; -.
DR   SignaLink; Q96IZ0; -.
DR   SIGNOR; Q96IZ0; -.
DR   Agora; ENSG00000177425; -.
DR   BioGRID-ORCS; 5074; 29 hits in 1161 CRISPR screens.
DR   CD-CODE; DEE660B4; Stress granule.
DR   ChiTaRS; PAWR; human.
DR   EvolutionaryTrace; Q96IZ0; -.
DR   GeneWiki; PAWR; -.
DR   GenomeRNAi; 5074; -.
DR   Pharos; Q96IZ0; Tbio.
DR   PRO; PR:Q96IZ0; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; Q96IZ0; protein.
DR   Bgee; ENSG00000177425; Expressed in germinal epithelium of ovary and 186 other cell types or tissues.
DR   ExpressionAtlas; Q96IZ0; baseline and differential.
DR   GO; GO:0015629; C:actin cytoskeleton; IDA:HPA.
DR   GO; GO:0005884; C:actin filament; IBA:GO_Central.
DR   GO; GO:0000785; C:chromatin; IEA:Ensembl.
DR   GO; GO:0097542; C:ciliary tip; IDA:HPA.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0003779; F:actin binding; ISS:UniProtKB.
DR   GO; GO:0019899; F:enzyme binding; IDA:UniProtKB.
DR   GO; GO:0043522; F:leucine zipper domain binding; IPI:UniProtKB.
DR   GO; GO:0003714; F:transcription corepressor activity; TAS:ProtInc.
DR   GO; GO:0051017; P:actin filament bundle assembly; ISS:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR   GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl.
DR   GO; GO:0030889; P:negative regulation of B cell proliferation; IEA:Ensembl.
DR   GO; GO:0048147; P:negative regulation of fibroblast proliferation; IEA:Ensembl.
DR   GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR   GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR   GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IEA:Ensembl.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:ProtInc.
DR   GO; GO:0042986; P:positive regulation of amyloid precursor protein biosynthetic process; IEA:Ensembl.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IBA:GO_Central.
DR   GO; GO:2000774; P:positive regulation of cellular senescence; IEA:Ensembl.
DR   GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR   GO; GO:1901300; P:positive regulation of hydrogen peroxide-mediated programmed cell death; IEA:Ensembl.
DR   DisProt; DP01603; -.
DR   IDEAL; IID00177; -.
DR   InterPro; IPR026117; Par-4.
DR   PANTHER; PTHR15093:SF1; PRKC APOPTOSIS WT1 REGULATOR PROTEIN; 1.
DR   PANTHER; PTHR15093; PROSTATE APOPTOSIS RESPONSE PROTEIN PAR-4; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Apoptosis; Coiled coil; Cytoplasm; Nucleus; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Transcription;
KW   Transcription regulation.
FT   CHAIN           1..340
FT                   /note="PRKC apoptosis WT1 regulator protein"
FT                   /id="PRO_0000058236"
FT   REGION          1..253
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          145..203
FT                   /note="Selective for apoptosis induction in cancer cells
FT                   (SAC)"
FT   REGION          300..340
FT                   /note="Leucine-zipper"
FT   COILED          186..206
FT                   /evidence="ECO:0000255"
FT   MOTIF           68..72
FT                   /note="B30.2/SPRY domain-binding motif"
FT                   /evidence="ECO:0000269|PubMed:20561531"
FT   MOTIF           145..161
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        1..18
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        47..82
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        182..192
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        193..203
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        242..253
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         108
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         163
FT                   /note="Phosphothreonine; by PKA"
FT                   /evidence="ECO:0000250|UniProtKB:Q62627"
FT   MOD_RES         231
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   VARIANT         42
FT                   /note="P -> L (in dbSNP:rs8176804)"
FT                   /evidence="ECO:0000269|Ref.3"
FT                   /id="VAR_022465"
FT   VARIANT         78
FT                   /note="P -> R (in dbSNP:rs8176805)"
FT                   /evidence="ECO:0000269|Ref.2, ECO:0000269|Ref.3"
FT                   /id="VAR_022466"
FT   VARIANT         137
FT                   /note="G -> A (in dbSNP:rs8176806)"
FT                   /evidence="ECO:0000269|Ref.3"
FT                   /id="VAR_022467"
FT   VARIANT         202
FT                   /note="E -> A (in dbSNP:rs8176870)"
FT                   /evidence="ECO:0000269|Ref.3"
FT                   /id="VAR_022468"
FT   MUTAGEN         66
FT                   /note="A->D: No loss of interaction with SPSB1, SPSB2 and
FT                   SPSB4."
FT                   /evidence="ECO:0000269|PubMed:20561531"
FT   MUTAGEN         68
FT                   /note="E->D: Increased interaction with SPSB2. Only
FT                   slightly increased interaction with SPSB4. Increased
FT                   interaction with SPSB1, SPSB2 and SPSB4; when associated
FT                   with A-69."
FT                   /evidence="ECO:0000269|PubMed:20561531"
FT   MUTAGEN         69
FT                   /note="L->I: Only slightly increased interaction with
FT                   SPSB2. Only slightly increased interaction with SPSB4.
FT                   Increased interaction with SPSB1, SPSB2 and SPSB4; when
FT                   associated with A-68."
FT                   /evidence="ECO:0000269|PubMed:20561531"
FT   MUTAGEN         71
FT                   /note="N->A: Loss of interaction with SPSB1, SPSB2 and
FT                   SPSB4."
FT                   /evidence="ECO:0000269|PubMed:20561531"
FT   MUTAGEN         72
FT                   /note="N->A: Loss of interaction with SPSB1-Elongin BC
FT                   complex and SPSB2 and SPSB4."
FT                   /evidence="ECO:0000269|PubMed:17189197,
FT                   ECO:0000269|PubMed:20561531"
FT   CONFLICT        102..103
FT                   /note="AP -> PPAR (in Ref. 1; AAC24947)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        199
FT                   /note="I -> M (in Ref. 2; CAG38786)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        281
FT                   /note="R -> T (in Ref. 1; AAC24947)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   340 AA;  36568 MW;  7E7515455402DBF8 CRC64;
     MATGGYRTSS GLGGSTTDFL EEWKAKREKM RAKQNPPGPA PPGGGSSDAA GKPPAGALGT
     PAAAAANELN NNLPGGAPAA PAVPGPGGVN CAVGSAMLTR AAPGPRRSED EPPAASASAA
     PPPQRDEEEP DGVPEKGKSS GPSARKGKGQ IEKRKLREKR RSTGVVNIPA AECLDEYEDD
     EAGQKERKRE DAITQQNTIQ NEAVNLLDPG SSYLLQEPPR TVSGRYKSTT SVSEEDVSSR
     YSRTDRSGFP RYNRDANVSG TLVSSSTLEK KIEDLEKEVV RERQENLRLV RLMQDKEEMI
     GKLKEEIDLL NRDLDDIEDE NEQLKQENKT LLKVVGQLTR
//
ID   PSN1_HUMAN              Reviewed;         467 AA.
AC   P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 1.
DT   28-JAN-2026, entry version 263.
DE   RecName: Full=Presenilin-1 {ECO:0000303|PubMed:9144240};
DE            Short=PS-1 {ECO:0000303|PubMed:9298817};
DE            EC=3.4.23.- {ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:26280335};
DE   AltName: Full=Protein S182 {ECO:0000303|PubMed:7550356};
DE   Contains:
DE     RecName: Full=Presenilin-1 NTF subunit {ECO:0000305|PubMed:9173929};
DE   Contains:
DE     RecName: Full=Presenilin-1 CTF subunit {ECO:0000305|PubMed:9173929};
DE   Contains:
DE     RecName: Full=Presenilin-1 CTF12 {ECO:0000305|PubMed:9485372};
DE              Short=PS1-CTF12;
GN   Name=PSEN1 {ECO:0000312|HGNC:HGNC:9508}; Synonyms=AD3, PS1, PSNL1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANTS AD3
RP   LEU-146; ARG-163; GLU-246 AND VAL-286, AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=7596406; DOI=10.1038/375754a0;
RA   Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M.,
RA   Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.-F.,
RA   Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L.,
RA   Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W.,
RA   da Silva H.A.R., Haines J.L., Pericak-Vance M.A., Tanzi R.E., Roses A.D.,
RA   Fraser P.E., Rommens J.M., St George-Hyslop P.H.;
RT   "Cloning of a gene bearing missense mutations in early-onset familial
RT   Alzheimer's disease.";
RL   Nature 375:754-760(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND TISSUE SPECIFICITY.
RC   TISSUE=Blood, and Brain;
RX   PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3;
RA   Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M.,
RA   Shirasawa T., Mori H.;
RT   "Identification and characterization of presenilin I-467, I-463 and I-
RT   374.";
RL   FEBS Lett. 381:7-11(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA   Powell C.S., Gegg M.E., Palmer M.S.;
RT   "Human presenilin 1 gene encodes an alternative protein-minilin.";
RL   Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A., Madan A.,
RA   Dickhoff R., Shaffer T., James R., Lasky S., Hood L.;
RT   "Complete sequence of the gene for presenilin 1.";
RL   Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RA   Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.;
RL   Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Tongue;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12508121; DOI=10.1038/nature01348;
RA   Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA   Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA   Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA   Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA   Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA   Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA   Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA   Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA   Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA   Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA   Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA   Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA   Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA   Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA   Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA   Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA   Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA   Waterston R., Hood L., Weissenbach J.;
RT   "The DNA sequence and analysis of human chromosome 14.";
RL   Nature 421:601-607(2003).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Skin;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [10]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113.
RX   PubMed=9070286; DOI=10.1006/bbrc.1996.6043;
RA   Tsujimura A., Yasojima K., Hashimoto-Gotoh T.;
RT   "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential
RT   expression in oogenesis and embryogenesis.";
RL   Biochem. Biophys. Res. Commun. 231:392-396(1997).
RN   [11]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING (ISOFORMS 6
RP   AND 7).
RC   TISSUE=Megakaryocyte, and Platelet;
RX   PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9;
RA   Vidal R., Ghiso J., Wisniewski T., Frangione B.;
RT   "Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes.
RT   Identification of a novel splice variant.";
RL   FEBS Lett. 393:19-23(1996).
RN   [12]
RP   PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320;
RP   345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY,
RP   IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY,
RP   AND SUBCELLULAR LOCATION.
RX   PubMed=15274632; DOI=10.1021/bi0494976;
RA   Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J.,
RA   Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.;
RT   "Purification and characterization of the human gamma-secretase complex.";
RL   Biochemistry 43:9774-9789(2004).
RN   [13]
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=8574969; DOI=10.1038/nm0296-224;
RA   Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E.,
RA   Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T.,
RA   Tanzi R.E., Wasco W.;
RT   "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and
RT   localization to intracellular membranes in mammalian cells.";
RL   Nat. Med. 2:224-229(1996).
RN   [14]
RP   PROTEOLYTIC PROCESSING.
RX   PubMed=9173929; DOI=10.1006/nbdi.1997.0129;
RA   Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J.,
RA   Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P.,
RA   St George-Hyslop P.H., Teplow D.B., Selkoe D.J.;
RT   "Presenilin proteins undergo heterogeneous endoproteolysis between Thr291
RT   and Ala299 and occur as stable N- and C-terminal fragments in normal and
RT   Alzheimer brain tissue.";
RL   Neurobiol. Dis. 3:325-337(1997).
RN   [15]
RP   PHOSPHORYLATION.
RX   PubMed=9144240; DOI=10.1073/pnas.94.10.5349;
RA   Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M.,
RA   Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C.;
RT   "Proteolytic processing of the Alzheimer disease-associated presenilin-1
RT   generates an in vivo substrate for protein kinase C.";
RL   Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997).
RN   [16]
RP   CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385.
RX   PubMed=9485372; DOI=10.1021/bi972106l;
RA   Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C.;
RT   "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa
RT   C-terminal fragment are death substrates for proteases of the caspase
RT   family.";
RL   Biochemistry 37:2263-2270(1998).
RN   [17]
RP   FUNCTION, INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION.
RX   PubMed=9738936; DOI=10.1016/s0014-5793(98)00886-2;
RA   Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X.,
RA   Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.;
RT   "Direct association of presenilin-1 with beta-catenin.";
RL   FEBS Lett. 433:73-77(1998).
RN   [18]
RP   INTERACTION WITH FLNA AND FLNB.
RX   PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998;
RA   Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.;
RT   "Interaction of presenilins with the filamin family of actin-binding
RT   proteins.";
RL   J. Neurosci. 18:914-922(1998).
RN   [19]
RP   FUNCTION, MUTAGENESIS OF MET-292, AND PROTEOLYTIC PROCESSING.
RX   PubMed=10545183; DOI=10.1021/bi9914210;
RA   Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M.,
RA   Loetscher H., Jacobsen H., Haass C.;
RT   "Amyloidogenic function of the Alzheimer's disease-associated presenilin 1
RT   in the absence of endoproteolysis.";
RL   Biochemistry 38:14600-14605(1999).
RN   [20]
RP   INTERACTION WITH MTCH1.
RX   PubMed=10551805; DOI=10.1074/jbc.274.46.32543;
RA   Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.;
RT   "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting
RT   with the C terminus of presenilin-1.";
RL   J. Biol. Chem. 274:32543-32546(1999).
RN   [21]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NOTCH.
RX   PubMed=10593990; DOI=10.1074/jbc.274.51.36801;
RA   Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M.,
RA   Selkoe D.J., Kopan R., Goate A.M.;
RT   "Cell surface presenilin-1 participates in the gamma-secretase-like
RT   proteolysis of Notch.";
RL   J. Biol. Chem. 274:36801-36807(1999).
RN   [22]
RP   INTERACTION WITH CTNND2 AND CTNNB1, AND SUBCELLULAR LOCATION.
RX   PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x;
RA   Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D.,
RA   Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L.,
RA   VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E.,
RA   St George-Hyslop P.H.;
RT   "Presenilins interact with armadillo proteins including neural-specific
RT   plakophilin-related protein and beta-catenin.";
RL   J. Neurochem. 72:999-1008(1999).
RN   [23]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND
RP   ASP-385.
RX   PubMed=10206644; DOI=10.1038/19077;
RA   Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T.,
RA   Selkoe D.J.;
RT   "Two transmembrane aspartates in presenilin-1 required for presenilin
RT   endoproteolysis and gamma-secretase activity.";
RL   Nature 398:513-517(1999).
RN   [24]
RP   INTERACTION WITH DOCK3.
RX   PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x;
RA   Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R.,
RA   Schubert D., Kimura H.;
RT   "Isolation and characterization of novel presenilin binding protein.";
RL   J. Neurochem. 75:109-116(2000).
RN   [25]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND
RP   ASP-385.
RX   PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x;
RA   Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W.,
RA   Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.;
RT   "Aspartate mutations in presenilin and gamma-secretase inhibitors both
RT   impair notch1 proteolysis and nuclear translocation with relative
RT   preservation of notch1 signaling.";
RL   J. Neurochem. 75:583-593(2000).
RN   [26]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LEU-286.
RX   PubMed=10811883; DOI=10.1073/pnas.100049897;
RA   Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H.,
RA   Capell A., Steiner H., Haass C.;
RT   "Separation of presenilin function in amyloid beta-peptide generation and
RT   endoproteolysis of Notch.";
RL   Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000).
RN   [27]
RP   INTERACTION WITH PARL.
RX   PubMed=12214059; DOI=10.3233/jad-2001-3203;
RA   Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K.,
RA   Fowlkes B.J., Koonin E.V., D'Adamio L.;
RT   "PAMP and PARL, two novel putative metalloproteases interacting with the
RT   COOH-terminus of presenilin-1 and -2.";
RL   J. Alzheimers Dis. 3:181-190(2001).
RN   [28]
RP   TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX   PubMed=11987239; DOI=10.1006/bcmd.2002.0486;
RA   Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L.,
RA   Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.;
RT   "Identification of the presenilins in hematopoietic cells with localization
RT   of presenilin 1 to neutrophil and platelet granules.";
RL   Blood Cells Mol. Dis. 28:28-38(2002).
RN   [29]
RP   FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH CDH1
RP   AND CTNNB1.
RX   PubMed=11953314; DOI=10.1093/emboj/21.8.1948;
RA   Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V.,
RA   Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K.;
RT   "A presenilin-1/gamma-secretase cleavage releases the E-cadherin
RT   intracellular domain and regulates disassembly of adherens junctions.";
RL   EMBO J. 21:1948-1956(2002).
RN   [30]
RP   INTERACTION WITH HERPUD1.
RX   PubMed=11799129; DOI=10.1074/jbc.m112372200;
RA   Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R.,
RA   Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B.,
RA   Yanagisawa K., Komano H.;
RT   "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-
RT   mediated generation of amyloid beta-protein.";
RL   J. Biol. Chem. 277:12915-12920(2002).
RN   [31]
RP   INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77;
RP   82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF VARIANTS
RP   AD3 VAL-79 AND LEU-82.
RX   PubMed=12058025; DOI=10.1074/jbc.m112121200;
RA   Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P.,
RA   Jorgensen A.L.;
RT   "A new splice variant of glial fibrillary acidic protein GFAPepsilon,
RT   interacts with the presenilin proteins.";
RL   J. Biol. Chem. 277:29983-29991(2002).
RN   [32]
RP   INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-385.
RX   PubMed=14515347; DOI=10.1002/jnr.10753;
RA   Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K.,
RA   Shibasaki H., Shimohama S.;
RT   "Presenilin 1 is involved in maturation and trafficking of N-cadherin to
RT   the plasma membrane.";
RL   J. Neurosci. Res. 74:184-191(2003).
RN   [33]
RP   ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, CATALYTIC ACTIVITY, FUNCTION,
RP   AND SUBUNIT.
RX   PubMed=12679784; DOI=10.1038/ncb960;
RA   Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.;
RT   "Reconstitution of gamma-secretase activity.";
RL   Nat. Cell Biol. 5:486-488(2003).
RN   [34]
RP   COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN.
RX   PubMed=12740439; DOI=10.1073/pnas.1037392100;
RA   Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S.,
RA   Selkoe D.J.;
RT   "Gamma-secretase is a membrane protein complex comprised of presenilin,
RT   nicastrin, Aph-1, and Pen-2.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003).
RN   [35]
RP   SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX   PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA   Hillman R.T., Green R.E., Brenner S.E.;
RT   "An unappreciated role for RNA surveillance.";
RL   Genome Biol. 5:R8.1-R8.16(2004).
RN   [36]
RP   FUNCTION, SUBCELLULAR LOCATION, VARIANT AD3 SER-117, AND CHARACTERIZATION
RP   OF VARIANTS AD3 LEU-117 AND SER-117.
RX   PubMed=15004326; DOI=10.3233/jad-2004-6105;
RA   Dowjat W.K., Kuchna I., Wisniewski T., Wegiel J.;
RT   "A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117
RT   (Pro117Ser): Comparison of clinical, neuropathological and cell culture
RT   phenotypes of Pro117Leu and Pro117Ser mutations.";
RL   J. Alzheimers Dis. 6:31-43(2004).
RN   [37]
RP   PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND
RP   SER-346.
RX   PubMed=14576165; DOI=10.1074/jbc.m306653200;
RA   Fluhrer R., Friedlein A., Haass C., Walter J.;
RT   "Phosphorylation of presenilin 1 at the caspase recognition site regulates
RT   its proteolytic processing and the progression of apoptosis.";
RL   J. Biol. Chem. 279:1585-1593(2004).
RN   [38]
RP   TOPOLOGY.
RX   PubMed=15385547; DOI=10.1074/jbc.m407898200;
RA   Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G.,
RA   Martoglio B.;
RT   "Consensus analysis of signal peptide peptidase and homologous human
RT   aspartic proteases reveals opposite topology of catalytic domains compared
RT   with presenilins.";
RL   J. Biol. Chem. 279:50790-50798(2004).
RN   [39]
RP   FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF TYR-256;
RP   ASP-257; ASP-385 AND TYR-389.
RX   PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x;
RA   Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A.,
RA   De Strooper B., Shearman M.S., Beher D.;
RT   "Conserved residues within the putative active site of gamma-secretase
RT   differentially influence enzyme activity and inhibitor binding.";
RL   J. Neurochem. 90:1312-1320(2004).
RN   [40]
RP   INTERACTION WITH CDH1 AND CTNNB1.
RX   PubMed=16126725; DOI=10.1074/jbc.m507503200;
RA   Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J.,
RA   Robakis N.K.;
RT   "Cadherins mediate both the association between PS1 and beta-catenin and
RT   the effects of PS1 on beta-catenin stability.";
RL   J. Biol. Chem. 280:36007-36012(2005).
RN   [41]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA   Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT   networks.";
RL   Cell 127:635-648(2006).
RN   [42]
RP   FUNCTION, AND CHARACTERIZATION OF VARIANT AD3 VAL-146.
RX   PubMed=16959576; DOI=10.1016/j.cell.2006.06.059;
RA   Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H.,
RA   Serneels L., De Strooper B., Yu G., Bezprozvanny I.;
RT   "Presenilins form ER Ca2+ leak channels, a function disrupted by familial
RT   Alzheimer's disease-linked mutations.";
RL   Cell 126:981-993(2006).
RN   [43]
RP   FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435, AND
RP   CHARACTERIZATION OF VARIANT AD3 PHE-435.
RX   PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x;
RA   Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.;
RT   "C-terminal PAL motif of presenilin and presenilin homologues required for
RT   normal active site conformation.";
RL   J. Neurochem. 96:218-227(2006).
RN   [44]
RP   VARIANTS AD3 ILE-139 AND CYS-289.
RX   PubMed=8875251; DOI=10.1093/hmg/5.supplement_1.1449;
RA   Cruts M., Hendriks L., Van Broeckhoven C.;
RT   "The presenilin genes: a new gene family involved in Alzheimer disease
RT   pathology.";
RL   Hum. Mol. Genet. 5:1449-1455(1996).
RN   [45]
RP   REVIEW ON VARIANTS.
RX   PubMed=9521418;
RX   DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j;
RA   Cruts M., van Broeckhoven C.;
RT   "Presenilin mutations in Alzheimer's disease.";
RL   Hum. Mutat. 11:183-190(1998).
RN   [46]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [47]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [48]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [49]
RP   IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, AND INTERACTION WITH CRB2.
RX   PubMed=20299451; DOI=10.1074/jbc.m109.038760;
RA   Mitsuishi Y., Hasegawa H., Matsuo A., Araki W., Suzuki T., Tagami S.,
RA   Okochi M., Takeda M., Roepman R., Nishimura M.;
RT   "Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein
RT   by binding to the presenilin complex.";
RL   J. Biol. Chem. 285:14920-14931(2010).
RN   [50]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [51]
RP   INVOLVEMENT IN ACNINV3.
RX   PubMed=20929727; DOI=10.1126/science.1196284;
RA   Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y.,
RA   Qu T., Chen M., Sun M., Shen Y., Zhang X.;
RT   "Gamma-secretase gene mutations in familial acne inversa.";
RL   Science 330:1065-1065(2010).
RN   [52]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA   Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA   Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT   "System-wide temporal characterization of the proteome and phosphoproteome
RT   of human embryonic stem cell differentiation.";
RL   Sci. Signal. 4:RS3-RS3(2011).
RN   [53]
RP   SUBCELLULAR LOCATION, AND INTERACTION WITH UBQLN1.
RX   PubMed=21143716; DOI=10.1111/j.1600-0854.2010.01149.x;
RA   Viswanathan J., Haapasalo A., Bottcher C., Miettinen R., Kurkinen K.M.,
RA   Lu A., Thomas A., Maynard C.J., Romano D., Hyman B.T., Berezovska O.,
RA   Bertram L., Soininen H., Dantuma N.P., Tanzi R.E., Hiltunen M.;
RT   "Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1
RT   accumulation and aggresome formation.";
RL   Traffic 12:330-348(2011).
RN   [54]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [55]
RP   FUNCTION, INTERACTION WITH APH1A/APH1B AND PEN2, SUBCELLULAR LOCATION, AND
RP   CHARACTERIZATION OF VARIANT AD3 ASP-206.
RX   PubMed=25394380; DOI=10.1007/s12035-014-8969-1;
RA   Chen W.T., Hsieh Y.F., Huang Y.J., Lin C.C., Lin Y.T., Liu Y.C., Lien C.C.,
RA   Cheng I.H.;
RT   "G206D mutation of presenilin-1 reduces Pen2 interaction, increases
RT   Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation.";
RL   Mol. Neurobiol. 52:1835-1849(2015).
RN   [56] {ECO:0007744|PDB:2KR6}
RP   STRUCTURE BY NMR OF 292-467.
RA   Doetsch V.;
RT   "Solution structure of presenilin-1 CTF subunit.";
RL   Submitted (DEC-2009) to the PDB data bank.
RN   [57]
RP   STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR
RP   LOCATION, SUBUNIT, AND TOPOLOGY.
RX   PubMed=25043039; DOI=10.1038/nature13567;
RA   Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R.,
RA   Scheres S.H., Shi Y.;
RT   "Three-dimensional structure of human gamma-secretase.";
RL   Nature 512:166-170(2014).
RN   [58] {ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5}
RP   STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, AND TOPOLOGY.
RX   PubMed=26623517; DOI=10.7554/elife.11182;
RA   Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.;
RT   "Sampling the conformational space of the catalytic subunit of human gamma-
RT   secretase.";
RL   Elife 4:0-0(2015).
RN   [59] {ECO:0007744|PDB:5A63}
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION,
RP   TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF
RP   VARIANTS AD3 LEU-213; ILE-237 AND PHE-261, AND MUTAGENESIS OF ILE-202;
RP   LEU-226; LEU-248 AND LEU-424.
RX   PubMed=26280335; DOI=10.1038/nature14892;
RA   Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H.,
RA   Shi Y.;
RT   "An atomic structure of human gamma-secretase.";
RL   Nature 525:212-217(2015).
RN   [60] {ECO:0007744|PDB:4UIS}
RP   STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 81-463, SUBUNIT, AND
RP   TOPOLOGY.
RX   PubMed=25918421; DOI=10.1073/pnas.1506242112;
RA   Sun L., Zhao L., Yang G., Yan C., Zhou R., Zhou X., Xie T., Zhao Y., Wu S.,
RA   Li X., Shi Y.;
RT   "Structural basis of human gamma-secretase assembly.";
RL   Proc. Natl. Acad. Sci. U.S.A. 112:6003-6008(2015).
RN   [61]
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF MUTANT ALA-385 IN
RP   COMPLEX WITH NOTCH1; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, CATALYTIC
RP   ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF GLN-112; 288-TYR--SER-290;
RP   377-ARG--LEU-381; ASP-385; LEU-432 AND 432-LEU--ALA-434, AND DOMAIN.
RX   PubMed=30598546; DOI=10.1038/s41586-018-0813-8;
RA   Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.;
RT   "Structural basis of Notch recognition by human gamma-secretase.";
RL   Nature 565:192-197(2019).
RN   [62]
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-385 IN
RP   COMPLEX WITH APP CHAIN C83; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY,
RP   CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF
RP   GLN-112; 288-TYR--SER-290; 377-ARG--LEU-381; ASP-385; LEU-432 AND
RP   432-LEU--ALA-434.
RX   PubMed=30630874; DOI=10.1126/science.aaw0930;
RA   Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.;
RT   "Recognition of the amyloid precursor protein by human gamma-secretase.";
RL   Science 0:0-0(2019).
RN   [63]
RP   VARIANTS AD3 THR-143 AND ALA-384.
RX   PubMed=8634711; DOI=10.1093/hmg/4.12.2363;
RA   Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J.,
RA   de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M.,
RA   Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L.,
RA   Van Broeckhoven C.;
RT   "Molecular genetic analysis of familial early-onset Alzheimer's disease
RT   linked to chromosome 14q24.3.";
RL   Hum. Mol. Genet. 4:2363-2372(1995).
RN   [64]
RP   VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392
RP   AND TYR-410.
RX   PubMed=8634712; DOI=10.1093/hmg/4.12.2373;
RA   Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C.,
RA   Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M.,
RA   Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M.,
RA   Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T.;
RT   "Mutations of the presenilin I gene in families with early-onset
RT   Alzheimer's disease.";
RL   Hum. Mol. Genet. 4:2373-2377(1995).
RN   [65]
RP   VARIANTS AD3 VAL-260; VAL-285 AND VAL-392.
RX   PubMed=7651536; DOI=10.1038/376775a0;
RA   Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y.,
RA   Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B.,
RA   Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L.,
RA   Fraser P.E., Rommens J.M., St George-Hyslop P.H.;
RT   "Familial Alzheimer's disease in kindreds with missense mutations in a gene
RT   on chromosome 1 related to the Alzheimer's disease type 3 gene.";
RL   Nature 376:775-778(1995).
RN   [66]
RP   VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280.
RX   PubMed=7550356; DOI=10.1038/ng1095-219;
RA   Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C.,
RA   Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A.,
RA   Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J.,
RA   Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J.,
RA   Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L.,
RA   Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R.,
RA   Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L.,
RA   Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B.,
RA   Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D.,
RA   Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D.,
RA   Hardy J., Goate A.M.;
RT   "The structure of the presenilin 1 (S182) gene and identification of six
RT   novel mutations in early onset AD families.";
RL   Nat. Genet. 11:219-222(1995).
RN   [67]
RP   VARIANT AD3 ALA-280, AND INVOLVEMENT IN AD3.
RX   PubMed=8837617; DOI=10.1038/nm1096-1146;
RA   Lemere C.A., Lopera F., Kosik K.S., Lendon C.L., Ossa J., Saido T.C.,
RA   Yamaguchi H., Ruiz A., Martinez A., Madrigal L., Hincapie L., Arango J.C.,
RA   Anthony D.C., Koo E.H., Goate A.M., Selkoe D.J., Arango J.C.;
RT   "The E280A presenilin 1 Alzheimer mutation produces increased A beta 42
RT   deposition and severe cerebellar pathology.";
RL   Nat. Med. 2:1146-1150(1996).
RN   [68]
RP   VARIANTS AD3 PHE-96; ARG-163 AND THR-213.
RX   PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8;
RA   Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H.,
RA   Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T.;
RT   "Three different mutations of presenilin 1 gene in early-onset Alzheimer's
RT   disease families.";
RL   Neurosci. Lett. 208:195-198(1996).
RN   [69]
RP   VARIANT AD3 ASP-135.
RX   PubMed=9225696; DOI=10.1002/ana.410420121;
RA   Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M.,
RA   Hutton M., Haltia T., Hardy J., Galasko D.;
RT   "Early-onset Alzheimer's disease with a presenilin-1 mutation at the site
RT   corresponding to the Volga German presenilin-2 mutation.";
RL   Ann. Neurol. 42:124-128(1997).
RN   [70]
RP   VARIANT AD3 ALA-280.
RX   PubMed=9298817;
RX   DOI=10.1002/(sici)1098-1004(1997)10:3<186::aid-humu2>3.0.co;2-h;
RA   Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J.,
RA   Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C.,
RA   Ossa J., Ruiz A., Goate A.M., Lopera F.;
RT   "E280A PS-1 mutation causes Alzheimer's disease but age of onset is not
RT   modified by ApoE alleles.";
RL   Hum. Mutat. 10:186-195(1997).
RN   [71]
RP   VARIANTS AD3 THR-233 AND THR-278.
RX   PubMed=9172170; DOI=10.1097/00001756-199704140-00043;
RA   Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A.,
RA   Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H.,
RA   Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E.,
RA   Schofield P.R., Martins R.N.;
RT   "Two novel (M233T and R278T) presenilin-1 mutations in early-onset
RT   Alzheimer's disease pedigrees and preliminary evidence for association of
RT   presenilin-1 mutations with a novel phenotype.";
RL   NeuroReport 8:1537-1542(1997).
RN   [72]
RP   VARIANT AD3 PRO-171.
RX   PubMed=9833068;
RA   Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C.,
RA   Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H.,
RA   Cantu J.M.;
RT   "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with
RT   early onset Alzheimer disease.";
RL   Ann. Genet. 41:149-153(1998).
RN   [73]
RP   VARIANT GLY-318.
RX   PubMed=9851443; DOI=10.1002/ana.410440617;
RA   Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M.,
RA   Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L.;
RT   "The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause
RT   Alzheimer's disease.";
RL   Ann. Neurol. 44:965-967(1998).
RN   [74]
RP   VARIANT GLY-318.
RX   PubMed=9851450; DOI=10.1002/ana.410440624;
RA   Aldudo J., Bullido M.J., Frank A., Valdivieso F.;
RT   "Missense mutation E318G of the presenilin-1 gene appears to be a
RT   nonpathogenic polymorphism.";
RL   Ann. Neurol. 44:985-986(1998).
RN   [75]
RP   VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318.
RX   PubMed=9384602; DOI=10.1093/hmg/7.1.43;
RA   Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A.,
RA   Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H.,
RA   Hofman A., van Broeckhoven C.;
RT   "Estimation of the genetic contribution of presenilin-1 and -2 mutations in
RT   a population-based study of presenile Alzheimer disease.";
RL   Hum. Mol. Genet. 7:43-51(1998).
RN   [76]
RP   VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND
RP   PRO-426.
RX   PubMed=9521423;
RX   DOI=10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f;
RA   Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H.,
RA   White J., Heston L., Bird T.D., Schellenberg G.D.;
RT   "Missense mutations in the chromosome 14 familial Alzheimer's disease
RT   presenilin 1 gene.";
RL   Hum. Mutat. 11:216-221(1998).
RN   [77]
RP   VARIANT AD3 GLU-378.
RX   PubMed=10200054;
RX   DOI=10.1002/(sici)1098-1004(1998)11:6<481::aid-humu12>3.0.co;2-q;
RA   Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E.,
RA   Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A.;
RT   "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a
RT   French family with early-onset Alzheimer's disease and transmission study
RT   by mismatch enhanced allele specific amplification.";
RL   Hum. Mutat. 11:481-481(1998).
RN   [78]
RP   VARIANT AD3 LYS-139.
RX   PubMed=9719376; DOI=10.1136/jmg.35.8.672;
RA   Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V.,
RA   Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.;
RT   "De novo presenilin 1 mutations are rare in clinically sporadic, early
RT   onset Alzheimer's disease cases.";
RL   J. Med. Genet. 35:672-673(1998).
RN   [79]
RP   VARIANT AD3 LEU-117.
RX   PubMed=9507958; DOI=10.1097/00001756-199801260-00008;
RA   Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S.,
RA   Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B.;
RT   "A novel Polish presenilin-1 mutation (P117L) is associated with familial
RT   Alzheimer's disease and leads to death as early as the age of 28 years.";
RL   NeuroReport 9:217-221(1998).
RN   [80]
RP   VARIANTS AD3 LEU-169 AND GLN-436.
RX   PubMed=9831473; DOI=10.1097/00001756-199810050-00034;
RA   Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M.,
RA   Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R.,
RA   Martins R.N.;
RT   "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with
RT   very early onset Alzheimer's disease.";
RL   NeuroReport 9:3335-3339(1998).
RN   [81]
RP   VARIANT GLY-318.
RX   PubMed=9915968; DOI=10.1086/302200;
RA   Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C.,
RA   Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A.,
RA   van Duijn C.M., van Broeckhoven C.;
RT   "The Glu318Gly substitution in presenilin 1 is not causally related to
RT   Alzheimer disease.";
RL   Am. J. Hum. Genet. 64:290-292(1999).
RN   [82]
RP   VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163;
RP   CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND
RP   TYR-410, AND VARIANT GLY-318.
RX   PubMed=10441572; DOI=10.1086/302553;
RA   Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M.,
RA   Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G.,
RA   Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F.,
RA   Brice A., Frebourg T.;
RT   "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
RT   heterogeneity, and mutation spectrum.";
RL   Am. J. Hum. Genet. 65:664-670(1999).
RN   [83]
RP   VARIANTS AD3 PHE-143 AND SER-436.
RX   PubMed=10090481;
RX   DOI=10.1002/(sici)1098-1004(1999)13:3<256::aid-humu11>3.0.co;2-p;
RA   Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K.,
RA   Fox N.C., Harvey R., Rossor M.N., Collinge J.;
RT   "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset
RT   Alzheimer's disease in the UK.";
RL   Hum. Mutat. 13:256-256(1999).
RN   [84]
RP   VARIANT AD3 ARG-209.
RX   PubMed=10447269;
RX   DOI=10.1002/(sici)1098-1004(1999)14:1<90::aid-humu19>3.0.co;2-s;
RA   Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y.,
RA   Iseki E., Kosaka K.;
RT   "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a
RT   Japanese family with presenile familial Alzheimer's disease.";
RL   Hum. Mutat. 14:90-90(1999).
RN   [85]
RP   VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318.
RX   PubMed=10533070;
RX   DOI=10.1002/(sici)1098-1004(199911)14:5<433::aid-humu10>3.0.co;2-k;
RA   Aldudo J., Bullido M.J., Valdivieso F.;
RT   "DGGE method for the mutational analysis of the coding and proximal
RT   promoter regions of the Alzheimer's disease presenilin-1 gene: two novel
RT   mutations.";
RL   Hum. Mutat. 14:433-439(1999).
RN   [86]
RP   VARIANT AD3 PRO-169.
RX   PubMed=10025789; DOI=10.1212/wnl.52.3.566;
RA   Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.;
RT   "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and
RT   myoclonic seizures.";
RL   Neurology 52:566-570(1999).
RN   [87]
RP   VARIANT AD3 PRO-219.
RX   PubMed=10208579; DOI=10.1097/00001756-199902250-00011;
RA   Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K.,
RA   Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.;
RT   "Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of
RT   the presenilin-1 gene.";
RL   NeuroReport 10:503-507(1999).
RN   [88]
RP   VARIANT AD3 ASN-116.
RX   PubMed=10439444; DOI=10.1097/00001756-199908020-00006;
RA   Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D.,
RA   Havsager A.-M., Joergensen A.L.;
RT   "A presenilin-1 Thr116Asn substitution in a family with early-onset
RT   Alzheimer's disease.";
RL   NeuroReport 10:2255-2260(1999).
RN   [89]
RP   VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318.
RX   PubMed=10631141; DOI=10.1086/302702;
RA   Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J.,
RA   Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.;
RT   "High prevalence of pathogenic mutations in patients with early-onset
RT   dementia detected by sequence analyses of four different genes.";
RL   Am. J. Hum. Genet. 66:110-117(2000).
RN   [90]
RP   VARIANT AD3 SER-405.
RX   PubMed=10644793; DOI=10.1136/jnnp.68.2.220;
RA   Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S.,
RA   Maeda K., Tanaka C.;
RT   "Novel presenilin-1 mutation with widespread cortical amyloid deposition
RT   but limited cerebral amyloid angiopathy.";
RL   J. Neurol. Neurosurg. Psych. 68:220-223(2000).
RN   [91]
RP   VARIANT AD3 SER-92.
RX   PubMed=11027672; DOI=10.1006/bbrc.2000.3646;
RA   Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.;
RT   "The presenilin 1 C92S mutation increases abeta 42 production.";
RL   Biochem. Biophys. Res. Commun. 277:261-263(2000).
RN   [92]
RP   VARIANT FTD1 PRO-113.
RX   PubMed=11094121; DOI=10.1212/wnl.55.10.1577;
RA   Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P.,
RA   Hannequin D., Brice A., Frebourg T., Campion D.;
RT   "Dementia with prominent frontotemporal features associated with L113P
RT   presenilin 1 mutation.";
RL   Neurology 55:1577-1578(2000).
RN   [93]
RP   VARIANTS AD3 MET-94; THR-143 AND ALA-280, AND VARIANT GLY-318.
RX   PubMed=11568920;
RX   DOI=10.1002/1096-8628(20011001)103:2<138::aid-ajmg1529>3.0.co;2-8;
RA   Arango D., Cruts M., Torres O., Backhovens H., Serrano M.L., Villareal E.,
RA   Montanes P., Matallana D., Cano C., Van Broeckhoven C., Jacquier M.;
RT   "Systematic genetic study of Alzheimer disease in Latin America: mutation
RT   frequencies of the amyloid beta precursor protein and presenilin genes in
RT   Colombia.";
RL   Am. J. Med. Genet. 103:138-143(2001).
RN   [94]
RP   VARIANT AD3 VAL-282, AND CHARACTERIZATION OF VARIANT AD3 VAL-282.
RX   PubMed=11701593; DOI=10.1093/brain/124.12.2383;
RA   Dermaut B., Kumar-Singh S., De Jonghe C., Cruts M., Loefgren A., Luebke U.,
RA   Cras P., Dom R., De Deyn P.P., Martin J.J., Van Broeckhoven C.;
RT   "Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease
RT   due to a novel presenilin 1 mutation.";
RL   Brain 124:2383-2392(2001).
RN   [95]
RP   ERRATUM OF PUBMED:11701593, AND VARIANT AD3 GLU-431.
RA   Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.;
RL   Hum. Genet. 109:242-242(2001).
RN   [96]
RP   VARIANT AD3 ALA-206.
RX   PubMed=11710891; DOI=10.1001/jama.286.18.2257;
RA   Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H.,
RA   Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E.,
RA   Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K.,
RA   Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.;
RT   "A founder mutation in presenilin 1 causing early-onset Alzheimer disease
RT   in unrelated Caribbean Hispanic families.";
RL   JAMA 286:2257-2263(2001).
RN   [97]
RP   VARIANT AD3 ILE-237.
RX   PubMed=11561050; DOI=10.1136/jnnp.71.4.556;
RA   Sodeyama N., Iwata T., Ishikawa K., Mizusawa H., Yamada M., Itoh Y.,
RA   Otomo E., Matsushita M., Komatsuzaki Y.;
RT   "Very early onset Alzheimer's disease with spastic paraparesis associated
RT   with a novel presenilin 1 mutation (Phe237Ile).";
RL   J. Neurol. Neurosurg. Psych. 71:556-557(2001).
RN   [98]
RP   VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146;
RP   VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178;
RP   ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235;
RP   PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418;
RP   GLU-431; PHE-435 AND VAL-439, AND VARIANT GLY-318.
RX   PubMed=11524469; DOI=10.1212/wnl.57.4.621;
RA   Rogaeva E.A., Fafel K.C., Song Y.Q., Medeiros H., Sato C., Liang Y.,
RA   Richard E., Rogaev E.I., Frommelt P., Sadovnick A.D., Meschino W.,
RA   Rockwood K., Boss M.A., Mayeux R., St George-Hyslop P.;
RT   "Screening for PS1 mutations in a referral-based series of AD cases: 21
RT   novel mutations.";
RL   Neurology 57:621-625(2001).
RN   [99]
RP   VARIANT AD3 SER-266.
RX   PubMed=11920851; DOI=10.1002/ajmg.10250;
RA   Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K.,
RA   Kohara K., Miyoshi K., Miki T.;
RT   "Molecular evidence of presenilin 1 mutation in familial early onset
RT   dementia.";
RL   Am. J. Med. Genet. 114:292-298(2002).
RN   [100]
RP   VARIANT AD3 LEU-89.
RX   PubMed=11796781; DOI=10.1136/jnnp.72.2.266;
RA   Queralt R., Ezquerra M., Lleo A., Castellvi M., Gelpi J., Ferrer I.,
RA   Acarin N., Pasarin L., Blesa R., Oliva R.;
RT   "A novel mutation (V89L) in the presenilin 1 gene in a family with early
RT   onset Alzheimer's disease and marked behavioural disturbances.";
RL   J. Neurol. Neurosurg. Psych. 72:266-269(2002).
RN   [101]
RP   VARIANT AD3 GLY-280.
RX   PubMed=12370477; DOI=10.1212/wnl.59.7.1108;
RA   O'Riordan S., McMonagle P., Janssen J.C., Fox N.C., Farrell M.,
RA   Collinge J., Rossor M.N., Hutchinson M.;
RT   "Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-
RT   matter abnormalities.";
RL   Neurology 59:1108-1110(2002).
RN   [102]
RP   VARIANT AD3 PRO-166.
RX   PubMed=12048239; DOI=10.1073/pnas.112686799;
RA   Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A.,
RA   Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.;
RT   "Presenilin-1 mutations of leucine 166 equally affect the generation of the
RT   Notch and APP intracellular domains independent of their effect on Abeta 42
RT   production.";
RL   Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002).
RN   [103]
RP   VARIANT AD3 MET-174.
RX   PubMed=12484344; DOI=10.1007/s10048-002-0136-6;
RA   Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J.,
RA   Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M.,
RA   van Duijn C.M., Heredero Baute L., Heutink P.;
RT   "A novel presenilin 1 mutation (L174 M) in a large Cuban family with early
RT   onset Alzheimer disease.";
RL   Neurogenetics 4:97-104(2002).
RN   [104]
RP   VARIANT AD3 VAL-271.
RX   PubMed=12493737; DOI=10.1074/jbc.m211827200;
RA   Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O.,
RA   Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A.,
RA   Gandy S.E., Schofield P.R.;
RT   "Presenilin-1 mutation L271V results in altered exon 8 splicing and
RT   Alzheimer's disease with non-cored plaques and no neuritic dystrophy.";
RL   J. Biol. Chem. 278:6748-6754(2003).
RN   [105]
RP   VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171;
RP   ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND
RP   VAL-378, AND VARIANT GLY-318.
RX   PubMed=12552037; DOI=10.1212/01.wnl.0000042088.22694.e3;
RA   Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C.,
RA   Harvey R.J., Houlden H., Rossor M.N., Collinge J.;
RT   "Early onset familial Alzheimer's disease: Mutation frequency in 31
RT   families.";
RL   Neurology 60:235-239(2003).
RN   [106]
RP   VARIANT PIDB VAL-183, CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282,
RP   AND CHARACTERIZATION OF VARIANT PIDB VAL-183.
RX   PubMed=15122701; DOI=10.1002/ana.20083;
RA   Dermaut B., Kumar-Singh S., Engelborghs S., Theuns J., Rademakers R.,
RA   Saerens J., Pickut B.A., Peeters K., van den Broeck M., Vennekens K.,
RA   Claes S., Cruts M., Cras P., Martin J.J., Van Broeckhoven C., De Deyn P.P.;
RT   "A novel presenilin 1 mutation associated with Pick's disease but not beta-
RT   amyloid plaques.";
RL   Ann. Neurol. 55:617-626(2004).
RN   [107]
RP   VARIANT AD3 PRO-85, AND CHARACTERIZATION OF VARIANT AD3 PRO-85.
RX   PubMed=15534188; DOI=10.1001/archneur.61.11.1773;
RA   Ataka S., Tomiyama T., Takuma H., Yamashita T., Shimada H., Tsutada T.,
RA   Kawabata K., Mori H., Miki T.;
RT   "A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease
RT   with spastic paraparesis.";
RL   Arch. Neurol. 61:1773-1776(2004).
RN   [108]
RP   VARIANT AD3 ILE-278.
RX   PubMed=15534260; DOI=10.1212/01.wnl.0000143060.98164.1a;
RA   Godbolt A.K., Beck J.A., Collinge J., Garrard P., Warren J.D., Fox N.C.,
RA   Rossor M.N.;
RT   "A presenilin 1 R278I mutation presenting with language impairment.";
RL   Neurology 63:1702-1704(2004).
RN   [109]
RP   VARIANT AD3 ASN-154.
RX   PubMed=15364419; DOI=10.1016/j.neulet.2004.07.057;
RA   Hattori S., Sakuma K., Wakutani Y., Wada K., Shimoda M., Urakami K.,
RA   Kowa H., Nakashima K.;
RT   "A novel presenilin 1 mutation (Y154N) in a patient with early onset
RT   Alzheimer's disease with spastic paraparesis.";
RL   Neurosci. Lett. 368:319-322(2004).
RN   [110]
RP   VARIANT AD3 PHE-170.
RX   PubMed=16344340; DOI=10.1001/archneur.62.12.1821;
RA   Snider B.J., Norton J., Coats M.A., Chakraverty S., Hou C.E., Jervis R.,
RA   Lendon C.L., Goate A.M., McKeel D.W. Jr., Morris J.C.;
RT   "Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy
RT   bodies in the third decade of life.";
RL   Arch. Neurol. 62:1821-1830(2005).
RN   [111]
RP   VARIANT AD3 LEU-97.
RX   PubMed=15851849; DOI=10.3233/jad-2005-7204;
RA   Jia J., Xu E., Shao Y., Jia J., Sun Y., Li D.;
RT   "One novel presenilin-1 gene mutation in a Chinese pedigree of familial
RT   Alzheimer's disease.";
RL   J. Alzheimers Dis. 7:119-124(2005).
RN   [112]
RP   VARIANT CMD1U GLY-333.
RX   PubMed=17186461; DOI=10.1086/509900;
RA   Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S.,
RA   Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M.,
RA   Hershberger R.E.;
RT   "Mutations of presenilin genes in dilated cardiomyopathy and heart
RT   failure.";
RL   Am. J. Hum. Genet. 79:1030-1039(2006).
RN   [113]
RP   CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262;
RP   PHE-263; VAL-282 AND ALA-384.
RX   PubMed=16752394; DOI=10.1002/humu.20336;
RA   Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K.,
RA   Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.;
RT   "Mean age-of-onset of familial alzheimer disease caused by presenilin
RT   mutations correlates with both increased Abeta42 and decreased Abeta40.";
RL   Hum. Mutat. 27:686-695(2006).
RN   [114]
RP   VARIANT AD3 GLU-431.
RX   PubMed=16628450; DOI=10.1007/s10048-006-0043-3;
RA   Yescas P., Huertas-Vazquez A., Villarreal-Molina M.T., Rasmussen A.,
RA   Tusie-Luna M.T., Lopez M., Canizales-Quinteros S., Alonso M.E.;
RT   "Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing
RT   early-onset Alzheimer's disease in Mexican families.";
RL   Neurogenetics 7:195-200(2006).
RN   [115]
RP   VARIANT AD3 GLU-431.
RX   PubMed=16897084; DOI=10.1007/s10048-006-0053-1;
RA   Murrell J., Ghetti B., Cochran E., Macias-Islas M.A., Medina L.,
RA   Varpetian A., Cummings J.L., Mendez M.F., Kawas C., Chui H., Ringman J.M.;
RT   "The A431E mutation in PSEN1 causing familial Alzheimer's disease
RT   originating in Jalisco State, Mexico: an additional fifteen families.";
RL   Neurogenetics 7:277-279(2006).
RN   [116]
RP   VARIANT AD3 VAL-79, AND CHARACTERIZATION OF VARIANT AD3 VAL-79.
RX   PubMed=17366635; DOI=10.1002/ana.21099;
RA   Kauwe J.S., Jacquart S., Chakraverty S., Wang J., Mayo K., Fagan A.M.,
RA   Holtzman D.M., Morris J.C., Goate A.M.;
RT   "Extreme cerebrospinal fluid amyloid beta levels identify family with late-
RT   onset Alzheimer's disease presenilin 1 mutation.";
RL   Ann. Neurol. 61:446-453(2007).
RN   [117]
RP   VARIANT AD3 PHE-170.
RX   PubMed=17502474; DOI=10.1001/archneur.64.5.738;
RA   Piccini A., Zanusso G., Borghi R., Noviello C., Monaco S., Russo R.,
RA   Damonte G., Armirotti A., Gelati M., Giordano R., Zambenedetti P.,
RA   Russo C., Ghetti B., Tabaton M.;
RT   "Association of a presenilin 1 S170F mutation with a novel Alzheimer
RT   disease molecular phenotype.";
RL   Arch. Neurol. 64:738-745(2007).
RN   [118]
RP   CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260;
RP   LEU-264 AND GLY-280, FUNCTION, AND MUTAGENESIS OF ASP-257.
RX   PubMed=17428795; DOI=10.1074/jbc.m611449200;
RA   Litterst C., Georgakopoulos A., Shioi J., Ghersi E., Wisniewski T.,
RA   Wang R., Ludwig A., Robakis N.K.;
RT   "Ligand binding and calcium influx induce distinct ectodomain/gamma-
RT   secretase-processing pathways of EphB2 receptor.";
RL   J. Biol. Chem. 282:16155-16163(2007).
RN   [119]
RP   VARIANT GLY-318.
RX   PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014;
RA   Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F.,
RA   Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J.,
RA   Emans J.B., Turnpenny P.D., Pourquie O.;
RT   "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin
RT   syndrome.";
RL   Am. J. Hum. Genet. 82:1334-1341(2008).
RN   [120]
RP   CHARACTERIZATION OF VARIANT AD3 THR-213.
RX   PubMed=18430735; DOI=10.1074/jbc.m801279200;
RA   Shimojo M., Sahara N., Mizoroki T., Funamoto S., Morishima-Kawashima M.,
RA   Kudo T., Takeda M., Ihara Y., Ichinose H., Takashima A.;
RT   "Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in
RT   cell models and knock-in mouse brains: familial Alzheimer disease-linked
RT   mutation impairs gamma-site cleavage of amyloid precursor protein C-
RT   terminal fragment beta.";
RL   J. Biol. Chem. 283:16488-16496(2008).
RN   [121]
RP   VARIANT AD3 VAL-381.
RX   PubMed=19797784; DOI=10.1177/1533317509341464;
RA   Dintchov Traykov L., Mehrabian S., Van den Broeck M.,
RA   Radoslavova Raycheva M., Cruts M., Kirilova Jordanova A.,
RA   Van Broeckhoven C.;
RT   "Novel PSEN1 mutation in a Bulgarian patient with very early-onset
RT   Alzheimer's disease, spastic paraparesis, and extrapyramidal signs.";
RL   Am. J. Alzheimers Dis. Other Demen. 24:404-407(2009).
RN   [122]
RP   VARIANT AD3 ARG-217, AND CHARACTERIZATION OF VARIANT AD3 ARG-217.
RX   PubMed=19667325; DOI=10.1212/wnl.0b013e3181b163ba;
RA   Norton J.B., Cairns N.J., Chakraverty S., Wang J., Levitch D., Galvin J.E.,
RA   Goate A.;
RT   "Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool
RT   plaques.";
RL   Neurology 73:480-482(2009).
RN   [123]
RP   VARIANT AD3 LEU-146.
RX   PubMed=20164095; DOI=10.1212/wnl.0b013e3181d52785;
RA   Bruni A.C., Bernardi L., Colao R., Rubino E., Smirne N., Frangipane F.,
RA   Terni B., Curcio S.A., Mirabelli M., Clodomiro A., Di Lorenzo R.,
RA   Maletta R., Anfossi M., Gallo M., Geracitano S., Tomaino C., Muraca M.G.,
RA   Leotta A., Lio S.G., Pinessi L., Rainero I., Sorbi S., Nee L., Milan G.,
RA   Pappata S., Postiglione A., Abbamondi N., Forloni G., St George Hyslop P.,
RA   Rogaeva E., Bugiani O., Giaccone G., Foncin J.F., Spillantini M.G.,
RA   Puccio G.;
RT   "Worldwide distribution of PSEN1 Met146Leu mutation: a large variability
RT   for a founder mutation.";
RL   Neurology 74:798-806(2010).
RN   [124]
RP   VARIANT AD3 PHE-435, CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND
RP   SER-436, MUTAGENESIS OF PRO-433 AND LEU-435, AND FUNCTION.
RX   PubMed=20460383; DOI=10.1074/jbc.m110.116962;
RA   Heilig E.A., Xia W., Shen J., Kelleher R.J. III;
RT   "A presenilin-1 mutation identified in familial Alzheimer disease with
RT   cotton wool plaques causes a nearly complete loss of gamma-secretase
RT   activity.";
RL   J. Biol. Chem. 285:22350-22359(2010).
RN   [125]
RP   VARIANT AD3 ASP-206.
RX   PubMed=21335660; DOI=10.3233/jad-2011-102031;
RA   Wu Y.Y., Cheng I.H., Lee C.C., Chiu M.J., Lee M.J., Chen T.F., Hsu J.L.;
RT   "Clinical phenotype of G206D mutation in the presenilin 1 gene in
RT   pathologically confirmed familial Alzheimer's disease.";
RL   J. Alzheimers Dis. 25:145-150(2011).
RN   [126]
RP   VARIANT CYS-315.
RX   PubMed=21248752; DOI=10.1038/nature09639;
RA   Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H.,
RA   Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J.,
RA   Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M.,
RA   Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L.,
RA   Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J.,
RA   Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A.,
RA   Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K.,
RA   Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.;
RT   "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene
RT   PBRM1 in renal carcinoma.";
RL   Nature 469:539-542(2011).
RN   [127]
RP   VARIANT AD3 ARG-235.
RX   PubMed=21501661; DOI=10.1016/j.neulet.2011.03.084;
RA   Antonell A., Balasa M., Oliva R., Llado A., Bosch B., Fabregat N.,
RA   Fortea J., Molinuevo J.L., Sanchez-Valle R.;
RT   "A novel PSEN1 gene mutation (L235R) associated with familial early-onset
RT   Alzheimer's disease.";
RL   Neurosci. Lett. 496:40-42(2011).
RN   [128]
RP   CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280.
RX   PubMed=22461631; DOI=10.1074/jbc.m111.300483;
RA   Chau D.M., Crump C.J., Villa J.C., Scheinberg D.A., Li Y.M.;
RT   "Familial Alzheimer disease presenilin-1 mutations alter the active site
RT   conformation of gamma-secretase.";
RL   J. Biol. Chem. 287:17288-17296(2012).
RN   [129]
RP   VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214.
RX   PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020;
RA   Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B.,
RA   Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.;
RT   "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish
RT   dementia patients.";
RL   Neurobiol. Aging 33:1850.E17-1850.E27(2012).
RN   [130]
RP   VARIANT AD3 PHE-159.
RX   PubMed=23123781; DOI=10.1016/j.neulet.2012.10.037;
RA   Kerchner G.A., Holbrook K.;
RT   "Novel presenilin-1 Y159F sequence variant associated with early-onset
RT   Alzheimer's disease.";
RL   Neurosci. Lett. 531:142-144(2012).
RN   [131]
RP   CHARACTERIZATION OF VARIANTS AD3 PRO-166 AND GLN-436, AND MUTAGENESIS OF
RP   ASP-257 AND ASP-385.
RX   PubMed=22529981; DOI=10.1371/journal.pone.0035133;
RA   Cacquevel M., Aeschbach L., Houacine J., Fraering P.C.;
RT   "Alzheimer's disease-linked mutations in presenilin-1 result in a drastic
RT   loss of activity in purified gamma-secretase complexes.";
RL   PLoS ONE 7:E35133-E35133(2012).
RN   [132]
RP   CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392;
RP   TYR-410 AND PHE-435.
RX   PubMed=23843529; DOI=10.1523/jneurosci.0954-13.2013;
RA   Heilig E.A., Gutti U., Tai T., Shen J., Kelleher R.J. III;
RT   "Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma-
RT   secretase activity and Abeta production.";
RL   J. Neurosci. 33:11606-11617(2013).
RN   [133]
RP   VARIANT AD3 PHE-381.
RX   PubMed=24121961; DOI=10.3233/jad-131340;
RA   Dolzhanskaya N., Gonzalez M.A., Sperziani F., Stefl S., Messing J.,
RA   Wen G.Y., Alexov E., Zuchner S., Velinov M.;
RT   "A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very
RT   early onset and unusually fast progressing dementia as well as lysosomal
RT   inclusions typically seen in Kufs disease.";
RL   J. Alzheimers Dis. 39:23-27(2014).
RN   [134]
RP   VARIANT AD3 VAL-153.
RX   PubMed=24495933; DOI=10.1016/j.neulet.2014.01.016;
RA   Cornejo-Olivas M.R., Yu C.E., Mazzetti P., Mata I.F., Meza M.,
RA   Lindo-Samanamud S., Leverenz J.B., Bird T.D.;
RT   "Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a
RT   Peruvian family with early-onset Alzheimer's disease.";
RL   Neurosci. Lett. 563:140-143(2014).
RN   [135]
RP   VARIANT AD3 VAL-275.
RX   PubMed=24582897; DOI=10.1016/j.neulet.2014.02.034;
RA   Luedecke D., Becktepe J.S., Lehmbeck J.T., Finckh U., Yamamoto R., Jahn H.,
RA   Boelmans K.;
RT   "A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial
RT   Alzheimer disease.";
RL   Neurosci. Lett. 566:115-119(2014).
RN   [136]
RP   VARIANT AD3 THR-83.
RX   PubMed=26145164; DOI=10.1016/j.neurobiolaging.2015.06.007;
RA   Achouri-Rassas A., Ben Ali N., Fray S., Hadj Fredj S., Kechaou M.,
RA   Zakraoui N.O., Cherif A., Chabbi S., Anane N., Messaoud T., Gouider R.,
RA   Belal S.;
RT   "Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset
RT   Alzheimer's disease.";
RL   Neurobiol. Aging 36:2904.E09-2904.E11(2015).
RN   [137]
RP   VARIANTS AD3 ALA-206 AND VAL-378.
RX   PubMed=27073747;
RA   Ravenscroft T.A., Pottier C., Murray M.E., Baker M., Christopher E.,
RA   Levitch D., Brown P.H., Barker W., Duara R., Greig-Custo M., Betancourt A.,
RA   English M., Sun X., Ertekin-Taner N., Graff-Radford N.R., Dickson D.W.,
RA   Rademakers R.;
RT   "The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset
RT   Alzheimer's disease in Hispanics in Florida.";
RL   Am. J. Neurodegener. Dis. 5:94-101(2016).
RN   [138]
RP   VARIANT AD3 THR-408.
RX   PubMed=26549787; DOI=10.1016/j.neulet.2015.11.004;
RA   Tedde A., Bartoli A., Piaceri I., Ferrara S., Bagnoli S., Serio A.,
RA   Sorbi S., Nacmias B.;
RT   "Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-
RT   onset Alzheimer's disease.";
RL   Neurosci. Lett. 610:150-153(2016).
RN   [139]
RP   VARIANT ARG-311, CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311, AND
RP   FUNCTION.
RX   PubMed=28269784; DOI=10.3233/jad-161188;
RA   Dong J., Qin W., Wei C., Tang Y., Wang Q., Jia J.;
RT   "A novel PSEN1 K311R mutation discovered in Chinese families with late-
RT   onset Alzheimer's disease affects amyloid-beta production and tau
RT   phosphorylation.";
RL   J. Alzheimers Dis. 57:613-623(2017).
RN   [140]
RP   CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89;
RP   SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120;
RP   ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154;
RP   ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174;
RP   LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209;
RP   LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235;
RP   PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262;
RP   ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275;
RP   ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378;
RP   VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405;
RP   THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439,
RP   CHARACTERIZATION OF VARIANT CMD1U GLY-333, AND MUTAGENESIS OF THR-99;
RP   PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143;
RP   LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214;
RP   LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248;
RP   TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365;
RP   ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437.
RX   PubMed=27930341; DOI=10.1073/pnas.1618657114;
RA   Sun L., Zhou R., Yang G., Shi Y.;
RT   "Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro
RT   production of Abeta42 and Abeta40 peptides by gamma-secretase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017).
RN   [141]
RP   VARIANT AD3 ILE-116.
RX   PubMed=30200536; DOI=10.3390/ijms19092604;
RA   Bagyinszky E., Lee H.M., Van Giau V., Koh S.B., Jeong J.H., An S.S.A.,
RA   Kim S.;
RT   "PSEN1 p.Thr116Ile variant in two Korean families with young onset
RT   Alzheimer's disease.";
RL   Int. J. Mol. Sci. 19:0-0(2018).
RN   [142]
RP   VARIANT AD3 ASN-116.
RX   PubMed=29404783; DOI=10.1007/s00702-018-1850-z;
RA   Sutovsky S., Smolek T., Turcani P., Petrovic R., Brandoburova P.,
RA   Jadhav S., Novak P., Attems J., Zilka N.;
RT   "Neuropathology and biochemistry of early onset familial Alzheimer's
RT   disease caused by presenilin-1 missense mutation Thr116Asn.";
RL   J. Neural Transm. 125:965-976(2018).
RN   [143]
RP   VARIANTS AD3 PHE-142 AND ASP-206.
RX   PubMed=29175279; DOI=10.1016/j.neurobiolaging.2017.10.011;
RA   Wang J.C., Alinaghi S., Tafakhori A., Sikora E., Azcona L.J.,
RA   Karkheiran S., Goate A., Paisan-Ruiz C., Darvish H.;
RT   "Genetic screening in two Iranian families with early-onset Alzheimer's
RT   disease identified a novel PSEN1 mutation.";
RL   Neurobiol. Aging 62:E15-E17(2018).
RN   [144]
RP   VARIANT AD3 ALA-417.
RX   PubMed=30180983; DOI=10.1016/j.neurobiolaging.2018.08.003;
RA   Giau V.V., Wang M.J., Bagyinszky E., Youn Y.C., An S.S.A., Kim S.;
RT   "Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset
RT   Alzheimer's disease with parkinsonism.";
RL   Neurobiol. Aging 72:E13-E17(2018).
RN   [145]
RP   VARIANT AD3 PHE-170.
RX   PubMed=29466804; DOI=10.1159/000485899;
RA   Tiedt H.O., Benjamin B., Niedeggen M., Lueschow A.;
RT   "Phenotypic variability in autosomal dominant familial Alzheimer disease
RT   due to the S170F mutation of presenilin-1.";
RL   Neurodegener. Dis. 18:57-68(2018).
CC   -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an
CC       endoprotease complex that catalyzes the intramembrane cleavage of
CC       integral membrane proteins such as Notch receptors and APP (amyloid-
CC       beta precursor protein) (PubMed:10206644, PubMed:10545183,
CC       PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784,
CC       PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039,
CC       PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874).
CC       Requires the presence of the other members of the gamma-secretase
CC       complex for protease activity (PubMed:15274632, PubMed:25043039,
CC       PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in
CC       Notch and Wnt signaling cascades and regulation of downstream processes
CC       via its role in processing key regulatory proteins, and by regulating
CC       cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883,
CC       PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its
CC       interaction with CDH1; this stabilizes the complexes between CDH1 (E-
CC       cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1
CC       and JUP (gamma-catenin) (PubMed:11953314). Under conditions of
CC       apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This
CC       promotes the disassembly of the complexes between CDH1 and CTNND1, JUP
CC       and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby
CC       negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936).
CC       Required for normal embryonic brain and skeleton development, and for
CC       normal angiogenesis (By similarity). Mediates the proteolytic cleavage
CC       of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The
CC       holoprotein functions as a calcium-leak channel that allows the passive
CC       movement of calcium from endoplasmic reticulum to cytosol and is
CC       therefore involved in calcium homeostasis (PubMed:16959576,
CC       PubMed:25394380). Involved in the regulation of neurite outgrowth
CC       (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic
CC       facilitation, spike transmission and synaptic vesicles replenishment in
CC       a process that depends on gamma-secretase activity. It acts through the
CC       control of SYT7 presynaptic expression (By similarity).
CC       {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644,
CC       ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990,
CC       ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933,
CC       ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784,
CC       ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15004326,
CC       ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515,
CC       ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16959576,
CC       ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:20460383,
CC       ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380,
CC       ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:28269784,
CC       ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874,
CC       ECO:0000269|PubMed:9738936}.
CC   -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed
CC       of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2),
CC       nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:12679784,
CC       PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:25394380,
CC       PubMed:26280335, PubMed:30598546, PubMed:30630874). Such minimal
CC       complex is sufficient for secretase activity (PubMed:12679784,
CC       PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:26280335,
CC       PubMed:30598546, PubMed:30630874). Other components which are
CC       associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1
CC       isoform 3. As part of the gamma-secretase complex, interacts with CRB2
CC       (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer
CC       of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment
CC       (PubMed:15274632). Associates with proteolytic processed C-terminal
CC       fragments C83 and C99 of the amyloid precursor protein (APP) (via
CC       transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via
CC       transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates
CC       with cadherin/catenin adhesion complexes through direct binding to CDH1
CC       or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725).
CC       Interaction with CDH1 stabilizes the complex and stimulates cell-cell
CC       aggregation (PubMed:11953314). Interaction with CDH2 is essential for
CC       trafficking of CDH2 from the endoplasmic reticulum to the plasma
CC       membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP,
CC       HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:10037471,
CC       PubMed:10551805, PubMed:11799129, PubMed:11953314, PubMed:12214059,
CC       PubMed:16126725, PubMed:9437013, PubMed:9738936). Interacts through its
CC       N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with
CC       DOCK3; this interaction mediates the membrane association of DOCK3
CC       (PubMed:10854253). Interacts with isoform 1 and isoform 3 of UBQLN1
CC       (PubMed:21143716). {ECO:0000250|UniProtKB:P49769,
CC       ECO:0000269|PubMed:10037471, ECO:0000269|PubMed:10551805,
CC       ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129,
CC       ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12058025,
CC       ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:12679784,
CC       ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:14515347,
CC       ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:16126725,
CC       ECO:0000269|PubMed:20299451, ECO:0000269|PubMed:21143716,
CC       ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380,
CC       ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546,
CC       ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:9437013,
CC       ECO:0000269|PubMed:9738936}.
CC   -!- INTERACTION:
CC       P49768; Q02410: APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690;
CC       P49768; Q96BI3: APH1A; NbExp=3; IntAct=EBI-297277, EBI-2606935;
CC       P49768; P05067: APP; NbExp=6; IntAct=EBI-297277, EBI-77613;
CC       P49768; P05067-4: APP; NbExp=4; IntAct=EBI-297277, EBI-302641;
CC       P49768; P56817: BACE1; NbExp=6; IntAct=EBI-297277, EBI-2433139;
CC       P49768; Q16543: CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634;
CC       P49768; P12830: CDH1; NbExp=2; IntAct=EBI-297277, EBI-727477;
CC       P49768; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452;
CC       P49768; P21333: FLNA; NbExp=2; IntAct=EBI-297277, EBI-350432;
CC       P49768; O75369: FLNB; NbExp=2; IntAct=EBI-297277, EBI-352089;
CC       P49768; Q92542: NCSTN; NbExp=6; IntAct=EBI-297277, EBI-998440;
CC       P49768; Q99569: PKP4; NbExp=3; IntAct=EBI-297277, EBI-726447;
CC       P49768; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-297277, EBI-998468;
CC       P49768; P50502: ST13; NbExp=3; IntAct=EBI-297277, EBI-357285;
CC       P49768; P55061: TMBIM6; NbExp=12; IntAct=EBI-297277, EBI-1045825;
CC       P49768; P49755: TMED10; NbExp=4; IntAct=EBI-297277, EBI-998422;
CC       P49768; Q9NZC2: TREM2; NbExp=5; IntAct=EBI-297277, EBI-14036387;
CC       P49768; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-297277, EBI-741480;
CC       P49768; O35430: Apba1; Xeno; NbExp=2; IntAct=EBI-297277, EBI-704760;
CC       P49768; P98084: Apba2; Xeno; NbExp=2; IntAct=EBI-297277, EBI-81669;
CC       P49768; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-297277, EBI-7030357;
CC       P49768-2; P63010-2: AP2B1; NbExp=6; IntAct=EBI-11047108, EBI-11529439;
CC       P49768-2; P05067: APP; NbExp=6; IntAct=EBI-11047108, EBI-77613;
CC       P49768-2; P16870: CPE; NbExp=3; IntAct=EBI-11047108, EBI-711320;
CC       P49768-2; Q5D0E6-2: DALRD3; NbExp=3; IntAct=EBI-11047108, EBI-9090939;
CC       P49768-2; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-11047108, EBI-3508943;
CC       P49768-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-11047108, EBI-396453;
CC       P49768-2; Q06787-7: FMR1; NbExp=3; IntAct=EBI-11047108, EBI-25856644;
CC       P49768-2; P02792: FTL; NbExp=3; IntAct=EBI-11047108, EBI-713279;
CC       P49768-2; P68431: H3C12; NbExp=6; IntAct=EBI-11047108, EBI-79722;
CC       P49768-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-11047108, EBI-2806068;
CC       P49768-2; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-11047108, EBI-21911304;
CC       P49768-2; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-11047108, EBI-25871195;
CC       P49768-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-11047108, EBI-1044640;
CC       P49768-2; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-11047108, EBI-1108377;
CC       P49768-2; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-11047108, EBI-4397720;
CC       P49768-2; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-11047108, EBI-21250407;
CC       P49768-2; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-11047108, EBI-995714;
CC       P49768-2; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-11047108, EBI-25888682;
CC       P49768-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-11047108, EBI-1058491;
CC       P49768-2; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-11047108, EBI-716063;
CC       P49768-2; P53350: PLK1; NbExp=3; IntAct=EBI-11047108, EBI-476768;
CC       P49768-2; O14494: PLPP1; NbExp=3; IntAct=EBI-11047108, EBI-2865290;
CC       P49768-2; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-11047108, EBI-998468;
CC       P49768-2; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-11047108, EBI-21535400;
CC       P49768-2; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-11047108, EBI-25829984;
CC       P49768-2; Q8N488: RYBP; NbExp=6; IntAct=EBI-11047108, EBI-752324;
CC       P49768-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-11047108, EBI-10182463;
CC       P49768-2; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-11047108, EBI-358545;
CC       P49768-2; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11047108, EBI-18159983;
CC       P49768-2; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-11047108, EBI-11959123;
CC       P49768-2; O00300: TNFRSF11B; NbExp=3; IntAct=EBI-11047108, EBI-15481185;
CC       P49768-2; Q96NC0: ZMAT2; NbExp=6; IntAct=EBI-11047108, EBI-2682299;
CC       PRO_0000025591; Q63053: Arc; Xeno; NbExp=3; IntAct=EBI-2606326, EBI-5275794;
CC       PRO_0000025592; P35613: BSG; NbExp=6; IntAct=EBI-2606356, EBI-750709;
CC       PRO_0000025592; Q92542: NCSTN; NbExp=2; IntAct=EBI-2606356, EBI-998440;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC       {ECO:0000269|PubMed:25394380}. Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:8574969,
CC       ECO:0000269|PubMed:9738936, ECO:0000305|PubMed:10037471,
CC       ECO:0000305|PubMed:15274632}; Multi-pass membrane protein
CC       {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421,
CC       ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517,
CC       ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Golgi
CC       apparatus membrane {ECO:0000269|PubMed:10593990,
CC       ECO:0000269|PubMed:8574969, ECO:0000305|PubMed:10037471,
CC       ECO:0000305|PubMed:15274632}; Multi-pass membrane protein
CC       {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421,
CC       ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517,
CC       ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cytoplasmic
CC       granule {ECO:0000269|PubMed:11987239}. Cell membrane
CC       {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11953314,
CC       ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716}; Multi-pass
CC       membrane protein {ECO:0000269|PubMed:25918421,
CC       ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546,
CC       ECO:0000269|PubMed:30630874}. Cell projection, growth cone
CC       {ECO:0000269|PubMed:15004326}. Early endosome
CC       {ECO:0000269|PubMed:25394380}. Early endosome membrane
CC       {ECO:0000305|PubMed:25394380}; Multi-pass membrane protein
CC       {ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26623517,
CC       ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cell
CC       projection, neuron projection {ECO:0000269|PubMed:15004326}. Cell
CC       projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Synapse
CC       {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1
CC       from the endoplasmic reticulum and/or Golgi to the cell surface
CC       (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell
CC       contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the
CC       proximity of the plasma membrane (PubMed:9738936). Also present in
CC       azurophil granules of neutrophils (PubMed:11987239). Colocalizes with
CC       UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures
CC       called aggresomes (PubMed:21143716). Also highly enriched in
CC       mitochondria-associated endoplasmic reticulum membrane contact site (By
CC       similarity). {ECO:0000250|UniProtKB:P49769,
CC       ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11987239,
CC       ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:9738936}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=7;
CC       Name=1; Synonyms=I-467;
CC         IsoId=P49768-1; Sequence=Displayed;
CC       Name=2; Synonyms=I-463;
CC         IsoId=P49768-2; Sequence=VSP_005191;
CC       Name=3; Synonyms=I-374;
CC         IsoId=P49768-3; Sequence=VSP_005191, VSP_005192;
CC       Name=4; Synonyms=Minilin;
CC         IsoId=P49768-4; Sequence=VSP_007986, VSP_007987;
CC       Name=5;
CC         IsoId=P49768-5; Sequence=VSP_005192;
CC       Name=6;
CC         IsoId=P49768-6; Sequence=VSP_012288;
CC       Name=7;
CC         IsoId=P49768-7; Sequence=VSP_041440;
CC   -!- TISSUE SPECIFICITY: Detected in azurophile granules in neutrophils and
CC       in platelet cytoplasmic granules (at protein level) (PubMed:11987239).
CC       Expressed in a wide range of tissues including various regions of the
CC       brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8574969,
CC       PubMed:8641442). {ECO:0000269|PubMed:11987239,
CC       ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8574969,
CC       ECO:0000269|PubMed:8641442}.
CC   -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC       {ECO:0000269|PubMed:16305624}.
CC   -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between
CC       PSEN1 transmembrane domains and via the first lumenal loop and the
CC       cytoplasmic loop between the sixth and seventh transmembrane domains.
CC       Substrate binding causes a conformation change and formation of an
CC       intermolecular antiparallel beta-sheet between PSEN1 and its
CC       substrates. {ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}.
CC   -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF)
CC       and C-terminal (CTF) fragments of approximately 35 and 20 kDa,
CC       respectively. During apoptosis, the C-terminal fragment (CTF) is
CC       further cleaved by caspase-3 to produce the fragment, PS1-CTF12.
CC       {ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:15274632,
CC       ECO:0000269|PubMed:9173929, ECO:0000269|PubMed:9485372}.
CC   -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is
CC       phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on
CC       Ser-346 inhibits endoproteolysis. {ECO:0000269|PubMed:14576165,
CC       ECO:0000269|PubMed:9144240}.
CC   -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset
CC       form of Alzheimer disease. Alzheimer disease is a neurodegenerative
CC       disorder characterized by progressive dementia, loss of cognitive
CC       abilities, and deposition of fibrillar amyloid proteins as
CC       intraneuronal neurofibrillary tangles, extracellular amyloid plaques
CC       and vascular amyloid deposits. The major constituents of these plaques
CC       are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42,
CC       that are produced by the proteolysis of the transmembrane APP protein.
CC       The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved
CC       products, such as C31, are also implicated in neuronal death.
CC       {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481,
CC       ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579,
CC       ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572,
CC       ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070,
CC       ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793,
CC       ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469,
CC       ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920,
CC       ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891,
CC       ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851,
CC       ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025,
CC       ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344,
CC       ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037,
CC       ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701,
CC       ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188,
CC       ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849,
CC       ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340,
CC       ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394,
CC       ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576,
CC       ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795,
CC       ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735,
CC       ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784,
CC       ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383,
CC       ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661,
CC       ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161,
CC       ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781,
CC       ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961,
CC       ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897,
CC       ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164,
CC       ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787,
CC       ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341,
CC       ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783,
CC       ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983,
CC       ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356,
CC       ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536,
CC       ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712,
CC       ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617,
CC       ECO:0000269|PubMed:8875251, ECO:0000269|PubMed:9172170,
CC       ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817,
CC       ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958,
CC       ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376,
CC       ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068,
CC       ECO:0000269|Ref.95}. Note=The disease is caused by variants affecting
CC       the gene represented in this entry.
CC   -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of
CC       dementia characterized by pathologic finding of frontotemporal lobar
CC       degeneration, presenile dementia with behavioral changes, deterioration
CC       of cognitive capacities and loss of memory. In some cases, parkinsonian
CC       symptoms are prominent. Neuropathological changes include
CC       frontotemporal atrophy often associated with atrophy of the basal
CC       ganglia, substantia nigra, amygdala. In most cases, protein tau
CC       deposits are found in glial cells and/or neurons.
CC       {ECO:0000269|PubMed:11094121}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Cardiomyopathy, dilated, 1U (CMD1U) [MIM:613694]: A disorder
CC       characterized by ventricular dilation and impaired systolic function,
CC       resulting in congestive heart failure and arrhythmia. Patients are at
CC       risk of premature death. {ECO:0000269|PubMed:17186461,
CC       ECO:0000269|PubMed:27930341}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic
CC       relapsing inflammatory disease of the hair follicles characterized by
CC       recurrent draining sinuses, painful skin abscesses, and disfiguring
CC       scars. Manifestations typically appear after puberty.
CC       {ECO:0000269|PubMed:20929727}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of
CC       dementia pathologically defined by severe atrophy, neuronal loss and
CC       gliosis. It is characterized by the occurrence of tau-positive
CC       inclusions, swollen neurons (Pick cells) and argentophilic neuronal
CC       inclusions known as Pick bodies that disproportionally affect the
CC       frontal and temporal cortical regions. Clinical features include
CC       aphasia, apraxia, confusion, anomia, memory loss and personality
CC       deterioration. {ECO:0000269|PubMed:15122701}. Note=The gene represented
CC       in this entry may be involved in disease pathogenesis.
CC   -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a
CC       premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC       decay. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a
CC       premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC       decay. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins
CC       mutations;
CC       URL="https://www.alzforum.org/mutations/psen-1";
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DR   EMBL; L42110; AAB46416.1; -; mRNA.
DR   EMBL; L76517; AAB46370.1; -; mRNA.
DR   EMBL; L76528; AAB46371.1; -; Genomic_DNA.
DR   EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA.
DR   EMBL; U40379; AAB05894.1; -; mRNA.
DR   EMBL; U40380; AAB05895.1; -; mRNA.
DR   EMBL; AJ008005; CAA07825.1; -; mRNA.
DR   EMBL; AF109907; AAC97960.1; -; Genomic_DNA.
DR   EMBL; AF416717; AAL16811.1; -; mRNA.
DR   EMBL; AK312531; BAG35430.1; -; mRNA.
DR   EMBL; AC004858; AAF19253.1; -; Genomic_DNA.
DR   EMBL; AC004858; AAF19254.1; -; Genomic_DNA.
DR   EMBL; CH471061; EAW81092.1; -; Genomic_DNA.
DR   EMBL; BC011729; AAH11729.1; -; mRNA.
DR   EMBL; D84149; BAA20883.1; -; Genomic_DNA.
DR   CCDS; CCDS9812.1; -. [P49768-1]
DR   CCDS; CCDS9813.1; -. [P49768-2]
DR   PIR; S58396; S58396.
DR   PIR; S63683; S63683.
DR   PIR; S63684; S63684.
DR   RefSeq; NP_000012.1; NM_000021.4. [P49768-1]
DR   RefSeq; NP_015557.2; NM_007318.3. [P49768-2]
DR   RefSeq; XP_005267921.1; XM_005267864.4. [P49768-1]
DR   RefSeq; XP_005267923.1; XM_005267866.3. [P49768-2]
DR   RefSeq; XP_011535274.1; XM_011536972.3. [P49768-1]
DR   RefSeq; XP_011535275.1; XM_011536973.3. [P49768-2]
DR   RefSeq; XP_011535276.1; XM_011536974.3. [P49768-2]
DR   RefSeq; XP_047287556.1; XM_047431600.1. [P49768-1]
DR   RefSeq; XP_047287557.1; XM_047431601.1. [P49768-1]
DR   RefSeq; XP_047287558.1; XM_047431602.1. [P49768-2]
DR   RefSeq; XP_054232388.1; XM_054376413.1. [P49768-1]
DR   RefSeq; XP_054232389.1; XM_054376414.1. [P49768-1]
DR   RefSeq; XP_054232390.1; XM_054376415.1. [P49768-1]
DR   RefSeq; XP_054232391.1; XM_054376416.1. [P49768-1]
DR   RefSeq; XP_054232392.1; XM_054376417.1. [P49768-2]
DR   RefSeq; XP_054232393.1; XM_054376418.1. [P49768-2]
DR   RefSeq; XP_054232394.1; XM_054376419.1. [P49768-2]
DR   RefSeq; XP_054232395.1; XM_054376420.1. [P49768-2]
DR   PDB; 2KR6; NMR; -; A=292-467.
DR   PDB; 4UIS; EM; 4.40 A; B=81-463.
DR   PDB; 5A63; EM; 3.40 A; B=1-467.
DR   PDB; 5FN2; EM; 4.20 A; B=1-467.
DR   PDB; 5FN3; EM; 4.10 A; B=1-467.
DR   PDB; 5FN4; EM; 4.00 A; B=1-467.
DR   PDB; 5FN5; EM; 4.30 A; B=1-467.
DR   PDB; 6IDF; EM; 2.70 A; B=1-467.
DR   PDB; 6IYC; EM; 2.60 A; B=1-467.
DR   PDB; 6LQG; EM; 3.10 A; B=1-467.
DR   PDB; 6LR4; EM; 3.00 A; B=1-467.
DR   PDB; 7C9I; EM; 3.10 A; B=1-467.
DR   PDB; 7D8X; EM; 2.60 A; B=1-467.
DR   PDB; 7Y5T; EM; 2.90 A; B=1-467.
DR   PDB; 8IM7; EM; 3.40 A; B=1-467.
DR   PDB; 8K8E; EM; 2.60 A; B=1-467.
DR   PDB; 8KCO; EM; 2.80 A; B=1-467.
DR   PDB; 8KCP; EM; 3.00 A; B=1-467.
DR   PDB; 8KCS; EM; 2.40 A; B=1-467.
DR   PDB; 8KCT; EM; 2.60 A; B=1-467.
DR   PDB; 8KCU; EM; 2.70 A; B=1-467.
DR   PDB; 8OQY; EM; 3.30 A; B=1-467.
DR   PDB; 8OQZ; EM; 3.40 A; B=1-467.
DR   PDB; 8X52; EM; 2.90 A; B=1-467.
DR   PDB; 8X53; EM; 3.00 A; B=1-467.
DR   PDB; 8X54; EM; 2.90 A; B=1-467.
DR   PDBsum; 2KR6; -.
DR   PDBsum; 4UIS; -.
DR   PDBsum; 5A63; -.
DR   PDBsum; 5FN2; -.
DR   PDBsum; 5FN3; -.
DR   PDBsum; 5FN4; -.
DR   PDBsum; 5FN5; -.
DR   PDBsum; 6IDF; -.
DR   PDBsum; 6IYC; -.
DR   PDBsum; 6LQG; -.
DR   PDBsum; 6LR4; -.
DR   PDBsum; 7C9I; -.
DR   PDBsum; 7D8X; -.
DR   PDBsum; 7Y5T; -.
DR   PDBsum; 8IM7; -.
DR   PDBsum; 8K8E; -.
DR   PDBsum; 8KCO; -.
DR   PDBsum; 8KCP; -.
DR   PDBsum; 8KCS; -.
DR   PDBsum; 8KCT; -.
DR   PDBsum; 8KCU; -.
DR   PDBsum; 8OQY; -.
DR   PDBsum; 8OQZ; -.
DR   PDBsum; 8X52; -.
DR   PDBsum; 8X53; -.
DR   PDBsum; 8X54; -.
DR   AlphaFoldDB; P49768; -.
DR   EMDB; EMD-0944; -.
DR   EMDB; EMD-0957; -.
DR   EMDB; EMD-17112; -.
DR   EMDB; EMD-17113; -.
DR   EMDB; EMD-2477; -.
DR   EMDB; EMD-2478; -.
DR   EMDB; EMD-30312; -.
DR   EMDB; EMD-30614; -.
DR   EMDB; EMD-33624; -.
DR   EMDB; EMD-35572; -.
DR   EMDB; EMD-36948; -.
DR   EMDB; EMD-37106; -.
DR   EMDB; EMD-37107; -.
DR   EMDB; EMD-37108; -.
DR   EMDB; EMD-37109; -.
DR   EMDB; EMD-37110; -.
DR   EMDB; EMD-38059; -.
DR   EMDB; EMD-38060; -.
DR   EMDB; EMD-38061; -.
DR   EMDB; EMD-9648; -.
DR   EMDB; EMD-9751; -.
DR   SMR; P49768; -.
DR   BioGRID; 111642; 203.
DR   ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant.
DR   ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant.
DR   CORUM; P49768; -.
DR   DIP; DIP-1134N; -.
DR   ELM; P49768; -.
DR   FunCoup; P49768; 2287.
DR   IntAct; P49768; 299.
DR   MINT; P49768; -.
DR   STRING; 9606.ENSP00000326366; -.
DR   BindingDB; P49768; -.
DR   ChEMBL; CHEMBL2473; -.
DR   DrugBank; DB11893; Avagacestat.
DR   DrugBank; DB12263; Begacestat.
DR   DrugBank; DB05171; E-2012.
DR   DrugBank; DB16159; Esflurbiprofen.
DR   DrugBank; DB12819; GSI-136.
DR   DrugBank; DB16825; Itanapraced.
DR   DrugBank; DB12852; MK-0752.
DR   DrugBank; DB12005; Nirogacestat.
DR   DrugBank; DB11870; RG-4733.
DR   DrugBank; DB12463; Semagacestat.
DR   DrugBank; DB05289; Tarenflurbil.
DR   GuidetoPHARMACOLOGY; 2402; -.
DR   MEROPS; A22.001; -.
DR   TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family.
DR   iPTMnet; P49768; -.
DR   PhosphoSitePlus; P49768; -.
DR   SwissPalm; P49768; -.
DR   BioMuta; PSEN1; -.
DR   DMDM; 1709856; -.
DR   jPOST; P49768; -.
DR   MassIVE; P49768; -.
DR   PaxDb; 9606-ENSP00000326366; -.
DR   PeptideAtlas; P49768; -.
DR   ProteomicsDB; 56106; -. [P49768-1]
DR   ProteomicsDB; 56107; -. [P49768-2]
DR   ProteomicsDB; 56108; -. [P49768-3]
DR   ProteomicsDB; 56109; -. [P49768-4]
DR   ProteomicsDB; 56110; -. [P49768-5]
DR   ProteomicsDB; 56111; -. [P49768-6]
DR   ProteomicsDB; 56112; -. [P49768-7]
DR   Pumba; P49768; -.
DR   Antibodypedia; 3480; 972 antibodies from 47 providers.
DR   DNASU; 5663; -.
DR   Ensembl; ENST00000324501.10; ENSP00000326366.5; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000357710.8; ENSP00000350342.4; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000394157.7; ENSP00000377712.3; ENSG00000080815.21. [P49768-4]
DR   Ensembl; ENST00000394164.5; ENSP00000377719.1; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000553599.6; ENSP00000452477.2; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000553855.5; ENSP00000452242.1; ENSG00000080815.21. [P49768-5]
DR   Ensembl; ENST00000554131.6; ENSP00000451915.2; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000555386.6; ENSP00000450845.1; ENSG00000080815.21. [P49768-3]
DR   Ensembl; ENST00000556951.6; ENSP00000450551.2; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000557511.5; ENSP00000451429.1; ENSG00000080815.21. [P49768-6]
DR   Ensembl; ENST00000700265.1; ENSP00000514901.1; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000700267.1; ENSP00000514903.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700268.1; ENSP00000514904.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700269.1; ENSP00000514905.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700273.1; ENSP00000514908.1; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000700306.1; ENSP00000514933.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700313.1; ENSP00000514940.1; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000700317.1; ENSP00000514944.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700321.1; ENSP00000514948.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700322.1; ENSP00000514949.1; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000700323.1; ENSP00000514950.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700324.1; ENSP00000514951.1; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000700375.1; ENSP00000514966.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700378.1; ENSP00000514968.1; ENSG00000080815.21. [P49768-1]
DR   Ensembl; ENST00000700389.1; ENSP00000514970.1; ENSG00000080815.21. [P49768-2]
DR   Ensembl; ENST00000700436.1; ENSP00000514987.1; ENSG00000080815.21. [P49768-5]
DR   Ensembl; ENST00000700469.1; ENSP00000515002.1; ENSG00000080815.21. [P49768-2]
DR   GeneID; 5663; -.
DR   KEGG; hsa:5663; -.
DR   MANE-Select; ENST00000324501.10; ENSP00000326366.5; NM_000021.4; NP_000012.1.
DR   UCSC; uc001xnq.5; human. [P49768-1]
DR   AGR; HGNC:9508; -.
DR   ClinPGx; PA33855; -.
DR   CTD; 5663; -.
DR   DisGeNET; 5663; -.
DR   GeneCards; PSEN1; -.
DR   GeneReviews; PSEN1; -.
DR   HGNC; HGNC:9508; PSEN1.
DR   HPA; ENSG00000080815; Low tissue specificity.
DR   MalaCards; PSEN1; -.
DR   MIM; 104311; gene.
DR   MIM; 172700; phenotype.
DR   MIM; 600274; phenotype.
DR   MIM; 607822; phenotype.
DR   MIM; 613694; phenotype.
DR   MIM; 613737; phenotype.
DR   OpenTargets; ENSG00000080815; -.
DR   Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR   Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR   Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR   Orphanet; 100070; Progressive non-fluent aphasia.
DR   Orphanet; 100069; Semantic dementia.
DR   VEuPathDB; HostDB:ENSG00000080815; -.
DR   eggNOG; KOG2736; Eukaryota.
DR   GeneTree; ENSGT00940000158751; -.
DR   HOGENOM; CLU_022975_3_0_1; -.
DR   InParanoid; P49768; -.
DR   OMA; NATCNQQ; -.
DR   OrthoDB; 20287at2759; -.
DR   PAN-GO; P49768; 26 GO annotations based on evolutionary models.
DR   PhylomeDB; P49768; -.
DR   PathwayCommons; P49768; -.
DR   Reactome; R-HSA-1251985; Nuclear signaling by ERBB4.
DR   Reactome; R-HSA-1474228; Degradation of the extracellular matrix.
DR   Reactome; R-HSA-193692; Regulated proteolysis of p75NTR.
DR   Reactome; R-HSA-205043; NRIF signals cell death from the nucleus.
DR   Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus.
DR   Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants.
DR   Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
DR   Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus.
DR   Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells.
DR   Reactome; R-HSA-6798695; Neutrophil degranulation.
DR   Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR   Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus.
DR   Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3.
DR   Reactome; R-HSA-9839383; TGFBR3 PTM regulation.
DR   SignaLink; P49768; -.
DR   SIGNOR; P49768; -.
DR   Agora; ENSG00000080815; -.
DR   BioGRID-ORCS; 5663; 16 hits in 1162 CRISPR screens.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   ChiTaRS; PSEN1; human.
DR   EvolutionaryTrace; P49768; -.
DR   GeneWiki; PSEN1; -.
DR   GenomeRNAi; 5663; -.
DR   Pharos; P49768; Tchem.
DR   PRO; PR:P49768; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; P49768; protein.
DR   Bgee; ENSG00000080815; Expressed in middle frontal gyrus and 202 other cell types or tissues.
DR   ExpressionAtlas; P49768; baseline and differential.
DR   GO; GO:0016235; C:aggresome; IDA:UniProtKB.
DR   GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome.
DR   GO; GO:0005938; C:cell cortex; IEA:Ensembl.
DR   GO; GO:0030054; C:cell junction; IDA:HPA.
DR   GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR   GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR   GO; GO:0035253; C:ciliary rootlet; IEA:Ensembl.
DR   GO; GO:0030425; C:dendrite; IDA:ARUK-UCL.
DR   GO; GO:0043198; C:dendritic shaft; IEA:Ensembl.
DR   GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR   GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0030426; C:growth cone; IDA:UniProtKB.
DR   GO; GO:0000776; C:kinetochore; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR   GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR   GO; GO:0043005; C:neuron projection; IDA:UniProtKB.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR   GO; GO:0005640; C:nuclear outer membrane; IDA:MGI.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IMP:CAFA.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0098794; C:postsynapse; IEA:GOC.
DR   GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl.
DR   GO; GO:0032991; C:protein-containing complex; IMP:CAFA.
DR   GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0042383; C:sarcolemma; IEA:Ensembl.
DR   GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR   GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB.
DR   GO; GO:0004190; F:aspartic-type endopeptidase activity; NAS:ARUK-UCL.
DR   GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL.
DR   GO; GO:0008013; F:beta-catenin binding; IPI:UniProtKB.
DR   GO; GO:0045296; F:cadherin binding; IEA:Ensembl.
DR   GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB.
DR   GO; GO:0004175; F:endopeptidase activity; IDA:MGI.
DR   GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL.
DR   GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB.
DR   GO; GO:0030165; F:PDZ domain binding; IPI:UniProtKB.
DR   GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL.
DR   GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB.
DR   GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL.
DR   GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl.
DR   GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL.
DR   GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL.
DR   GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl.
DR   GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR   GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl.
DR   GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl.
DR   GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central.
DR   GO; GO:0001708; P:cell fate specification; IEA:Ensembl.
DR   GO; GO:0098609; P:cell-cell adhesion; IMP:MGI.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL.
DR   GO; GO:0021549; P:cerebellum development; IEA:Ensembl.
DR   GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl.
DR   GO; GO:0015871; P:choline transport; IEA:Ensembl.
DR   GO; GO:0006974; P:DNA damage response; IDA:ARUK-UCL.
DR   GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl.
DR   GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl.
DR   GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IDA:MGI.
DR   GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
DR   GO; GO:0001947; P:heart looping; IEA:Ensembl.
DR   GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl.
DR   GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB.
DR   GO; GO:0098712; P:L-glutamate import across plasma membrane; IEA:Ensembl.
DR   GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL.
DR   GO; GO:0040011; P:locomotion; IEA:Ensembl.
DR   GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL.
DR   GO; GO:0007613; P:memory; IGI:ARUK-UCL.
DR   GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl.
DR   GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IEA:Ensembl.
DR   GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl.
DR   GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl.
DR   GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL.
DR   GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR   GO; GO:0003407; P:neural retina development; IEA:Ensembl.
DR   GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR   GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl.
DR   GO; GO:0048666; P:neuron development; IEA:Ensembl.
DR   GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR   GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL.
DR   GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL.
DR   GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central.
DR   GO; GO:1905908; P:positive regulation of amyloid fibril formation; IGI:ARUK-UCL.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl.
DR   GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:CACAO.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:CACAO.
DR   GO; GO:0010628; P:positive regulation of gene expression; IGI:ARUK-UCL.
DR   GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL.
DR   GO; GO:0002038; P:positive regulation of L-glutamate import across plasma membrane; IEA:Ensembl.
DR   GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR   GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl.
DR   GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL.
DR   GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR   GO; GO:0140249; P:protein catabolic process at postsynapse; IEA:Ensembl.
DR   GO; GO:0016485; P:protein processing; IDA:HGNC-UCL.
DR   GO; GO:0015031; P:protein transport; IEA:Ensembl.
DR   GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR   GO; GO:0010468; P:regulation of gene expression; IGI:ARUK-UCL.
DR   GO; GO:0010975; P:regulation of neuron projection development; IMP:UniProtKB.
DR   GO; GO:0099175; P:regulation of postsynapse organization; IEA:Ensembl.
DR   GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl.
DR   GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl.
DR   GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl.
DR   GO; GO:0098693; P:regulation of synaptic vesicle cycle; IEA:Ensembl.
DR   GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
DR   GO; GO:0051208; P:sequestering of calcium ion; IEA:Ensembl.
DR   GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl.
DR   GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl.
DR   GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IEA:Ensembl.
DR   GO; GO:0001756; P:somitogenesis; IEA:Ensembl.
DR   GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL.
DR   GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl.
DR   GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl.
DR   GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR   GO; GO:0048538; P:thymus development; IEA:Ensembl.
DR   DisProt; DP01292; -.
DR   FunFam; 1.10.472.100:FF:000001; Presenilin; 1.
DR   Gene3D; 1.10.472.100; Presenilin; 1.
DR   InterPro; IPR002031; Pept_A22A_PS1.
DR   InterPro; IPR001108; Peptidase_A22A.
DR   InterPro; IPR006639; Preselin/SPP.
DR   InterPro; IPR042524; Presenilin_C.
DR   PANTHER; PTHR10202; PRESENILIN; 1.
DR   PANTHER; PTHR10202:SF18; PRESENILIN-1; 1.
DR   Pfam; PF01080; Presenilin; 1.
DR   PRINTS; PR01072; PRESENILIN.
DR   PRINTS; PR01073; PRESENILIN1.
DR   SMART; SM00730; PSN; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis;
KW   Apoptosis; Cardiomyopathy; Cell adhesion; Cell membrane; Cell projection;
KW   Direct protein sequencing; Disease variant; Endoplasmic reticulum;
KW   Endosome; Golgi apparatus; Hydrolase; Membrane; Neurodegeneration;
KW   Notch signaling pathway; Phosphoprotein; Protease;
KW   Proteomics identification; Reference proteome; Synapse; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..298
FT                   /note="Presenilin-1 NTF subunit"
FT                   /evidence="ECO:0000269|PubMed:9173929"
FT                   /id="PRO_0000025591"
FT   CHAIN           299..467
FT                   /note="Presenilin-1 CTF subunit"
FT                   /evidence="ECO:0000269|PubMed:9173929"
FT                   /id="PRO_0000025592"
FT   CHAIN           346..467
FT                   /note="Presenilin-1 CTF12"
FT                   /evidence="ECO:0000269|PubMed:9485372"
FT                   /id="PRO_0000236055"
FT   TOPO_DOM        1..82
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        83..103
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        104..132
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        133..153
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        154..166
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        167..189
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        190..194
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        195..216
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        217..220
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        221..241
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        242..248
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        249..272
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        273..380
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        381..401
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        402..407
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        408..428
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        429..432
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TRANSMEM        433..453
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   TOPO_DOM        454..467
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:26280335"
FT   REGION          13..68
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          288..290
FT                   /note="Important for cleavage of target proteins"
FT                   /evidence="ECO:0000269|PubMed:30598546"
FT   REGION          305..333
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          322..450
FT                   /note="Required for interaction with CTNNB1"
FT                   /evidence="ECO:0000269|PubMed:9738936"
FT   REGION          372..399
FT                   /note="Required for interaction with CTNND2"
FT                   /evidence="ECO:0000269|PubMed:10037471"
FT   REGION          377..381
FT                   /note="Important for cleavage of target proteins"
FT                   /evidence="ECO:0000269|PubMed:30598546"
FT   REGION          432..434
FT                   /note="Important for cleavage of target proteins"
FT                   /evidence="ECO:0000269|PubMed:30598546"
FT   REGION          464..467
FT                   /note="Interaction with MTCH1"
FT                   /evidence="ECO:0000269|PubMed:10551805"
FT   MOTIF           433..435
FT                   /note="PAL"
FT                   /evidence="ECO:0000305|PubMed:16305624"
FT   COMPBIAS        13..29
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        30..45
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        257
FT                   /evidence="ECO:0000305|PubMed:10206644,
FT                   ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515"
FT   ACT_SITE        385
FT                   /evidence="ECO:0000305|PubMed:10206644,
FT                   ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515,
FT                   ECO:0000305|PubMed:30598546, ECO:0000305|PubMed:30630874"
FT   SITE            291..292
FT                   /note="Cleavage; alternate"
FT                   /evidence="ECO:0000269|PubMed:9173929"
FT   SITE            292..293
FT                   /note="Cleavage; alternate"
FT                   /evidence="ECO:0000269|PubMed:9173929"
FT   SITE            298..299
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000269|PubMed:9173929"
FT   SITE            345..346
FT                   /note="Cleavage; by caspase"
FT                   /evidence="ECO:0000269|PubMed:9485372"
FT   MOD_RES         43
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17081983,
FT                   ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT   MOD_RES         51
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P97887"
FT   MOD_RES         310
FT                   /note="Phosphoserine; by PKA"
FT                   /evidence="ECO:0000269|PubMed:14576165"
FT   MOD_RES         346
FT                   /note="Phosphoserine; by PKC"
FT                   /evidence="ECO:0000269|PubMed:14576165"
FT   MOD_RES         367
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21406692,
FT                   ECO:0007744|PubMed:23186163"
FT   VAR_SEQ         26..29
FT                   /note="Missing (in isoform 2 and isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:7596406, ECO:0000303|PubMed:8641442"
FT                   /id="VSP_005191"
FT   VAR_SEQ         162..184
FT                   /note="IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFLWLGILVTVT
FT                   (in isoform 4)"
FT                   /evidence="ECO:0000303|Ref.3"
FT                   /id="VSP_007986"
FT   VAR_SEQ         185..467
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000303|Ref.3"
FT                   /id="VSP_007987"
FT   VAR_SEQ         257..289
FT                   /note="Missing (in isoform 7)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_041440"
FT   VAR_SEQ         319..467
FT                   /note="STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILA
FT                   GEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFK
FT                   KALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPM
FT                   APRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI (in isoform 3
FT                   and isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:8641442, ECO:0000303|Ref.5"
FT                   /id="VSP_005192"
FT   VAR_SEQ         319..376
FT                   /note="Missing (in isoform 6)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_012288"
FT   VARIANT         35
FT                   /note="R -> Q (in AD3; uncertain significance; decreased
FT                   protease activity with APP; dbSNP:rs63750592)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075260"
FT   VARIANT         79
FT                   /note="A -> V (in AD3; also found in late-onset Alzheimer
FT                   disease; impaired protease activity with APP; results in
FT                   altered amyloid-beta production and increased amyloid-beta
FT                   42/amyloid-beta 40 ratio; no effect on interaction with
FT                   GFAP; dbSNP:rs63749824)"
FT                   /evidence="ECO:0000269|PubMed:10631141,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:12058025,
FT                   ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:17366635,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9384602"
FT                   /id="VAR_006413"
FT   VARIANT         82
FT                   /note="V -> L (in AD3; decreased protease activity with
FT                   APP; no effect on interaction with GFAP; dbSNP:rs63749967)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:8634712"
FT                   /id="VAR_006414"
FT   VARIANT         83
FT                   /note="I -> T (in AD3)"
FT                   /evidence="ECO:0000269|PubMed:26145164"
FT                   /id="VAR_075261"
FT   VARIANT         85
FT                   /note="L -> P (in AD3; the patient also manifest spastic
FT                   paraparesis and apraxia; loss of protease activity with APP
FT                   in vitro; altered amyloid-beta production in cells
FT                   transfected with the mutant and increased amyloid-beta 42/
FT                   amyloid-beta 40 ratio; dbSNP:rs63750599)"
FT                   /evidence="ECO:0000269|PubMed:15534188,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081228"
FT   VARIANT         89
FT                   /note="V -> L (in AD3; decreased protease activity with
FT                   APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63750815)"
FT                   /evidence="ECO:0000269|PubMed:11796781"
FT                   /id="VAR_081229"
FT   VARIANT         92
FT                   /note="C -> S (in AD3; loss of protease activity with APP;
FT                   dbSNP:rs63751141)"
FT                   /evidence="ECO:0000269|PubMed:11027672,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_016214"
FT   VARIANT         94
FT                   /note="V -> M (in AD3; uncertain significance; reduced
FT                   protease activity with APP; no relevant change in amyloid-
FT                   beta 42/amyloid-beta 40 ratio; dbSNP:rs63750831)"
FT                   /evidence="ECO:0000269|PubMed:11568920"
FT                   /id="VAR_081230"
FT   VARIANT         96
FT                   /note="V -> F (in AD3; loss of protease activity with APP;
FT                   dbSNP:rs63750601)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:8733303"
FT                   /id="VAR_006415"
FT   VARIANT         97
FT                   /note="V -> L (in AD3; uncertain significance; slightly
FT                   reduced protease activity with APP; dbSNP:rs63750852)"
FT                   /evidence="ECO:0000269|PubMed:15851849,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081231"
FT   VARIANT         105
FT                   /note="F -> L (in AD3; dbSNP:rs63750321)"
FT                   /evidence="ECO:0000269|PubMed:10631141"
FT                   /id="VAR_009208"
FT   VARIANT         113
FT                   /note="L -> P (in FTD1; dbSNP:rs63751399)"
FT                   /evidence="ECO:0000269|PubMed:11094121"
FT                   /id="VAR_016215"
FT   VARIANT         115
FT                   /note="Y -> C (in AD3; dbSNP:rs63750450)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:9384602"
FT                   /id="VAR_006416"
FT   VARIANT         115
FT                   /note="Y -> H (in AD3; impaired protease activity with APP
FT                   and increased amyloid-beta 42/amyloid-beta 40 ratio)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:8634712"
FT                   /id="VAR_006417"
FT   VARIANT         116
FT                   /note="T -> I (in AD3; dbSNP:rs63750730)"
FT                   /evidence="ECO:0000269|PubMed:30200536"
FT                   /id="VAR_081232"
FT   VARIANT         116
FT                   /note="T -> N (in AD3; unusual amyloid cotton wool plaques
FT                   detected in one patient's brain; severe decrease of
FT                   protease activity with APP; results in increased amyloid-
FT                   beta 42/amyloid-beta 40 ratio; dbSNP:rs63750730)"
FT                   /evidence="ECO:0000269|PubMed:10439444,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:29404783"
FT                   /id="VAR_010120"
FT   VARIANT         117
FT                   /note="P -> L (in AD3; impaired ability to cleave Ephb2/
FT                   CTF1; results in altered amyloid-beta production and
FT                   increased amyloid-beta 42/amyloid-beta 40 ratio; impaired
FT                   regulation of neurite outgrowth; dbSNP:rs63749805)"
FT                   /evidence="ECO:0000269|PubMed:15004326,
FT                   ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:9507958"
FT                   /id="VAR_009209"
FT   VARIANT         117
FT                   /note="P -> S (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; impaired regulation of neurite outgrowth;
FT                   dbSNP:rs63750550)"
FT                   /evidence="ECO:0000269|PubMed:15004326"
FT                   /id="VAR_081233"
FT   VARIANT         120
FT                   /note="E -> D (in AD3; impaired protease activity with APP
FT                   and increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63751272)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9521423"
FT                   /id="VAR_006418"
FT   VARIANT         120
FT                   /note="E -> K (in AD3; impaired protease activity with APP
FT                   and increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63750800)"
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006419"
FT   VARIANT         134
FT                   /note="L -> R (in AD3; uncertain significance; loss of
FT                   protease activity with APP; dbSNP:rs1595002439)"
FT                   /evidence="ECO:0000269|PubMed:22503161,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_070023"
FT   VARIANT         135
FT                   /note="N -> D (in AD3; impaired protease activity with APP
FT                   and increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63750353)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:9225696"
FT                   /id="VAR_010121"
FT   VARIANT         139
FT                   /note="M -> I (in AD3; dbSNP:rs63750522)"
FT                   /evidence="ECO:0000269|PubMed:8875251"
FT                   /id="VAR_006420"
FT   VARIANT         139
FT                   /note="M -> K (in AD3; dbSNP:rs63751106)"
FT                   /evidence="ECO:0000269|PubMed:9719376"
FT                   /id="VAR_010122"
FT   VARIANT         139
FT                   /note="M -> T (in AD3; dbSNP:rs63751106)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:8634712"
FT                   /id="VAR_006421"
FT   VARIANT         139
FT                   /note="M -> V (in AD3; increased amyloid-beta 42/amyloid-
FT                   beta 40 ratio; dbSNP:rs63751037)"
FT                   /evidence="ECO:0000269|PubMed:10631141,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7550356"
FT                   /id="VAR_006422"
FT   VARIANT         142
FT                   /note="V -> F (in AD3; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:29175279"
FT                   /id="VAR_081234"
FT   VARIANT         143
FT                   /note="I -> F (in AD3; dbSNP:rs63750322)"
FT                   /evidence="ECO:0000269|PubMed:10090481"
FT                   /id="VAR_006423"
FT   VARIANT         143
FT                   /note="I -> T (in AD3; impaired protease activity with APP;
FT                   results in altered amyloid-beta production and increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750004)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:15122701,
FT                   ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:8634711"
FT                   /id="VAR_006424"
FT   VARIANT         146
FT                   /note="M -> I (in AD3; dbSNP:rs63750391)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:12552037"
FT                   /id="VAR_006425"
FT   VARIANT         146
FT                   /note="M -> L (in AD3; disease phenotype shows high
FT                   clinical variability; founder mutation originating from
FT                   Southern Italy and distributed worldwide; alters the
FT                   conformation of the active site; slightly increased
FT                   protease activity with APP; decreased activity for Notch1
FT                   cleavage; no loss of its ability to cleave Ephb2/CTF1;
FT                   dbSNP:rs63750306)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:17428795,
FT                   ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:22461631,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406"
FT                   /id="VAR_006426"
FT   VARIANT         146
FT                   /note="M -> V (in AD3; loss of function as calcium-leak
FT                   channel; results in calcium overload in the endoplasmic
FT                   reticulum; dbSNP:rs63750306)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:7550356"
FT                   /id="VAR_006427"
FT   VARIANT         147
FT                   /note="T -> I (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750907)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_010123"
FT   VARIANT         153
FT                   /note="L -> V (in AD3; abolishes protease activity with APP
FT                   resulting in decreased amyloid-beta 42 and amyloid-beta 40
FT                   production; dbSNP:rs63751441)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081235"
FT   VARIANT         154
FT                   /note="Y -> C (in AD3; uncertain significance;
FT                   dbSNP:rs63751292)"
FT                   /evidence="ECO:0000269|PubMed:12552037"
FT                   /id="VAR_081236"
FT   VARIANT         154
FT                   /note="Y -> N (in AD3; disease phenotype includes spastic
FT                   paraparesis; abolishes protease activity with APP resulting
FT                   in decreased amyloid-beta 42 and amyloid-beta 40
FT                   production; dbSNP:rs63750588)"
FT                   /evidence="ECO:0000269|PubMed:15364419,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081237"
FT   VARIANT         156
FT                   /note="Y -> FTY (in AD3; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:11524469"
FT                   /id="VAR_075262"
FT   VARIANT         159
FT                   /note="Y -> F (in AD3; uncertain significance;
FT                   dbSNP:rs778630379)"
FT                   /evidence="ECO:0000269|PubMed:23123781"
FT                   /id="VAR_081238"
FT   VARIANT         163
FT                   /note="H -> R (in AD3; abolishes protease activity with
FT                   APP; decreased activity for Notch cleavage;
FT                   dbSNP:rs63750590)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:22461631,
FT                   ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8634712,
FT                   ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9521423"
FT                   /id="VAR_006428"
FT   VARIANT         163
FT                   /note="H -> Y (in AD3; slightly increased protease activity
FT                   with APP and slightly increased amyloid-beta 42 production;
FT                   dbSNP:rs63749885)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7550356"
FT                   /id="VAR_006429"
FT   VARIANT         165
FT                   /note="W -> C (in AD3; dbSNP:rs63751484)"
FT                   /evidence="ECO:0000269|PubMed:10441572"
FT                   /id="VAR_010124"
FT   VARIANT         166
FT                   /note="L -> P (in AD3; onset in adolescence; severe
FT                   decrease of protease activity with APP; results in altered
FT                   amyloid-beta production and increased amyloid-beta 42/
FT                   amyloid-beta 40 ratio; results in reduced Notch
FT                   proteolysis; dbSNP:rs63750265)"
FT                   /evidence="ECO:0000269|PubMed:12048239,
FT                   ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23843529,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_016216"
FT   VARIANT         168
FT                   /note="Missing (in AD3; uncertain significance; abolishes
FT                   protease activity with APP resulting in decreased amyloid-
FT                   beta 42 and amyloid-beta 40 production)"
FT                   /evidence="ECO:0000269|PubMed:12552037"
FT                   /id="VAR_081239"
FT   VARIANT         169
FT                   /note="S -> L (in AD3; dbSNP:rs63751210)"
FT                   /evidence="ECO:0000269|PubMed:9831473"
FT                   /id="VAR_006430"
FT   VARIANT         169
FT                   /note="S -> P (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750418)"
FT                   /evidence="ECO:0000269|PubMed:10025789,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006431"
FT   VARIANT         170
FT                   /note="S -> F (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750577)"
FT                   /evidence="ECO:0000269|PubMed:16344340,
FT                   ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:29466804"
FT                   /id="VAR_081240"
FT   VARIANT         171
FT                   /note="L -> P (in AD3; abolishes protease activity with
FT                   APP; dbSNP:rs63750963)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9833068"
FT                   /id="VAR_006432"
FT   VARIANT         173
FT                   /note="L -> W (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750299)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_010125"
FT   VARIANT         174
FT                   /note="L -> M (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63751144)"
FT                   /evidence="ECO:0000269|PubMed:12484344,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_016217"
FT   VARIANT         177
FT                   /note="F -> L (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63749911)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075263"
FT   VARIANT         177
FT                   /note="F -> S (in AD3; uncertain significance;
FT                   dbSNP:rs63749806)"
FT                   /evidence="ECO:0000269|PubMed:11524469"
FT                   /id="VAR_075264"
FT   VARIANT         178
FT                   /note="S -> P (in AD3; uncertain significance; abolishes
FT                   protease activity with APP; dbSNP:rs63750155)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075265"
FT   VARIANT         183
FT                   /note="G -> V (in PIDB and AD3; uncertain significance;
FT                   neuropathologic examination of brain sections from a
FT                   patient shows the presence of Pick bodies and absence of
FT                   beta-amyloid plaques; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio in vitro; dbSNP:rs63751068)"
FT                   /evidence="ECO:0000269|PubMed:15122701,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081241"
FT   VARIANT         184
FT                   /note="E -> D (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750311)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081242"
FT   VARIANT         205
FT                   /note="F -> L (in dbSNP:rs1042864)"
FT                   /id="VAR_011876"
FT   VARIANT         206
FT                   /note="G -> A (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750082)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:27073747,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_016218"
FT   VARIANT         206
FT                   /note="G -> D (in AD3; affects APP processing resulting in
FT                   increased amyloid-beta 42/amyloid-beta 40 ratio; does not
FT                   affect NOTCH processing; does not affect endoproteolysis;
FT                   reduced interaction with PEN2; results in decreased protein
FT                   levels in the endoplasmic reticulum but increased levels in
FT                   early endosome; reduced ability to maintain ER calcium
FT                   homeostasis; dbSNP:rs63750082)"
FT                   /evidence="ECO:0000269|PubMed:21335660,
FT                   ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:29175279"
FT                   /id="VAR_081243"
FT   VARIANT         206
FT                   /note="G -> S (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750569)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075266"
FT   VARIANT         209
FT                   /note="G -> E (in AD3; uncertain significance;
FT                   dbSNP:rs63750053)"
FT                   /evidence="ECO:0000269|PubMed:11524469"
FT                   /id="VAR_075267"
FT   VARIANT         209
FT                   /note="G -> R (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63749880)"
FT                   /evidence="ECO:0000269|PubMed:10447269,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_009210"
FT   VARIANT         209
FT                   /note="G -> V (in AD3; abolishes protease activity with
FT                   APP; dbSNP:rs63750053)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:9521423"
FT                   /id="VAR_006433"
FT   VARIANT         213
FT                   /note="I -> L (in AD3; increases protease activity with APP
FT                   resulting in altered amyloid-beta production and increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750861)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075268"
FT   VARIANT         213
FT                   /note="I -> T (in AD3; decreased protease activity with APP
FT                   resulting in altered amyloid-beta production and increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751309)"
FT                   /evidence="ECO:0000269|PubMed:18430735,
FT                   ECO:0000269|PubMed:8733303"
FT                   /id="VAR_006434"
FT   VARIANT         214
FT                   /note="H -> Y (found in a patient with dementia; uncertain
FT                   significance; dbSNP:rs63751003)"
FT                   /evidence="ECO:0000269|PubMed:22503161"
FT                   /id="VAR_070024"
FT   VARIANT         217
FT                   /note="G -> R (in AD3; with unusual amyloid cotton wool
FT                   plaques; decreased protease activity with APP resulting in
FT                   altered amyloid-beta production and increased amyloid-beta
FT                   42/amyloid-beta 40 ratio; dbSNP:rs267606983)"
FT                   /evidence="ECO:0000269|PubMed:19667325,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081244"
FT   VARIANT         219
FT                   /note="L -> P (in AD3; dbSNP:rs63750761)"
FT                   /evidence="ECO:0000269|PubMed:10208579"
FT                   /id="VAR_010126"
FT   VARIANT         222
FT                   /note="Q -> R (in AD3; uncertain significance; slightly
FT                   increased protease activity with APP and slightly increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750009)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075269"
FT   VARIANT         229
FT                   /note="I -> F (in AD3; decreased protease activity with APP
FT                   resulting in altered amyloid-beta production and increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749970)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081245"
FT   VARIANT         231
FT                   /note="A -> T (in AD3; decreased protease activity with APP
FT                   resulting in altered amyloid-beta production and increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749836)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:8634712"
FT                   /id="VAR_006435"
FT   VARIANT         231
FT                   /note="A -> V (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750799)"
FT                   /evidence="ECO:0000269|PubMed:16752394,
FT                   ECO:0000269|PubMed:9384602"
FT                   /id="VAR_006436"
FT   VARIANT         233
FT                   /note="M -> L (in AD3; slightly decreased protease activity
FT                   with APP resulting in altered amyloid-beta production and
FT                   mildly increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63751287)"
FT                   /evidence="ECO:0000269|PubMed:10533070,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_009211"
FT   VARIANT         233
FT                   /note="M -> T (in AD3; decreased protease activity with APP
FT                   resulting in altered amyloid-beta production and increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751024)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9172170"
FT                   /id="VAR_006437"
FT   VARIANT         235
FT                   /note="L -> P (in AD3; abolishes protease activity with
FT                   APP; dbSNP:rs63749835)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006438"
FT   VARIANT         235
FT                   /note="L -> R (in AD3; abolishes protease activity with
FT                   APP)"
FT                   /evidence="ECO:0000269|PubMed:21501661,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081246"
FT   VARIANT         235
FT                   /note="L -> V (in AD3; reduced APP cleavage resulting in
FT                   decreased amyloid-beta 42 and amyloid-beta 40 production;
FT                   no relevant change in amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63751130)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081247"
FT   VARIANT         237
FT                   /note="F -> I (in AD3; uncertain significance; disease
FT                   phenotype includes spastic paraparesis; severe decrease of
FT                   protease activity with APP; results in decreased amyloid-
FT                   beta 42 and amyloid-beta 40 production; dbSNP:rs63750858)"
FT                   /evidence="ECO:0000269|PubMed:11561050,
FT                   ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081248"
FT   VARIANT         237
FT                   /note="F -> L (in AD3; uncertain significance;
FT                   dbSNP:rs63750858)"
FT                   /evidence="ECO:0000269|PubMed:12552037"
FT                   /id="VAR_081249"
FT   VARIANT         246
FT                   /note="A -> E (in AD3; nearly abolishes protease activity
FT                   with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   no loss of its ability to cleave Ephb2/CTF1;
FT                   dbSNP:rs63750526)"
FT                   /evidence="ECO:0000269|PubMed:17428795,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406"
FT                   /id="VAR_006439"
FT   VARIANT         250
FT                   /note="L -> S (in AD3; nearly abolishes protease activity
FT                   with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63751163)"
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006440"
FT   VARIANT         260
FT                   /note="A -> V (in AD3; nearly abolishes protease activity
FT                   with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   impaired ability to cleave Ephb2/CTF1; dbSNP:rs63751420)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9521423"
FT                   /id="VAR_006441"
FT   VARIANT         261
FT                   /note="V -> F (in AD3; nearly abolishes protease activity
FT                   with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63750964)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075270"
FT   VARIANT         262
FT                   /note="L -> F (in AD3; decreased protease activity with APP
FT                   resulting in altered amyloid-beta production and increased
FT                   amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750248)"
FT                   /evidence="ECO:0000269|PubMed:16752394,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006442"
FT   VARIANT         262
FT                   /note="L -> V (in AD3)"
FT                   /evidence="ECO:0000269|PubMed:22503161"
FT                   /id="VAR_070025"
FT   VARIANT         263
FT                   /note="C -> F (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63751102)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:16752394"
FT                   /id="VAR_081250"
FT   VARIANT         263
FT                   /note="C -> R (in AD3; decreased protease activity with
FT                   APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63750543)"
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006443"
FT   VARIANT         264
FT                   /note="P -> L (in AD3; decreased protease activity with
FT                   APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   impaired ability to cleave Ephb2/CTF1; dbSNP:rs63750301)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423"
FT                   /id="VAR_006444"
FT   VARIANT         266
FT                   /note="G -> S (in AD3; nearly abolishes protease activity
FT                   with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs121917807)"
FT                   /evidence="ECO:0000269|PubMed:11920851,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_016219"
FT   VARIANT         267
FT                   /note="P -> S (in AD3; decreased protease activity with
FT                   APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63751229)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7550356"
FT                   /id="VAR_006445"
FT   VARIANT         269
FT                   /note="R -> G (in AD3; decreased protease activity with
FT                   APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63751019)"
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006447"
FT   VARIANT         269
FT                   /note="R -> H (in AD3; dbSNP:rs63750900)"
FT                   /evidence="ECO:0000269|PubMed:12552037"
FT                   /id="VAR_006448"
FT   VARIANT         271
FT                   /note="L -> V (in AD3; abolishes protease activity with
FT                   APP; dbSNP:rs63750886)"
FT                   /evidence="ECO:0000269|PubMed:12493737,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_016220"
FT   VARIANT         274
FT                   /note="T -> R (in AD3; uncertain significance; abolishes
FT                   protease activity with APP; dbSNP:rs63750284)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075271"
FT   VARIANT         275
FT                   /note="A -> V (in AD3; uncertain significance; reduced
FT                   protease activity with APP resulting in reduced amyloid-
FT                   beta 40 levels but no relevant changes in amyloid-beta 42/
FT                   amyloid-beta 40 ratio; dbSNP:rs1555355869)"
FT                   /evidence="ECO:0000269|PubMed:24582897,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081251"
FT   VARIANT         278
FT                   /note="R -> I (in AD3; atypical phenotype presenting as
FT                   language impairment, impaired frontal executive function
FT                   and relative preservation of memory; severe decrease of APP
FT                   and Notch proteolysis; dbSNP:rs63749891)"
FT                   /evidence="ECO:0000269|PubMed:15534260,
FT                   ECO:0000269|PubMed:23843529"
FT                   /id="VAR_081252"
FT   VARIANT         278
FT                   /note="R -> T (in AD3; dbSNP:rs63749891)"
FT                   /evidence="ECO:0000269|PubMed:9172170"
FT                   /id="VAR_006449"
FT   VARIANT         280
FT                   /note="E -> A (in AD3; strong deposition of amyloid-beta 42
FT                   is observed in brain regions of AD3 patients; decreased
FT                   protease activity with APP resulting in altered amyloid-
FT                   beta production and increased amyloid-beta 42/amyloid-beta
FT                   40 ratio; decreased activity for Notch1 cleavage;
FT                   dbSNP:rs63750231)"
FT                   /evidence="ECO:0000269|PubMed:11568920,
FT                   ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:28269784, ECO:0000269|PubMed:7550356,
FT                   ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9298817"
FT                   /id="VAR_006450"
FT   VARIANT         280
FT                   /note="E -> G (in AD3; some AD3 patients manifest spastic
FT                   paraparesis and unusual amyloid plaques with prominent
FT                   amyloid angiopathy on brain biopsy; decreased protease
FT                   activity with APP; increased amyloid-beta 42/amyloid-beta
FT                   40 ratio; impaired ability to cleave Ephb2/CTF1;
FT                   dbSNP:rs63750231)"
FT                   /evidence="ECO:0000269|PubMed:12370477,
FT                   ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7550356"
FT                   /id="VAR_006451"
FT   VARIANT         282
FT                   /note="L -> R (in AD3; abolishes protease activity with
FT                   APP; dbSNP:rs63750050)"
FT                   /evidence="ECO:0000269|PubMed:10533070,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_009212"
FT   VARIANT         282
FT                   /note="L -> V (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63749937)"
FT                   /evidence="ECO:0000269|PubMed:11701593,
FT                   ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:16752394"
FT                   /id="VAR_081253"
FT   VARIANT         285
FT                   /note="A -> V (in AD3; slightly decreased protease activity
FT                   with APP and slightly decreased amyloid-beta 42/amyloid-
FT                   beta 40 ratio; dbSNP:rs63751139)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7651536"
FT                   /id="VAR_006452"
FT   VARIANT         286
FT                   /note="L -> V (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63751235)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7596406"
FT                   /id="VAR_006453"
FT   VARIANT         289
FT                   /note="S -> C (in AD3)"
FT                   /evidence="ECO:0000269|PubMed:8875251"
FT                   /id="VAR_010127"
FT   VARIANT         311
FT                   /note="K -> R (found in patients with late-onset Alzheimer
FT                   disease; uncertain significance; results in altered
FT                   amyloid-beta production and increased amyloid-beta 42/
FT                   amyloid-beta 40 ratio; dbSNP:rs115865530)"
FT                   /evidence="ECO:0000269|PubMed:28269784"
FT                   /id="VAR_081254"
FT   VARIANT         315
FT                   /note="Y -> C (found in a renal cell carcinoma sample;
FT                   somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:21248752"
FT                   /id="VAR_064747"
FT   VARIANT         318
FT                   /note="E -> G (in dbSNP:rs17125721)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141,
FT                   ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11568920,
FT                   ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:18485326,
FT                   ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9851443,
FT                   ECO:0000269|PubMed:9851450, ECO:0000269|PubMed:9915968"
FT                   /id="VAR_006454"
FT   VARIANT         333
FT                   /note="D -> G (in CMD1U; results in slightly decreased
FT                   protease activity with APP and slightly decreased amyloid-
FT                   beta 42/amyloid-beta 40 ratio; dbSNP:rs121917809)"
FT                   /evidence="ECO:0000269|PubMed:17186461,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_064902"
FT   VARIANT         352
FT                   /note="R -> RR (in AD3; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:11524469"
FT                   /id="VAR_075272"
FT   VARIANT         354
FT                   /note="T -> I (in AD3; uncertain significance; results in
FT                   decreased protease activity with APP and decreased amyloid-
FT                   beta 42/amyloid-beta 40 ratio; dbSNP:rs63751164)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075273"
FT   VARIANT         358
FT                   /note="R -> Q (in AD3; uncertain significance; results in
FT                   altered amyloid-beta production and increased amyloid-beta
FT                   42/amyloid-beta 40 ratio; dbSNP:rs63751174)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075274"
FT   VARIANT         365
FT                   /note="S -> Y (in AD3; uncertain significance;
FT                   dbSNP:rs63750941)"
FT                   /evidence="ECO:0000269|PubMed:11524469"
FT                   /id="VAR_075275"
FT   VARIANT         377
FT                   /note="R -> M (in AD3; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:12552037"
FT                   /id="VAR_081255"
FT   VARIANT         378
FT                   /note="G -> E (in AD3; decreased protease activity with
FT                   APP; results in altered amyloid-beta production and
FT                   increased amyloid-beta 42/amyloid-beta 40 ratio)"
FT                   /evidence="ECO:0000269|PubMed:10200054,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_006455"
FT   VARIANT         378
FT                   /note="G -> V (in AD3; abolishes protease activity with
FT                   APP; dbSNP:rs63750323)"
FT                   /evidence="ECO:0000269|PubMed:12552037,
FT                   ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081256"
FT   VARIANT         381
FT                   /note="L -> F (in AD3; dbSNP:rs63750687)"
FT                   /evidence="ECO:0000269|PubMed:24121961"
FT                   /id="VAR_081257"
FT   VARIANT         381
FT                   /note="L -> V (in AD3; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; dbSNP:rs63750687)"
FT                   /evidence="ECO:0000269|PubMed:19797784,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_081258"
FT   VARIANT         384
FT                   /note="G -> A (in AD3; results in reduced APP and Notch
FT                   proteolysis; results in altered amyloid-beta production and
FT                   increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63750646)"
FT                   /evidence="ECO:0000269|PubMed:16752394,
FT                   ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:8634711"
FT                   /id="VAR_006456"
FT   VARIANT         390
FT                   /note="S -> I (in AD3; abolishes protease activity with
FT                   APP; dbSNP:rs63750883)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_010128"
FT   VARIANT         392
FT                   /note="L -> V (in AD3; results in reduced APP and Notch
FT                   proteolysis; results in altered amyloid-beta production and
FT                   increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63751416)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634712"
FT                   /id="VAR_006457"
FT   VARIANT         394
FT                   /note="G -> V (in AD3; uncertain significance; abolishes
FT                   protease activity with APP; dbSNP:rs63750929)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075276"
FT   VARIANT         396
FT                   /note="A -> T (in AD3; uncertain significance; decreased
FT                   protease activity with APP; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio)"
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT                   /id="VAR_070026"
FT   VARIANT         405
FT                   /note="N -> S (in AD3; uncertain significance; decreased
FT                   protease activity with APP; dbSNP:rs63751254)"
FT                   /evidence="ECO:0000269|PubMed:10644793,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_010129"
FT   VARIANT         408
FT                   /note="I -> T (in AD3; dbSNP:rs906454643)"
FT                   /evidence="ECO:0000269|PubMed:26549787"
FT                   /id="VAR_075277"
FT   VARIANT         409
FT                   /note="A -> T (in AD3; uncertain significance; decreased
FT                   protease activity with APP; dbSNP:rs63750227)"
FT                   /evidence="ECO:0000269|PubMed:10533070,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_009213"
FT   VARIANT         410
FT                   /note="C -> Y (in AD3; results in reduced APP and Notch
FT                   proteolysis; dbSNP:rs661)"
FT                   /evidence="ECO:0000269|PubMed:10441572,
FT                   ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423"
FT                   /id="VAR_006458"
FT   VARIANT         417
FT                   /note="G -> A (in AD3; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:30180983"
FT                   /id="VAR_081259"
FT   VARIANT         418
FT                   /note="L -> F (in AD3; uncertain significance; nearly
FT                   abolishes protease activity with APP; dbSNP:rs63751316)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075278"
FT   VARIANT         426
FT                   /note="A -> P (in AD3; uncertain significance; slightly
FT                   decreased protease activity with APP; dbSNP:rs63751223)"
FT                   /evidence="ECO:0000269|PubMed:27930341,
FT                   ECO:0000269|PubMed:9521423"
FT                   /id="VAR_006459"
FT   VARIANT         431
FT                   /note="A -> E (in AD3; decreased protease activity with
FT                   APP; results in altered amyloid-beta production and
FT                   increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63750083)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16897084,
FT                   ECO:0000269|PubMed:27930341, ECO:0000269|Ref.95"
FT                   /id="VAR_025605"
FT   VARIANT         435
FT                   /note="L -> F (in AD3; with unusual amyloid cotton wool
FT                   plaques; almost abolishes gamma-secretase activity; no
FT                   endoproteolytic cleavage; no APP nor NOTCH1 processing; no
FT                   detectable amyloid-beta; dbSNP:rs63750001)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383,
FT                   ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075280"
FT   VARIANT         436
FT                   /note="P -> Q (in AD3; severe decrease of protease activity
FT                   with APP; dbSNP:rs121917808)"
FT                   /evidence="ECO:0000269|PubMed:22529981,
FT                   ECO:0000269|PubMed:9831473"
FT                   /id="VAR_006460"
FT   VARIANT         436
FT                   /note="P -> S (in AD3; partially abolishes gamma-secretase
FT                   activity; results in altered amyloid-beta production and
FT                   increased amyloid-beta 42/amyloid-beta 40 ratio;
FT                   dbSNP:rs63749925)"
FT                   /evidence="ECO:0000269|PubMed:10090481,
FT                   ECO:0000269|PubMed:21248752, ECO:0000269|PubMed:27930341"
FT                   /id="VAR_008141"
FT   VARIANT         439
FT                   /note="I -> V (in AD3; uncertain significance; no
FT                   significant change of protease activity with APP;
FT                   dbSNP:rs63750249)"
FT                   /evidence="ECO:0000269|PubMed:11524469,
FT                   ECO:0000269|PubMed:27930341"
FT                   /id="VAR_075282"
FT   MUTAGEN         66..72
FT                   /note="Missing: No effect on interaction with GFAP."
FT                   /evidence="ECO:0000269|PubMed:12058025"
FT   MUTAGEN         76..77
FT                   /note="KY->AA: No effect on interaction with GFAP."
FT                   /evidence="ECO:0000269|PubMed:12058025"
FT   MUTAGEN         82..83
FT                   /note="VI->EE: Loss of interaction with GFAP."
FT                   /evidence="ECO:0000269|PubMed:12058025"
FT   MUTAGEN         82
FT                   /note="V->K,E: Loss of interaction with GFAP."
FT                   /evidence="ECO:0000269|PubMed:12058025"
FT   MUTAGEN         84..85
FT                   /note="ML->EE: Loss of interaction with GFAP."
FT                   /evidence="ECO:0000269|PubMed:12058025"
FT   MUTAGEN         99
FT                   /note="T->A: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         105
FT                   /note="F->I: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         108
FT                   /note="R->Q: Nearly abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         112
FT                   /note="Q->C: Formation of an artifactual disulfide bond
FT                   with a substrate protein."
FT                   /evidence="ECO:0000269|PubMed:30598546,
FT                   ECO:0000269|PubMed:30630874"
FT   MUTAGEN         113
FT                   /note="L->Q: Severe decrease of protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         117
FT                   /note="P->A: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         123
FT                   /note="E->K: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         131
FT                   /note="H->R: Severe decrease of protease activity with
FT                   APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         136
FT                   /note="A->G: Decreased protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         143
FT                   /note="I->V: Increased amyloid-beta 42/amyloid-beta 40
FT                   ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         150
FT                   /note="L->P: Nearly abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         165
FT                   /note="W->G: Decreased protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         168
FT                   /note="I->T: Nearly abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         176
FT                   /note="F->L: Nearly abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         184
FT                   /note="E->G: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         202
FT                   /note="I->F: Nearly abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:26280335,
FT                   ECO:0000269|PubMed:27930341"
FT   MUTAGEN         212
FT                   /note="S->Y: Nearly abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         214
FT                   /note="H->D: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         219
FT                   /note="L->F: Decreased protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         223
FT                   /note="Q->R: Abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         226
FT                   /note="L->F: Increases protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:26280335,
FT                   ECO:0000269|PubMed:27930341"
FT   MUTAGEN         230
FT                   /note="S->I: Abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         238
FT                   /note="I->M: Abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         239
FT                   /note="K->N: Abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         245
FT                   /note="T->P: Abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         248
FT                   /note="L->R: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:26280335,
FT                   ECO:0000269|PubMed:27930341"
FT   MUTAGEN         256
FT                   /note="Y->F: Alters gamma-secretase cleavage specificity.
FT                   Increased production of amyloid-beta protein 42. No effect
FT                   on enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:15341515"
FT   MUTAGEN         256
FT                   /note="Y->S: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         257
FT                   /note="D->A: Loss of endoproteolytic cleavage. Severe
FT                   decrease of protease activity with APP. Reduces production
FT                   of amyloid-beta. Reduces production of NICD in NOTCH1
FT                   processing. Impaired ability to cleave Ephb2/CTF1."
FT                   /evidence="ECO:0000269|PubMed:10206644,
FT                   ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515,
FT                   ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:22529981"
FT   MUTAGEN         257
FT                   /note="D->E: Abolishes gamma-secretase activity. Reduces
FT                   production of amyloid-beta in APP processing. Accumulation
FT                   of full-length PS1. Loss of binding of transition state
FT                   analog gamma-secretase inhibitor."
FT                   /evidence="ECO:0000269|PubMed:10206644,
FT                   ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515"
FT   MUTAGEN         272
FT                   /note="V->A: Increased amyloid-beta 42/amyloid-beta 40
FT                   ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         273
FT                   /note="E->A: Decreased protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         278
FT                   /note="R->K: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         284
FT                   /note="P->S: No significant change of protease activity
FT                   with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         286
FT                   /note="L->A,E,P,Q,R,W: Increases production of amyloid-beta
FT                   in APP processing."
FT                   /evidence="ECO:0000269|PubMed:10811883"
FT   MUTAGEN         286
FT                   /note="L->E,R: Reduces production of NICD in NOTCH1
FT                   processing."
FT                   /evidence="ECO:0000269|PubMed:10811883"
FT   MUTAGEN         288..290
FT                   /note="Missing: Loss of NOTCH1 and APP C83 cleavage."
FT                   /evidence="ECO:0000269|PubMed:30598546,
FT                   ECO:0000269|PubMed:30630874"
FT   MUTAGEN         291
FT                   /note="T->P: Abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         292
FT                   /note="M->D: Loss of endoproteolytic cleavage."
FT                   /evidence="ECO:0000269|PubMed:10545183"
FT   MUTAGEN         310
FT                   /note="S->A: Abolishes PKA-mediated phosphorylation; no
FT                   effect on caspase-mediated cleavage."
FT                   /evidence="ECO:0000269|PubMed:14576165"
FT   MUTAGEN         345
FT                   /note="D->N: Abolishes caspase cleavage."
FT                   /evidence="ECO:0000269|PubMed:9485372"
FT   MUTAGEN         346
FT                   /note="S->A: Abolishes PKC-mediated phosphorylation; no
FT                   effect on PKA-mediated phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:14576165"
FT   MUTAGEN         346
FT                   /note="S->E: Inhibits caspase-mediated cleavage. Modulates
FT                   progression of apoptosis."
FT                   /evidence="ECO:0000269|PubMed:14576165"
FT   MUTAGEN         352
FT                   /note="R->C: Decreased protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         365
FT                   /note="S->A: Slightly increased protease activity with
FT                   APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         373
FT                   /note="D->N: No effect on caspase cleavage."
FT                   /evidence="ECO:0000269|PubMed:9485372"
FT   MUTAGEN         377..381
FT                   /note="Missing: Loss of NOTCH1 and APP C83 cleavage."
FT                   /evidence="ECO:0000269|PubMed:30598546,
FT                   ECO:0000269|PubMed:30630874"
FT   MUTAGEN         377
FT                   /note="R->W: Nearly abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         385
FT                   /note="D->A: Loss of endoproteolytic cleavage. Severe
FT                   decrease of protease activity with APP. Reduces production
FT                   of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of
FT                   the N-cadherin/PS1 complex at the cell surface. Impairs
FT                   CDH2 processing."
FT                   /evidence="ECO:0000269|PubMed:10206644,
FT                   ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347,
FT                   ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:22529981,
FT                   ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874,
FT                   ECO:0000269|PubMed:9485372"
FT   MUTAGEN         385
FT                   /note="D->E: Abolishes gamma-secretase activity. Reduces
FT                   production of amyloid-beta in APP processing. Accumulation
FT                   of full-length PS1. Loss of binding of transition state
FT                   analog gamma-secretase inhibitor."
FT                   /evidence="ECO:0000269|PubMed:10206644,
FT                   ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347,
FT                   ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372"
FT   MUTAGEN         385
FT                   /note="D->N: No effect on caspase cleavage."
FT                   /evidence="ECO:0000269|PubMed:10206644,
FT                   ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347,
FT                   ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372"
FT   MUTAGEN         386
FT                   /note="F->S: Nearly abolishes protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         389
FT                   /note="Y->F: Alters gamma-secretase cleavage specificity.
FT                   Increased production of amyloid-beta protein 42. No effect
FT                   on enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:15341515"
FT   MUTAGEN         391
FT                   /note="V->F: Decreased protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         412
FT                   /note="V->I: Abolishes protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         420
FT                   /note="L->R: Decreased protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   MUTAGEN         424
FT                   /note="L->V: Increases protease activity with APP."
FT                   /evidence="ECO:0000269|PubMed:26280335,
FT                   ECO:0000269|PubMed:27930341"
FT   MUTAGEN         432..434
FT                   /note="Missing: Loss of NOTCH1 and APP C83 cleavage."
FT                   /evidence="ECO:0000269|PubMed:30598546,
FT                   ECO:0000269|PubMed:30630874"
FT   MUTAGEN         432
FT                   /note="L->P: Loss of NOTCH1 and APP C83 cleavage."
FT                   /evidence="ECO:0000269|PubMed:30598546,
FT                   ECO:0000269|PubMed:30630874"
FT   MUTAGEN         433
FT                   /note="P->A: No effect on endoproteolytic cleavage. No
FT                   effect on APP nor NOTCH1 processing. Slightly increased
FT                   amyloid-beta protein 42/40 ratio."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         433
FT                   /note="P->D,F,L,N,V: No endoproteolytic cleavage; no APP,
FT                   nor NOTCH1 processing. No detectable amyloid-beta."
FT                   /evidence="ECO:0000269|PubMed:16305624,
FT                   ECO:0000269|PubMed:20460383"
FT   MUTAGEN         433
FT                   /note="P->G: Very little endoproteolysis. Little APP
FT                   processing. No NOTCH1 processing. Very low levels amyloid-
FT                   beta protein 40 and no detectable amyloid-beta protein 42."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         434
FT                   /note="A->C: Some loss of endoproteolytic cleavage. Some
FT                   loss of APP and NOTCH1 processing. 6 to 13-fold increase in
FT                   amyloid-beta protein 42/40 ratio."
FT                   /evidence="ECO:0000269|PubMed:16305624,
FT                   ECO:0000269|PubMed:27930341"
FT   MUTAGEN         434
FT                   /note="A->D,I,L,V: No endoproteolytic cleavage. No APP nor
FT                   NOTCH1 processing. No detectable amyloid-beta."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         434
FT                   /note="A->G: No effect on endoproteolytic cleavage. No
FT                   effect on APP nor NOTCH1 processing. Reduced amyloid-beta
FT                   protein 42/40 ratio."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         435
FT                   /note="L->A: No effect on endoproteolytic cleavage. No
FT                   effect on APP processing. Impaired NOTCH1 processing.
FT                   Greatly reduced amyloid-beta protein 42/40 ratio."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         435
FT                   /note="L->G: Greatly reduced endoproteolytic cleavage. Very
FT                   little APP and NOTCH1 processing. Very low levels of
FT                   amyloid-beta protein 40 and no detectable amyloid-beta
FT                   protein 42."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         435
FT                   /note="L->I: No effect on endoproteolytic cleavage. No
FT                   effect on APP nor NOTCH1 processing."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         435
FT                   /note="L->R: No endoproteolytic cleavage; no APP, nor
FT                   NOTCH1 processing. No detectable amyloid-beta."
FT                   /evidence="ECO:0000269|PubMed:20460383"
FT   MUTAGEN         435
FT                   /note="L->V: No effect on endoproteolytic cleavage. No
FT                   effect on APP processing. Impaired NOTCH1 processing. Some
FT                   increase in amyloid-beta protein 42/40 ratio."
FT                   /evidence="ECO:0000269|PubMed:16305624"
FT   MUTAGEN         437
FT                   /note="I->V: Decreased protease activity with APP.
FT                   Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT                   /evidence="ECO:0000269|PubMed:27930341"
FT   CONFLICT        128
FT                   /note="R -> G (in Ref. 7; AAL16811)"
FT                   /evidence="ECO:0000305"
FT   STRAND          77..80
FT                   /evidence="ECO:0007829|PDB:6LR4"
FT   HELIX           83..102
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           105..107
FT                   /evidence="ECO:0007829|PDB:6IYC"
FT   STRAND          114..116
FT                   /evidence="ECO:0007829|PDB:8X52"
FT   STRAND          120..123
FT                   /evidence="ECO:0007829|PDB:6IYC"
FT   HELIX           125..155
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           159..175
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           177..188
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           195..214
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           219..240
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           243..262
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   STRAND          263..266
FT                   /evidence="ECO:0007829|PDB:6IDF"
FT   HELIX           267..277
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   STRAND          278..280
FT                   /evidence="ECO:0007829|PDB:6IDF"
FT   TURN            284..286
FT                   /evidence="ECO:0007829|PDB:8KCU"
FT   STRAND          287..289
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           293..299
FT                   /evidence="ECO:0007829|PDB:2KR6"
FT   STRAND          341..345
FT                   /evidence="ECO:0007829|PDB:2KR6"
FT   HELIX           356..368
FT                   /evidence="ECO:0007829|PDB:2KR6"
FT   STRAND          380..382
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           383..398
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   STRAND          400..402
FT                   /evidence="ECO:0007829|PDB:8OQY"
FT   HELIX           403..428
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   STRAND          432..434
FT                   /evidence="ECO:0007829|PDB:6IDF"
FT   HELIX           435..451
FT                   /evidence="ECO:0007829|PDB:8KCS"
FT   HELIX           454..463
FT                   /evidence="ECO:0007829|PDB:8KCS"
SQ   SEQUENCE   467 AA;  52668 MW;  5E0F451EF82BCF20 CRC64;
     MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR
     QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE
     DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI
     YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY
     LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE
     GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA
     VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL
     TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI
//
ID   S2538_HUMAN             Reviewed;         304 AA.
AC   Q96DW6; A1LP07; Q9NWX2;
DT   26-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-2001, sequence version 1.
DT   28-JAN-2026, entry version 167.
DE   RecName: Full=Mitochondrial glycine transporter {ECO:0000255|HAMAP-Rule:MF_03064};
DE   AltName: Full=Appoptosin {ECO:0000303|PubMed:23115192};
DE   AltName: Full=Mitochondrial glycine transporter GlyC {ECO:0000303|PubMed:27476175};
DE   AltName: Full=Solute carrier family 25 member 38 {ECO:0000255|HAMAP-Rule:MF_03064};
GN   Name=SLC25A38 {ECO:0000312|HGNC:HGNC:26054};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Carcinoma;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16641997; DOI=10.1038/nature04728;
RA   Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA   Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA   Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA   Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA   Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA   Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA   Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA   Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA   Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA   Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA   Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA   Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA   Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA   Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA   Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA   Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA   Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA   Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA   Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT   "The DNA sequence, annotation and analysis of human chromosome 3.";
RL   Nature 440:1194-1198(2006).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Skin;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [6]
RP   IDENTIFICATION.
RX   PubMed=16949250; DOI=10.1016/j.ygeno.2006.06.016;
RA   Haitina T., Lindblom J., Renstroem T., Fredriksson R.;
RT   "Fourteen novel human members of mitochondrial solute carrier family 25
RT   (SLC25) widely expressed in the central nervous system.";
RL   Genomics 88:779-790(2006).
RN   [7]
RP   VARIANTS SIDBA2 GLU-130; HIS-134; PRO-187 AND HIS-209, FUNCTION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=19412178; DOI=10.1038/ng.359;
RA   Guernsey D.L., Jiang H., Campagna D.R., Evans S.C., Ferguson M.,
RA   Kellogg M.D., Lachance M., Matsuoka M., Nightingale M., Rideout A.,
RA   Saint-Amant L., Schmidt P.J., Orr A., Bottomley S.S., Fleming M.D.,
RA   Ludman M., Dyack S., Fernandez C.V., Samuels M.E.;
RT   "Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic
RT   autosomal recessive congenital sideroblastic anemia.";
RL   Nat. Genet. 41:651-653(2009).
RN   [8]
RP   INDUCTION.
RX   PubMed=23115192; DOI=10.1523/jneurosci.3668-12.2012;
RA   Zhang H., Zhang Y.W., Chen Y., Huang X., Zhou F., Wang W., Xian B.,
RA   Zhang X., Masliah E., Chen Q., Han J.D., Bu G., Reed J.C., Liao F.F.,
RA   Chen Y.G., Xu H.;
RT   "Appoptosin is a novel pro-apoptotic protein and mediates cell death in
RT   neurodegeneration.";
RL   J. Neurosci. 32:15565-15576(2012).
RN   [9]
RP   FUNCTION, AND TRANSPORTER ACTIVITY.
RX   PubMed=27476175; DOI=10.1074/jbc.m116.736876;
RA   Lunetti P., Damiano F., De Benedetto G., Siculella L., Pennetta A.,
RA   Muto L., Paradies E., Marobbio C.M., Dolce V., Capobianco L.;
RT   "Characterization of human and yeast mitochondrial glycine carriers with
RT   implications for heme biosynthesis and anemia.";
RL   J. Biol. Chem. 291:19746-19759(2016).
CC   -!- FUNCTION: Mitochondrial glycine transporter that imports glycine into
CC       the mitochondrial matrix. Plays an important role in providing glycine
CC       for the first enzymatic step in heme biosynthesis, the condensation of
CC       glycine with succinyl-CoA to produce 5-aminolevulinate (ALA) in the
CC       mitochondrial matrix. Required during erythropoiesis.
CC       {ECO:0000255|HAMAP-Rule:MF_03064, ECO:0000269|PubMed:19412178,
CC       ECO:0000269|PubMed:27476175}.
CC   -!- FUNCTION: Plays a role as pro-apoptotic protein that induces caspase-
CC       dependent apoptosis. {ECO:0000250|UniProtKB:Q91XD8}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=glycine(in) = glycine(out); Xref=Rhea:RHEA:70715,
CC         ChEBI:CHEBI:57305; Evidence={ECO:0000269|PubMed:27476175};
CC   -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane {ECO:0000255|HAMAP-
CC       Rule:MF_03064}; Multi-pass membrane protein {ECO:0000255|HAMAP-
CC       Rule:MF_03064}.
CC   -!- TISSUE SPECIFICITY: Preferentially expressed in erythroid cells.
CC       {ECO:0000269|PubMed:19412178}.
CC   -!- INDUCTION: Up-regulated in the brains of patients with Alzheimer's
CC       disease. {ECO:0000269|PubMed:23115192}.
CC   -!- DISEASE: Anemia, sideroblastic, 2, pyridoxine-refractory (SIDBA2)
CC       [MIM:205950]: A form of sideroblastic anemia not responsive to
CC       pyridoxine. Sideroblastic anemia is characterized by anemia of varying
CC       severity, hypochromic peripheral erythrocytes, systemic iron overload
CC       secondary to chronic ineffective erythropoiesis, and the presence of
CC       bone marrow ringed sideroblasts. Sideroblasts are characterized by
CC       iron-loaded mitochondria clustered around the nucleus.
CC       {ECO:0000269|PubMed:19412178}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family.
CC       SLC25A38 subfamily. {ECO:0000255|HAMAP-Rule:MF_03064}.
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DR   EMBL; AK000558; BAA91253.1; -; mRNA.
DR   EMBL; CR457242; CAG33523.1; -; mRNA.
DR   EMBL; BC013194; AAH13194.1; -; mRNA.
DR   EMBL; AC099332; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC104850; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471055; EAW64580.1; -; Genomic_DNA.
DR   EMBL; CH471055; EAW64581.1; -; Genomic_DNA.
DR   CCDS; CCDS2685.1; -.
DR   RefSeq; NP_060345.2; NM_017875.4.
DR   AlphaFoldDB; Q96DW6; -.
DR   SMR; Q96DW6; -.
DR   BioGRID; 120313; 13.
DR   FunCoup; Q96DW6; 973.
DR   IntAct; Q96DW6; 12.
DR   STRING; 9606.ENSP00000497532; -.
DR   TCDB; 2.A.29.5.6; the mitochondrial carrier (mc) family.
DR   iPTMnet; Q96DW6; -.
DR   PhosphoSitePlus; Q96DW6; -.
DR   BioMuta; SLC25A38; -.
DR   DMDM; 74751821; -.
DR   jPOST; Q96DW6; -.
DR   MassIVE; Q96DW6; -.
DR   PaxDb; 9606-ENSP00000273158; -.
DR   PeptideAtlas; Q96DW6; -.
DR   ProteomicsDB; 76331; -.
DR   Pumba; Q96DW6; -.
DR   Antibodypedia; 12178; 117 antibodies from 26 providers.
DR   DNASU; 54977; -.
DR   Ensembl; ENST00000650617.1; ENSP00000497532.1; ENSG00000144659.14.
DR   GeneID; 54977; -.
DR   KEGG; hsa:54977; -.
DR   MANE-Select; ENST00000650617.1; ENSP00000497532.1; NM_017875.4; NP_060345.2.
DR   UCSC; uc003cjo.3; human.
DR   AGR; HGNC:26054; -.
DR   ClinPGx; PA162403607; -.
DR   CTD; 54977; -.
DR   DisGeNET; 54977; -.
DR   GeneCards; SLC25A38; -.
DR   HGNC; HGNC:26054; SLC25A38.
DR   HPA; ENSG00000144659; Low tissue specificity.
DR   MalaCards; SLC25A38; -.
DR   MIM; 205950; phenotype.
DR   MIM; 610819; gene.
DR   OpenTargets; ENSG00000144659; -.
DR   Orphanet; 260305; Autosomal recessive sideroblastic anemia.
DR   VEuPathDB; HostDB:ENSG00000144659; -.
DR   eggNOG; KOG0766; Eukaryota.
DR   GeneTree; ENSGT00550000075117; -.
DR   HOGENOM; CLU_015166_0_3_1; -.
DR   InParanoid; Q96DW6; -.
DR   OMA; WGIYEEL; -.
DR   OrthoDB; 1924968at2759; -.
DR   PAN-GO; Q96DW6; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; Q96DW6; -.
DR   PathwayCommons; Q96DW6; -.
DR   SignaLink; Q96DW6; -.
DR   Agora; ENSG00000144659; -.
DR   BioGRID-ORCS; 54977; 176 hits in 1125 CRISPR screens.
DR   ChiTaRS; SLC25A38; human.
DR   GenomeRNAi; 54977; -.
DR   Pharos; Q96DW6; Tbio.
DR   PRO; PR:Q96DW6; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; Q96DW6; protein.
DR   Bgee; ENSG00000144659; Expressed in body of pancreas and 184 other cell types or tissues.
DR   ExpressionAtlas; Q96DW6; baseline and differential.
DR   GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; HTP:FlyBase.
DR   GO; GO:0015187; F:glycine transmembrane transporter activity; IMP:UniProtKB.
DR   GO; GO:0030218; P:erythrocyte differentiation; IMP:UniProtKB.
DR   GO; GO:1904983; P:glycine import into mitochondrion; IMP:UniProtKB.
DR   GO; GO:0006783; P:heme biosynthetic process; TAS:UniProtKB.
DR   FunFam; 1.50.40.10:FF:000100; Mitochondrial glycine transporter; 1.
DR   FunFam; 1.50.40.10:FF:000118; Mitochondrial glycine transporter; 1.
DR   Gene3D; 1.50.40.10; Mitochondrial carrier domain; 2.
DR   HAMAP; MF_03064; SLC25A38; 1.
DR   InterPro; IPR030847; Hem25/SLC25A38.
DR   InterPro; IPR023395; MCP_dom_sf.
DR   InterPro; IPR018108; MCP_transmembrane.
DR   PANTHER; PTHR46181; MITOCHONDRIAL GLYCINE TRANSPORTER; 1.
DR   PANTHER; PTHR46181:SF3; MITOCHONDRIAL GLYCINE TRANSPORTER; 1.
DR   Pfam; PF00153; Mito_carr; 3.
DR   SUPFAM; SSF103506; Mitochondrial carrier; 1.
DR   PROSITE; PS50920; SOLCAR; 3.
PE   1: Evidence at protein level;
KW   Disease variant; Membrane; Mitochondrion; Mitochondrion inner membrane;
KW   Proteomics identification; Reference proteome; Repeat; Transmembrane;
KW   Transmembrane helix; Transport.
FT   CHAIN           1..304
FT                   /note="Mitochondrial glycine transporter"
FT                   /id="PRO_0000291802"
FT   TRANSMEM        31..56
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   TRANSMEM        89..115
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   TRANSMEM        127..152
FT                   /note="Helical; Name=3"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   TRANSMEM        180..203
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   TRANSMEM        219..245
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   TRANSMEM        274..292
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   REPEAT          25..114
FT                   /note="Solcar 1"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   REPEAT          121..205
FT                   /note="Solcar 2"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   REPEAT          215..299
FT                   /note="Solcar 3"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03064"
FT   VARIANT         66
FT                   /note="R -> G (in dbSNP:rs34127778)"
FT                   /id="VAR_032862"
FT   VARIANT         130
FT                   /note="G -> E (in SIDBA2; dbSNP:rs762562272)"
FT                   /evidence="ECO:0000269|PubMed:19412178"
FT                   /id="VAR_058093"
FT   VARIANT         134
FT                   /note="R -> H (in SIDBA2; dbSNP:rs2041767822)"
FT                   /evidence="ECO:0000269|PubMed:19412178"
FT                   /id="VAR_058094"
FT   VARIANT         187
FT                   /note="R -> P (in SIDBA2; dbSNP:rs121918331)"
FT                   /evidence="ECO:0000269|PubMed:19412178"
FT                   /id="VAR_058095"
FT   VARIANT         209
FT                   /note="D -> H (in SIDBA2; dbSNP:rs146864395)"
FT                   /evidence="ECO:0000269|PubMed:19412178"
FT                   /id="VAR_058096"
FT   CONFLICT        239
FT                   /note="D -> G (in Ref. 1; BAA91253)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   304 AA;  33566 MW;  026B8121C40F8FF0 CRC64;
     MIQNSRPSLL QPQDVGDTVE TLMLHPVIKA FLCGSISGTC STLLFQPLDL LKTRLQTLQP
     SDHGSRRVGM LAVLLKVVRT ESLLGLWKGM SPSIVRCVPG VGIYFGTLYS LKQYFLRGHP
     PTALESVMLG VGSRSVAGVC MSPITVIKTR YESGKYGYES IYAALRSIYH SEGHRGLFSG
     LTATLLRDAP FSGIYLMFYN QTKNIVPHDQ VDATLIPITN FSCGIFAGIL ASLVTQPADV
     IKTHMQLYPL KFQWIGQAVT LIFKDYGLRG FFQGGIPRAL RRTLMAAMAW TVYEEMMAKM
     GLKS
//
ID   SDIM1_HUMAN             Reviewed;         146 AA.
AC   Q6ZPB5;
DT   05-APR-2011, integrated into UniProtKB/Swiss-Prot.
DT   05-APR-2011, sequence version 2.
DT   28-JAN-2026, entry version 67.
DE   RecName: Full=Stress-responsive DNAJB4-interacting membrane protein 1;
DE   Flags: Precursor;
GN   Name=SDIM1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Synovium;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=14574404; DOI=10.1038/nature02055;
RA   Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA   Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA   Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA   Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA   Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA   Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA   Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA   Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA   Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA   French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA   Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA   Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA   Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA   Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA   Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA   Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA   Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA   Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA   Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA   Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA   Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA   Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA   Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA   Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA   Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA   West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA   Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA   Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA   Rogers J., Beck S.;
RT   "The DNA sequence and analysis of human chromosome 6.";
RL   Nature 425:805-811(2003).
RN   [3]
RP   FUNCTION, TISSUE SPECIFICITY, INDUCTION BY STRESS, AND INTERACTION WITH
RP   DNAJB4.
RX   PubMed=21255413; DOI=10.1186/1750-1326-6-9;
RA   Lei J.X., Cassone C.G., Luebbert C., Liu Q.Y.;
RT   "A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's
RT   brains and attenuates cell death induced by DNAJB4 over-expression in
RT   neuro-progenitor cells.";
RL   Mol. Neurodegener. 6:9-9(2011).
CC   -!- FUNCTION: Promotes neuronal cells survival to stress conditions.
CC       {ECO:0000269|PubMed:21255413}.
CC   -!- SUBUNIT: Homodimer. Interacts with DNAJB4.
CC       {ECO:0000269|PubMed:21255413}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Multi-pass membrane
CC       protein {ECO:0000305}.
CC   -!- TISSUE SPECIFICITY: Expressed in brain with higher detection in neurons
CC       than astrocytes. Decreased expression in Alzheimer brains. Detected at
CC       protein level in brain and cervix. {ECO:0000269|PubMed:21255413}.
CC   -!- INDUCTION: Down-regulated in NT2 neurons subjected to stress conditions
CC       which triggers neuronal apoptosis such as oxygen and glucose
CC       deprivation, followed by up-regulation in surviving cells.
CC       {ECO:0000269|PubMed:21255413}.
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DR   EMBL; AK129633; BAC85201.1; -; mRNA.
DR   EMBL; AL590482; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   AlphaFoldDB; Q6ZPB5; -.
DR   FunCoup; Q6ZPB5; 1.
DR   BioMuta; HGNC:38749; -.
DR   AGR; HGNC:38749; -.
DR   GeneCards; SDIM1; -.
DR   HGNC; HGNC:38749; SDIM1.
DR   InParanoid; Q6ZPB5; -.
DR   PAN-GO; Q6ZPB5; 0 GO annotations based on evolutionary models.
DR   Pharos; Q6ZPB5; Tbio.
DR   PRO; PR:Q6ZPB5; -.
DR   Proteomes; UP000005640; Unplaced.
DR   RNAct; Q6ZPB5; protein.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0006457; P:protein folding; IPI:UniProtKB.
PE   1: Evidence at protein level;
KW   Membrane; Reference proteome; Signal; Transmembrane; Transmembrane helix.
FT   SIGNAL          1..26
FT                   /evidence="ECO:0000255"
FT   CHAIN           27..146
FT                   /note="Stress-responsive DNAJB4-interacting membrane
FT                   protein 1"
FT                   /id="PRO_0000406571"
FT   TOPO_DOM        27..66
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        67..87
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        88..94
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        95..115
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        116..146
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   CONFLICT        22
FT                   /note="Y -> N (in Ref. 1; BAC85201)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        146
FT                   /note="I -> V (in Ref. 1; BAC85201)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   146 AA;  16112 MW;  B7DFA69DC26103FC CRC64;
     MWPAPCSVGR LLIFFMCSSS GYVVQGCGPS PGARTTLGSP LSLWSIKTPS HIFCTRRAIN
     LGFPSPPLVQ LIFWSLNAGL DLYLCLISSC GFSQVFWPVE AFCSFSLSFF ALALSHKFVI
     CRLDQHIFSG FTKSLKNLPP CHRTDI
//
ID   SPHK2_HUMAN             Reviewed;         654 AA.
AC   Q9NRA0; A0T4C8; B4DU87; Q9BRN1; Q9H0Q2; Q9NWU7;
DT   24-OCT-2001, integrated into UniProtKB/Swiss-Prot.
DT   26-JUL-2002, sequence version 2.
DT   28-JAN-2026, entry version 198.
DE   RecName: Full=Sphingosine kinase 2 {ECO:0000305};
DE            Short=SK 2;
DE            Short=SPK 2;
DE            EC=2.7.1.91 {ECO:0000269|PubMed:10751414, ECO:0000269|PubMed:12954646, ECO:0000269|PubMed:19729656};
GN   Name=SPHK2 {ECO:0000312|HGNC:HGNC:18859}; Synonyms=SK2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), CATALYTIC ACTIVITY, SUBSTRATE
RP   SPECIFICITY, AND TISSUE SPECIFICITY.
RX   PubMed=10751414; DOI=10.1074/jbc.m002759200;
RA   Liu H., Sugiura M., Nava V.E., Edsall L.C., Kono K., Poulton S.,
RA   Milstien S., Kohama T., Spiegel S.;
RT   "Molecular cloning and functional characterization of a novel mammalian
RT   sphingosine kinase type 2 isoform.";
RL   J. Biol. Chem. 275:19513-19520(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RA   Alemany R., Ruemenapp U., van Koppen C.J., Danneberg K.,
RA   Meyer zu Heringdorf D., Jakobs K.H.;
RT   "Variant of human sphingosine kinase-2 (SPHK2).";
RL   Submitted (NOV-2006) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Brain;
RX   PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA   Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA   Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA   Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA   Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA   Klein M., Poustka A.;
RT   "Towards a catalog of human genes and proteins: sequencing and analysis of
RT   500 novel complete protein coding human cDNAs.";
RL   Genome Res. 11:422-435(2001).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND NUCLEOTIDE SEQUENCE
RP   [LARGE SCALE MRNA] OF 1-354 (ISOFORM 3).
RC   TISSUE=Carcinoma, and Prostate;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA   Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA   Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA   Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA   Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA   Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA   Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA   Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA   Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA   McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA   Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA   Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA   She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA   Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA   Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Eye, and Lymph;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=12954646; DOI=10.1074/jbc.m306577200;
RA   Igarashi N., Okada T., Hayashi S., Fujita T., Jahangeer S., Nakamura S.;
RT   "Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis.";
RL   J. Biol. Chem. 278:46832-46839(2003).
RN   [8]
RP   ALTERNATIVE SPLICING, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX   PubMed=16103110; DOI=10.1074/jbc.m504507200;
RA   Okada T., Ding G., Sonoda H., Kajimoto T., Haga Y., Khosrowbeygi A.,
RA   Gao S., Miwa N., Jahangeer S., Nakamura S.;
RT   "Involvement of N-terminal-extended form of sphingosine kinase 2 in serum-
RT   dependent regulation of cell proliferation and apoptosis.";
RL   J. Biol. Chem. 280:36318-36325(2005).
RN   [9]
RP   FUNCTION.
RX   PubMed=16118219; DOI=10.1074/jbc.m502207200;
RA   Maceyka M., Sankala H., Hait N.C., Le Stunff H., Liu H., Toman R.,
RA   Collier C., Zhang M., Satin L.S., Merrill A.H. Jr., Milstien S.,
RA   Spiegel S.;
RT   "SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in
RT   sphingolipid metabolism.";
RL   J. Biol. Chem. 280:37118-37129(2005).
RN   [10]
RP   PHOSPHORYLATION AT SER-387 AND THR-614, MUTAGENESIS OF SER-387; SER-437;
RP   SER-466; SER-477 AND THR-614, AND ACTIVITY REGULATION.
RX   PubMed=17311928; DOI=10.1074/jbc.m609559200;
RA   Hait N.C., Bellamy A., Milstien S., Kordula T., Spiegel S.;
RT   "Sphingosine kinase type 2 activation by ERK-mediated phosphorylation.";
RL   J. Biol. Chem. 282:12058-12065(2007).
RN   [11]
RP   SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-419 AND SER-421, AND
RP   MUTAGENESIS OF 419-SER--SER-421 AND 423-LEU--LEU-425.
RX   PubMed=17635916; DOI=10.1074/jbc.m701641200;
RA   Ding G., Sonoda H., Yu H., Kajimoto T., Goparaju S.K., Jahangeer S.,
RA   Okada T., Nakamura S.;
RT   "Protein kinase D-mediated phosphorylation and nuclear export of
RT   sphingosine kinase 2.";
RL   J. Biol. Chem. 282:27493-27502(2007).
RN   [12]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS] (ISOFORM 2).
RC   TISSUE=Placenta;
RX   PubMed=17897319; DOI=10.1111/j.1600-0854.2007.00643.x;
RA   Schroeder B., Wrocklage C., Pan C., Jaeger R., Koesters B., Schaefer H.,
RA   Elsaesser H.-P., Mann M., Hasilik A.;
RT   "Integral and associated lysosomal membrane proteins.";
RL   Traffic 8:1676-1686(2007).
RN   [13]
RP   INTERACTION WITH EEF1A1.
RX   PubMed=18263879; DOI=10.1074/jbc.m708782200;
RA   Leclercq T.M., Moretti P.A., Vadas M.A., Pitson S.M.;
RT   "Eukaryotic elongation factor 1A interacts with sphingosine kinase and
RT   directly enhances its catalytic activity.";
RL   J. Biol. Chem. 283:9606-9614(2008).
RN   [14]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [15]
RP   FUNCTION, SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND REGION.
RX   PubMed=19168031; DOI=10.1016/j.bbrc.2009.01.075;
RA   Don A.S., Rosen H.;
RT   "A lipid binding domain in sphingosine kinase 2.";
RL   Biochem. Biophys. Res. Commun. 380:87-92(2009).
RN   [16]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HISTONE H3; HDAC1; HDAC2;
RP   MBD2 AND SIN3A, MUTAGENESIS OF GLY-212, AND CATALYTIC ACTIVITY.
RX   PubMed=19729656; DOI=10.1126/science.1176709;
RA   Hait N.C., Allegood J., Maceyka M., Strub G.M., Harikumar K.B., Singh S.K.,
RA   Luo C., Marmorstein R., Kordula T., Milstien S., Spiegel S.;
RT   "Regulation of histone acetylation in the nucleus by sphingosine-1-
RT   phosphate.";
RL   Science 325:1254-1257(2009).
RN   [17]
RP   SUBCELLULAR LOCATION, CLEAVAGE, AND MUTAGENESIS OF ASP-138; THR-220 AND
RP   ASP-552.
RX   PubMed=20197547; DOI=10.1182/blood-2009-10-243444;
RA   Weigert A., Cremer S., Schmidt M.V., von Knethen A., Angioni C.,
RA   Geisslinger G., Bruene B.;
RT   "Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from
RT   apoptotic cells.";
RL   Blood 115:3531-3540(2010).
RN   [18]
RP   FUNCTION.
RX   PubMed=20959514; DOI=10.1096/fj.10-167502;
RA   Strub G.M., Paillard M., Liang J., Gomez L., Allegood J.C., Hait N.C.,
RA   Maceyka M., Price M.M., Chen Q., Simpson D.C., Kordula T., Milstien S.,
RA   Lesnefsky E.J., Spiegel S.;
RT   "Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria
RT   interacts with prohibitin 2 to regulate complex IV assembly and
RT   respiration.";
RL   FASEB J. 25:600-612(2011).
RN   [19]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-387 AND SER-399, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [20]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-477, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [21]
RP   TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX   PubMed=29615132; DOI=10.1186/s40478-018-0527-z;
RA   Dominguez G., Maddelein M.L., Pucelle M., Nicaise Y., Maurage C.A.,
RA   Duyckaerts C., Cuvillier O., Delisle M.B.;
RT   "Neuronal sphingosine kinase 2 subcellular localization is altered in
RT   Alzheimer's disease brain.";
RL   Acta Neuropathol. Commun. 6:25-25(2018).
CC   -!- FUNCTION: Catalyzes the phosphorylation of sphingosine to form
CC       sphingosine-1-phosphate (SPP), a lipid mediator with both intra- and
CC       extracellular functions. Also acts on D-erythro-dihydrosphingosine, D-
CC       erythro-sphingosine and L-threo-dihydrosphingosine. Binds
CC       phosphoinositides (PubMed:12954646, PubMed:19168031). In contrast to
CC       prosurvival SPHK1, has a positive effect on intracellular ceramide
CC       levels, inhibits cells growth and enhances apoptosis (PubMed:16118219).
CC       In mitochondria, is important for cytochrome-c oxidase assembly and
CC       mitochondrial respiration. The SPP produced in mitochondria binds PHB2
CC       and modulates the regulation via PHB2 of complex IV assembly and
CC       respiration (PubMed:20959514). In nucleus, plays a role in epigenetic
CC       regulation of gene expression. Interacts with HDAC1 and HDAC2 and,
CC       through SPP production, inhibits their enzymatic activity, preventing
CC       the removal of acetyl groups from lysine residues with histones. Up-
CC       regulates acetylation of histone H3-K9, histone H4-K5 and histone H2B-
CC       K12 (PubMed:19729656). In nucleus, may have an inhibitory effect on DNA
CC       synthesis and cell cycle (PubMed:12954646, PubMed:16103110). In mast
CC       cells, is the main regulator of SPP production which mediates calcium
CC       influx, NF-kappa-B activation, cytokine production, such as TNF and
CC       IL6, and degranulation of mast cells (By similarity). In dopaminergic
CC       neurons, is involved in promoting mitochondrial functions regulating
CC       ATP and ROS levels (By similarity). Also involved in the regulation of
CC       glucose and lipid metabolism (By similarity).
CC       {ECO:0000250|UniProtKB:Q9JIA7, ECO:0000269|PubMed:12954646,
CC       ECO:0000269|PubMed:16103110, ECO:0000269|PubMed:16118219,
CC       ECO:0000269|PubMed:19168031, ECO:0000269|PubMed:19729656,
CC       ECO:0000269|PubMed:20959514}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a sphingoid base + ATP = a sphingoid 1-phosphate + ADP + H(+);
CC         Xref=Rhea:RHEA:51496, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:76941, ChEBI:CHEBI:84410, ChEBI:CHEBI:456216;
CC         EC=2.7.1.91; Evidence={ECO:0000269|PubMed:10751414,
CC         ECO:0000269|PubMed:12954646, ECO:0000269|PubMed:19729656};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=sphing-4-enine + ATP = sphing-4-enine 1-phosphate + ADP +
CC         H(+); Xref=Rhea:RHEA:35847, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:57756, ChEBI:CHEBI:60119, ChEBI:CHEBI:456216;
CC         EC=2.7.1.91; Evidence={ECO:0000269|PubMed:10751414};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35848;
CC         Evidence={ECO:0000269|PubMed:10751414};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=sphinganine + ATP = sphinganine 1-phosphate + ADP + H(+);
CC         Xref=Rhea:RHEA:15465, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:57817, ChEBI:CHEBI:57939, ChEBI:CHEBI:456216;
CC         EC=2.7.1.91; Evidence={ECO:0000250|UniProtKB:Q9JIA7};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(4R)-hydroxysphinganine + ATP = (4R)-hydroxysphinganine 1-
CC         phosphate + ADP + H(+); Xref=Rhea:RHEA:33563, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:64124, ChEBI:CHEBI:64795,
CC         ChEBI:CHEBI:456216; EC=2.7.1.91;
CC         Evidence={ECO:0000250|UniProtKB:Q9JIA7};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:Q9NYA1};
CC   -!- ACTIVITY REGULATION: Inhibited by sulfatide (PubMed:19168031). Kinase
CC       activity is increased by phosphorylation by MAPK2 upon PMA or EGF
CC       treatments (PubMed:17311928). {ECO:0000269|PubMed:17311928,
CC       ECO:0000269|PubMed:19168031}.
CC   -!- SUBUNIT: Interacts with histone H3 (PubMed:19729656). Interacts with
CC       HDAC1, HDAC2, MBD2 and SIN3A (PubMed:19729656). Interacts with EEF1A1;
CC       the interaction enhances SPHK2 kinase activity (PubMed:18263879).
CC       Interacts with PHB2 (By similarity). {ECO:0000250|UniProtKB:Q9JIA7,
CC       ECO:0000269|PubMed:18263879, ECO:0000269|PubMed:19729656}.
CC   -!- INTERACTION:
CC       Q9NRA0; Q96CV9: OPTN; NbExp=3; IntAct=EBI-985324, EBI-748974;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12954646,
CC       ECO:0000269|PubMed:16103110, ECO:0000269|PubMed:17635916,
CC       ECO:0000269|PubMed:20197547, ECO:0000269|PubMed:29615132}. Nucleus
CC       {ECO:0000269|PubMed:12954646, ECO:0000269|PubMed:16103110,
CC       ECO:0000269|PubMed:17635916, ECO:0000269|PubMed:19729656,
CC       ECO:0000269|PubMed:20197547, ECO:0000269|PubMed:29615132}. Endoplasmic
CC       reticulum {ECO:0000250|UniProtKB:Q9JIA7}. Mitochondrion inner membrane
CC       {ECO:0000250|UniProtKB:Q9JIA7}. Note=In nucleus, located in nucleosomes
CC       where it associates with core histone proteins such as histone 3
CC       (PubMed:19729656). In brains of patients with Alzheimer's disease, may
CC       be preferentially localized in the nucleus. Cytosolic expression
CC       decrease correlates with the density of amyloid deposits
CC       (PubMed:29615132). In apoptotic cells, colocalizes with CASP1 in cell
CC       membrane where is cleaved and released from cells in an active form
CC       (PubMed:20197547). {ECO:0000269|PubMed:19729656,
CC       ECO:0000269|PubMed:20197547, ECO:0000269|PubMed:29615132}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 2]: Lysosome membrane
CC       {ECO:0000269|PubMed:17897319}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=5;
CC         Comment=Experimental confirmation may be lacking for some isoforms.;
CC       Name=1; Synonyms=SK2B, SK2-L {ECO:0000303|PubMed:16103110};
CC         IsoId=Q9NRA0-1; Sequence=Displayed;
CC       Name=2; Synonyms=SK2A, SK2-S {ECO:0000303|PubMed:16103110};
CC         IsoId=Q9NRA0-2; Sequence=VSP_006217;
CC       Name=3;
CC         IsoId=Q9NRA0-3; Sequence=VSP_006217, VSP_006218;
CC       Name=4;
CC         IsoId=Q9NRA0-4; Sequence=VSP_046910;
CC       Name=5;
CC         IsoId=Q9NRA0-5; Sequence=VSP_047721, VSP_047722;
CC   -!- TISSUE SPECIFICITY: Mainly expressed in adult kidney, liver, and brain
CC       (PubMed:10751414). Expressed in cerebral cortex and hippocampus (at
CC       protein level) (PubMed:29615132). Isoform 1 is the predominant form
CC       expressed in most tissues (PubMed:16103110).
CC       {ECO:0000269|PubMed:10751414, ECO:0000269|PubMed:16103110,
CC       ECO:0000269|PubMed:29615132}.
CC   -!- PTM: Phosphorylated by PKD on Ser-419 and Ser-421 upon PMA treatment.
CC       Phosphorylation induces export from the nucleus to the cytoplasm
CC       (PubMed:17635916). Phosphorylated by MAPK1 and MAPK2 at Ser-387 and
CC       Thr-614, phosphorylation is induced by agonists such as EGF and PMA and
CC       increases kinase activity (PubMed:17311928).
CC       {ECO:0000269|PubMed:17311928, ECO:0000269|PubMed:17635916}.
CC   -!- PTM: Cleaved by CASP1 in apoptotic cells. The truncated form is
CC       released from cells. {ECO:0000269|PubMed:20197547}.
CC   -!- DISEASE: Note=In patients with Alzheimer's disease brains, may be
CC       preferentially localized in the nucleus. Cytosolic expression decrease
CC       correlates with the density of amyloid deposits.
CC       {ECO:0000269|PubMed:29615132}.
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DR   EMBL; AF245447; AAF74124.1; -; mRNA.
DR   EMBL; EF107108; ABK81123.1; -; mRNA.
DR   EMBL; AL136701; CAB66636.1; -; mRNA.
DR   EMBL; AK000599; BAA91280.1; -; mRNA.
DR   EMBL; AK300541; BAG62249.1; -; mRNA.
DR   EMBL; AC022154; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC006161; AAH06161.1; -; mRNA.
DR   EMBL; BC010671; AAH10671.1; -; mRNA.
DR   CCDS; CCDS12727.1; -. [Q9NRA0-1]
DR   CCDS; CCDS59404.1; -. [Q9NRA0-4]
DR   CCDS; CCDS59405.1; -. [Q9NRA0-2]
DR   RefSeq; NP_001191087.1; NM_001204158.3. [Q9NRA0-4]
DR   RefSeq; NP_001191088.1; NM_001204159.3. [Q9NRA0-1]
DR   RefSeq; NP_001191089.1; NM_001204160.3. [Q9NRA0-2]
DR   RefSeq; NP_064511.2; NM_020126.4. [Q9NRA0-1]
DR   AlphaFoldDB; Q9NRA0; -.
DR   SMR; Q9NRA0; -.
DR   BioGRID; 121208; 23.
DR   FunCoup; Q9NRA0; 3003.
DR   IntAct; Q9NRA0; 12.
DR   STRING; 9606.ENSP00000469158; -.
DR   BindingDB; Q9NRA0; -.
DR   ChEMBL; CHEMBL3023; -.
DR   DrugBank; DB12764; Opaganib.
DR   GuidetoPHARMACOLOGY; 2205; -.
DR   SwissLipids; SLP:000000112; -.
DR   GlyGen; Q9NRA0; 2 sites.
DR   iPTMnet; Q9NRA0; -.
DR   PhosphoSitePlus; Q9NRA0; -.
DR   SwissPalm; Q9NRA0; -.
DR   BioMuta; SPHK2; -.
DR   DMDM; 22001996; -.
DR   jPOST; Q9NRA0; -.
DR   MassIVE; Q9NRA0; -.
DR   PaxDb; 9606-ENSP00000245222; -.
DR   PeptideAtlas; Q9NRA0; -.
DR   ProteomicsDB; 82315; -. [Q9NRA0-1]
DR   ProteomicsDB; 82316; -. [Q9NRA0-2]
DR   ProteomicsDB; 82317; -. [Q9NRA0-3]
DR   ProteomicsDB; 86; -.
DR   Pumba; Q9NRA0; -.
DR   Antibodypedia; 31745; 448 antibodies from 37 providers.
DR   DNASU; 56848; -.
DR   Ensembl; ENST00000245222.9; ENSP00000245222.3; ENSG00000063176.17. [Q9NRA0-1]
DR   Ensembl; ENST00000598088.5; ENSP00000469158.1; ENSG00000063176.17. [Q9NRA0-1]
DR   Ensembl; ENST00000599748.5; ENSP00000471205.1; ENSG00000063176.17. [Q9NRA0-2]
DR   Ensembl; ENST00000600537.5; ENSP00000470092.1; ENSG00000063176.17. [Q9NRA0-4]
DR   GeneID; 56848; -.
DR   KEGG; hsa:56848; -.
DR   MANE-Select; ENST00000245222.9; ENSP00000245222.3; NM_020126.5; NP_064511.2.
DR   UCSC; uc002pjr.4; human. [Q9NRA0-1]
DR   AGR; HGNC:18859; -.
DR   ClinPGx; PA38719; -.
DR   CTD; 56848; -.
DR   DisGeNET; 56848; -.
DR   GeneCards; SPHK2; -.
DR   HGNC; HGNC:18859; SPHK2.
DR   HPA; ENSG00000063176; Low tissue specificity.
DR   MIM; 607092; gene.
DR   OpenTargets; ENSG00000063176; -.
DR   VEuPathDB; HostDB:ENSG00000063176; -.
DR   eggNOG; KOG1116; Eukaryota.
DR   GeneTree; ENSGT00940000161197; -.
DR   HOGENOM; CLU_013399_1_1_1; -.
DR   InParanoid; Q9NRA0; -.
DR   OMA; KHYVMYS; -.
DR   OrthoDB; 3853857at2759; -.
DR   PAN-GO; Q9NRA0; 9 GO annotations based on evolutionary models.
DR   PhylomeDB; Q9NRA0; -.
DR   BRENDA; 2.7.1.91; 2681.
DR   PathwayCommons; Q9NRA0; -.
DR   Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR   SignaLink; Q9NRA0; -.
DR   SIGNOR; Q9NRA0; -.
DR   Agora; ENSG00000063176; -.
DR   BioGRID-ORCS; 56848; 27 hits in 1164 CRISPR screens.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   ChiTaRS; SPHK2; human.
DR   GeneWiki; SPHK2; -.
DR   GenomeRNAi; 56848; -.
DR   Pharos; Q9NRA0; Tchem.
DR   PRO; PR:Q9NRA0; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; Q9NRA0; protein.
DR   Bgee; ENSG00000063176; Expressed in mucosa of transverse colon and 145 other cell types or tissues.
DR   ExpressionAtlas; Q9NRA0; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR   GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0000786; C:nucleosome; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0042393; F:histone binding; IDA:GO_Central.
DR   GO; GO:0001727; F:lipid kinase activity; TAS:Reactome.
DR   GO; GO:0031267; F:small GTPase binding; NAS:UniProtKB.
DR   GO; GO:0008481; F:sphingosine kinase activity; IDA:UniProtKB.
DR   GO; GO:0038036; F:sphingosine-1-phosphate receptor activity; IMP:UniProtKB.
DR   GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR   GO; GO:0007420; P:brain development; IEA:Ensembl.
DR   GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR   GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; IDA:UniProtKB.
DR   GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR   GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR   GO; GO:0030308; P:negative regulation of cell growth; ISS:UniProtKB.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
DR   GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0002720; P:positive regulation of cytokine production involved in immune response; ISS:UniProtKB.
DR   GO; GO:0032736; P:positive regulation of interleukin-13 production; ISS:UniProtKB.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB.
DR   GO; GO:0033008; P:positive regulation of mast cell activation involved in immune response; ISS:UniProtKB.
DR   GO; GO:0043306; P:positive regulation of mast cell degranulation; ISS:UniProtKB.
DR   GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:UniProtKB.
DR   GO; GO:2001169; P:regulation of ATP biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; ISS:UniProtKB.
DR   GO; GO:1904959; P:regulation of cytochrome-c oxidase activity; IMP:UniProtKB.
DR   GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0006669; P:sphinganine-1-phosphate biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:Reactome.
DR   GO; GO:0046512; P:sphingosine biosynthetic process; IMP:UniProtKB.
DR   GO; GO:0006670; P:sphingosine metabolic process; ISS:UniProtKB.
DR   GO; GO:0045815; P:transcription initiation-coupled chromatin remodeling; IDA:UniProtKB.
DR   FunFam; 3.40.50.10330:FF:000005; Sphingosine kinase 2; 1.
DR   Gene3D; 2.60.200.40; -; 1.
DR   Gene3D; 3.40.50.10330; Probable inorganic polyphosphate/atp-NAD kinase, domain 1; 1.
DR   InterPro; IPR017438; ATP-NAD_kinase_N.
DR   InterPro; IPR001206; Diacylglycerol_kinase_cat_dom.
DR   InterPro; IPR050187; Lipid_Phosphate_FormReg.
DR   InterPro; IPR016064; NAD/diacylglycerol_kinase_sf.
DR   InterPro; IPR045540; YegS/DAGK_C.
DR   PANTHER; PTHR12358; SPHINGOSINE KINASE; 1.
DR   PANTHER; PTHR12358:SF40; SPHINGOSINE KINASE 2; 1.
DR   Pfam; PF00781; DAGK_cat; 1.
DR   Pfam; PF19279; YegS_C; 1.
DR   SMART; SM00046; DAGKc; 1.
DR   SUPFAM; SSF111331; NAD kinase/diacylglycerol kinase-like; 1.
DR   PROSITE; PS50146; DAGK; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; ATP-binding; Cytoplasm; Endoplasmic reticulum;
KW   Kinase; Lipid metabolism; Lysosome; Membrane; Mitochondrion;
KW   Mitochondrion inner membrane; Nucleotide-binding; Nucleus; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Transferase.
FT   CHAIN           1..654
FT                   /note="Sphingosine kinase 2"
FT                   /id="PRO_0000181358"
FT   DOMAIN          178..325
FT                   /note="DAGKc"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   REGION          1..175
FT                   /note="Required for binding to sulfatide and
FT                   phosphoinositides and for membrane localizatione"
FT                   /evidence="ECO:0000269|PubMed:19168031"
FT   REGION          1..28
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          400..509
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           122..130
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:Q9JIA7"
FT   MOTIF           416..425
FT                   /note="Nuclear export signal"
FT                   /evidence="ECO:0000269|PubMed:17635916"
FT   COMPBIAS        1..17
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        447..461
FT                   /note="Gly residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        462..482
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        247
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT   BINDING         188..190
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   BINDING         220..224
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   BINDING         245..248
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT   BINDING         252
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   BINDING         277..279
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   BINDING         344
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT   BINDING         351
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   BINDING         357
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   BINDING         622..624
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT   MOD_RES         387
FT                   /note="Phosphoserine; by MAPK"
FT                   /evidence="ECO:0000269|PubMed:17311928,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         393
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9JIA7"
FT   MOD_RES         399
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         419
FT                   /note="Phosphoserine; by PKD"
FT                   /evidence="ECO:0000269|PubMed:17635916"
FT   MOD_RES         421
FT                   /note="Phosphoserine; by PKD"
FT                   /evidence="ECO:0000269|PubMed:17635916"
FT   MOD_RES         477
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         614
FT                   /note="Phosphothreonine; by MAPK"
FT                   /evidence="ECO:0000269|PubMed:17311928"
FT   VAR_SEQ         1..36
FT                   /note="Missing (in isoform 2 and isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:10751414,
FT                   ECO:0000303|PubMed:11230166, ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:15489334"
FT                   /id="VSP_006217"
FT   VAR_SEQ         1..12
FT                   /note="MNGHLEAEEQQD -> MIGCLHARVSGPLWDAGLCPASSRSAHTCLSLSVSD
FT                   APVSPATAPHCLLLSTAPAPPCPCHGVLNSHPFSPPFP (in isoform 5)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_047721"
FT   VAR_SEQ         13..71
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_046910"
FT   VAR_SEQ         292..390
FT                   /note="FEPALGLDLLLNCSLLLCRGGGHPLDLLSVTLASGSRCFSFLSVAWGFVSDV
FT                   DIQSERFRALGSARFTLGTVLGLATLHTYRGRLSYLPATVEPASPTP -> PREDSDSS
FT                   TSSSACPLWTTARSCPRAAASMPGSCPLLPQQLALGFSRFIQDRVNGGGGRIGSLTCRG
FT                   HTQRTLPAPAREGGGSLFLKNINVFICKKKKK (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_006218"
FT   VAR_SEQ         640..654
FT                   /note="GTLLTGPPGCPGREP -> ARGRTQTPALPAAPALYGRQPGAAHGLQPVCQG
FT                   AALFFHNSWLWGSQDLFRIVLTEAVGG (in isoform 5)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_047722"
FT   VARIANT         652
FT                   /note="R -> Q (in dbSNP:rs11881285)"
FT                   /id="VAR_060112"
FT   MUTAGEN         138
FT                   /note="D->A: Abolishes cleavage and secretion in apoptotic
FT                   cells. No effect on kinase activity."
FT                   /evidence="ECO:0000269|PubMed:20197547"
FT   MUTAGEN         212
FT                   /note="G->E: Decreases SPP production in nucleus. Abolishes
FT                   increase of histone acetylation. No effect on association
FT                   with histone 3."
FT                   /evidence="ECO:0000269|PubMed:19729656"
FT   MUTAGEN         220
FT                   /note="T->A: Loss of location to cell membrane. Not
FT                   secreted. No effect on kinase activity."
FT                   /evidence="ECO:0000269|PubMed:20197547"
FT   MUTAGEN         387
FT                   /note="S->A: Strongly reduces phosphorylation levels."
FT                   /evidence="ECO:0000269|PubMed:17311928"
FT   MUTAGEN         419..421
FT                   /note="SVS->AVA: Abolishes nuclear export in response to
FT                   PMA treatment."
FT                   /evidence="ECO:0000269|PubMed:17635916"
FT   MUTAGEN         423..425
FT                   /note="LPL->APA: Abolishes nuclear export."
FT                   /evidence="ECO:0000269|PubMed:17635916"
FT   MUTAGEN         437
FT                   /note="S->A: Reduces phosphorylation levels."
FT                   /evidence="ECO:0000269|PubMed:17311928"
FT   MUTAGEN         466
FT                   /note="S->A: Reduces phosphorylation levels."
FT                   /evidence="ECO:0000269|PubMed:17311928"
FT   MUTAGEN         477
FT                   /note="S->A: Reduces phosphorylation levels."
FT                   /evidence="ECO:0000269|PubMed:17311928"
FT   MUTAGEN         552
FT                   /note="D->A: No effect on cleavage and secretion in
FT                   apoptotic cells. No effect on kinase activity."
FT                   /evidence="ECO:0000269|PubMed:20197547"
FT   MUTAGEN         614
FT                   /note="T->A: Abolishes phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:17311928"
FT   CONFLICT        49
FT                   /note="P -> S (in Ref. 3; CAB66636)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   654 AA;  69217 MW;  F73FFCEC930DA50F CRC64;
     MNGHLEAEEQ QDQRPDQELT GSWGHGPRST LVRAKAMAPP PPPLAASTPL LHGEFGSYPA
     RGPRFALTLT SQALHIQRLR PKPEARPRGG LVPLAEVSGC CTLRSRSPSD SAAYFCIYTY
     PRGRRGARRR ATRTFRADGA ATYEENRAEA QRWATALTCL LRGLPLPGDG EITPDLLPRP
     PRLLLLVNPF GGRGLAWQWC KNHVLPMISE AGLSFNLIQT ERQNHARELV QGLSLSEWDG
     IVTVSGDGLL HEVLNGLLDR PDWEEAVKMP VGILPCGSGN ALAGAVNQHG GFEPALGLDL
     LLNCSLLLCR GGGHPLDLLS VTLASGSRCF SFLSVAWGFV SDVDIQSERF RALGSARFTL
     GTVLGLATLH TYRGRLSYLP ATVEPASPTP AHSLPRAKSE LTLTPDPAPP MAHSPLHRSV
     SDLPLPLPQP ALASPGSPEP LPILSLNGGG PELAGDWGGA GDAPLSPDPL LSSPPGSPKA
     ALHSPVSEGA PVIPPSSGLP LPTPDARVGA STCGPPDHLL PPLGTPLPPD WVTLEGDFVL
     MLAISPSHLG ADLVAAPHAR FDDGLVHLCW VRSGISRAAL LRLFLAMERG SHFSLGCPQL
     GYAAARAFRL EPLTPRGVLT VDGEQVEYGP LQAQMHPGIG TLLTGPPGCP GREP
//
ID   SPTC1_HUMAN             Reviewed;         473 AA.
AC   O15269; A8K681; Q5VWB4; Q96IX6;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1998, sequence version 1.
DT   28-JAN-2026, entry version 218.
DE   RecName: Full=Serine palmitoyltransferase 1;
DE            EC=2.3.1.50 {ECO:0000269|PubMed:19416851};
DE   AltName: Full=Long chain base biosynthesis protein 1;
DE            Short=LCB 1;
DE   AltName: Full=Serine-palmitoyl-CoA transferase 1;
DE            Short=SPT 1;
DE            Short=SPT1;
GN   Name=SPTLC1; Synonyms=LCB1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Kidney;
RX   PubMed=9363775; DOI=10.1111/j.1432-1033.1997.00239.x;
RA   Weiss B., Stoffel W.;
RT   "Human and murine serine-palmitoyl-CoA transferase. Cloning, expression and
RT   characterization of the key enzyme in sphingolipid synthesis.";
RL   Eur. J. Biochem. 249:239-247(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANTS HSAN1A
RP   TRP-133; TYR-133 AND ASP-144.
RX   PubMed=11242114; DOI=10.1038/85879;
RA   Dawkins J.L., Hulme D.J., Brahmbhatt S.B., Auer-Grumbach M.,
RA   Nicholson G.A.;
RT   "Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base
RT   subunit-1, cause hereditary sensory neuropathy type I.";
RL   Nat. Genet. 27:309-312(2001).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Placenta;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164053; DOI=10.1038/nature02465;
RA   Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA   Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA   Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA   Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA   Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA   Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA   Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA   Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA   Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA   Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA   Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA   Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA   Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA   Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA   Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA   Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA   Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA   McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA   Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA   Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA   Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA   Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA   West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA   Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA   Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA   Dunham I.;
RT   "DNA sequence and analysis of human chromosome 9.";
RL   Nature 429:369-374(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   TISSUE SPECIFICITY.
RX   PubMed=17023427; DOI=10.1074/jbc.m608066200;
RA   Hornemann T., Richard S., Ruetti M.F., Wei Y., von Eckardstein A.;
RT   "Cloning and initial characterization of a new subunit for mammalian
RT   serine-palmitoyltransferase.";
RL   J. Biol. Chem. 281:37275-37281(2006).
RN   [8]
RP   FUNCTION.
RX   PubMed=19648650; DOI=10.1074/jbc.m109.023192;
RA   Hornemann T., Penno A., Ruetti M.F., Ernst D., Kivrak-Pfiffner F.,
RA   Rohrer L., von Eckardstein A.;
RT   "The SPTLC3 subunit of serine palmitoyltransferase generates short chain
RT   sphingoid bases.";
RL   J. Biol. Chem. 284:26322-26330(2009).
RN   [9]
RP   FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE SPT COMPLEX, AND
RP   INTERACTION WITH SPTSSA AND SPTSSB.
RX   PubMed=19416851; DOI=10.1073/pnas.0811269106;
RA   Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P., Eichler F.,
RA   Brown R.H. Jr., Harmon J.M., Dunn T.M.;
RT   "Identification of small subunits of mammalian serine palmitoyltransferase
RT   that confer distinct acyl-CoA substrate specificities.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:8186-8191(2009).
RN   [10]
RP   BIOPHYSICOCHEMICAL PROPERTIES, AND CHARACTERIZATION OF VARIANT HSAN1A
RP   TRP-133.
RX   PubMed=20504773; DOI=10.1074/jbc.m110.122259;
RA   Gable K., Gupta S.D., Han G., Niranjanakumari S., Harmon J.M., Dunn T.M.;
RT   "A disease-causing mutation in the active site of serine
RT   palmitoyltransferase causes catalytic promiscuity.";
RL   J. Biol. Chem. 285:22846-22852(2010).
RN   [11]
RP   INTERACTION WITH ORMDL3.
RX   PubMed=20182505; DOI=10.1038/nature08787;
RA   Breslow D.K., Collins S.R., Bodenmiller B., Aebersold R., Simons K.,
RA   Shevchenko A., Ejsing C.S., Weissman J.S.;
RT   "Orm family proteins mediate sphingolipid homeostasis.";
RL   Nature 463:1048-1053(2010).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [13]
RP   INDUCTION IN ALZHEIMER DISEASE.
RX   PubMed=21994399; DOI=10.1523/jneurosci.3883-11.2011;
RA   Geekiyanage H., Chan C.;
RT   "MicroRNA-137/181c regulates serine palmitoyltransferase and in turn
RT   amyloid beta, novel targets in sporadic Alzheimer's disease.";
RL   J. Neurosci. 31:14820-14830(2011).
RN   [14]
RP   PHOSPHORYLATION AT TYR-164, AND MUTAGENESIS OF TYR-164.
RX   PubMed=23629659; DOI=10.1074/jbc.m112.409185;
RA   Taouji S., Higa A., Delom F., Palcy S., Mahon F.X., Pasquet J.M., Bosse R.,
RA   Segui B., Chevet E.;
RT   "Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on
RT   tyrosine 164 inhibits its activity and promotes cell survival.";
RL   J. Biol. Chem. 288:17190-17201(2013).
RN   [15]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [16]
RP   REGULATION OF SPT COMPLEX ACTIVITY BY ORMDL PROTEINS IN THE PRESENCE OF
RP   CERAMIDES.
RX   PubMed=30700557; DOI=10.1074/jbc.ra118.007291;
RA   Davis D.L., Gable K., Suemitsu J., Dunn T.M., Wattenberg B.W.;
RT   "The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly
RT   regulated by ceramide: Reconstitution of SPT regulation in isolated
RT   membranes.";
RL   J. Biol. Chem. 294:5146-5156(2019).
RN   [17]
RP   FUNCTION.
RX   PubMed=36170811; DOI=10.1016/j.celrep.2022.111415;
RA   Spears M.E., Lee N., Hwang S., Park S.J., Carlisle A.E., Li R., Doshi M.B.,
RA   Armando A.M., Gao J., Simin K., Zhu L.J., Greer P.L., Quehenberger O.,
RA   Torres E.M., Kim D.;
RT   "De novo sphingolipid biosynthesis necessitates detoxification in cancer
RT   cells.";
RL   Cell Rep. 40:111415-111415(2022).
RN   [18] {ECO:0007744|PDB:7K0I, ECO:0007744|PDB:7K0J, ECO:0007744|PDB:7K0K, ECO:0007744|PDB:7K0L, ECO:0007744|PDB:7K0M, ECO:0007744|PDB:7K0N, ECO:0007744|PDB:7K0O, ECO:0007744|PDB:7K0P, ECO:0007744|PDB:7K0Q}
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) IN COMPLEX WITH SPTLC2;
RP   SPTSSA AND ORMDL3, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=33558761; DOI=10.1038/s41594-020-00551-9;
RA   Wang Y., Niu Y., Zhang Z., Gable K., Gupta S.D., Somashekarappa N., Han G.,
RA   Zhao H., Myasnikov A.G., Kalathur R.C., Dunn T.M., Lee C.H.;
RT   "Structural insights into the regulation of human serine
RT   palmitoyltransferase complexes.";
RL   Nat. Struct. Mol. Biol. 28:240-248(2021).
RN   [19] {ECO:0007744|PDB:6M4N, ECO:0007744|PDB:6M4O, ECO:0007744|PDB:7CQI, ECO:0007744|PDB:7CQK}
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) IN COMPLEX WITH SPTLC2;
RP   SPTSSA AND ORMDL3, FUNCTION, AND MUTAGENESIS OF PHE-138; PHE-337 AND
RP   SER-338.
RX   PubMed=33558762; DOI=10.1038/s41594-020-00553-7;
RA   Li S., Xie T., Liu P., Wang L., Gong X.;
RT   "Structural insights into the assembly and substrate selectivity of human
RT   SPT-ORMDL3 complex.";
RL   Nat. Struct. Mol. Biol. 28:249-257(2021).
RN   [20] {ECO:0007744|PDB:7YIU, ECO:0007744|PDB:7YIY, ECO:0007744|PDB:7YJ1, ECO:0007744|PDB:7YJ2}
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) IN COMPLEX WITH SPTLC2;
RP   SPTSSA AND ORMDL3, CHARACTERIZATION OF VARIANTS ALS27 PHE-23; LEU-39 DEL
RP   AND 40-PHE-SER-41 DEL, AND ACTIVITY REGULATION.
RX   PubMed=37308477; DOI=10.1038/s41467-023-39274-y;
RA   Xie T., Liu P., Wu X., Dong F., Zhang Z., Yue J., Mahawar U., Farooq F.,
RA   Vohra H., Fang Q., Liu W., Wattenberg B.W., Gong X.;
RT   "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid
RT   homeostasis.";
RL   Nat. Commun. 14:3475-3475(2023).
RN   [21]
RP   VARIANT ALA-387.
RX   PubMed=15037712; DOI=10.1212/01.wnl.0000115388.10828.5c;
RA   Verhoeven K., Coen K., De Vriendt E., Jacobs A., Van Gerwen V., Smouts I.,
RA   Pou-Serradell A., Martin J.-J., Timmerman V., De Jonghe P.;
RT   "SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type
RT   I.";
RL   Neurology 62:1001-1002(2004).
RN   [22]
RP   VARIANT LEU-151.
RX   PubMed=17060578; DOI=10.1212/01.wnl.0000240068.21499.f5;
RA   Meggouh F., Bienfait H.M.E., Weterman M.A.J., de Visser M., Baas F.;
RT   "Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene.";
RL   Neurology 67:1476-1478(2006).
RN   [23]
RP   VARIANT [LARGE SCALE ANALYSIS] TRP-239.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
RN   [24]
RP   VARIANTS HSAN1A PHE-331 AND VAL-352, AND VARIANT ALA-387.
RX   PubMed=19651702; DOI=10.1093/brain/awp198;
RA   Rotthier A., Baets J., De Vriendt E., Jacobs A., Auer-Grumbach M., Levy N.,
RA   Bonello-Palot N., Kilic S.S., Weis J., Nascimento A., Swinkels M.,
RA   Kruyt M.C., Jordanova A., De Jonghe P., Timmerman V.;
RT   "Genes for hereditary sensory and autonomic neuropathies: a genotype-
RT   phenotype correlation.";
RL   Brain 132:2699-2711(2009).
RN   [25]
RP   CHARACTERIZATION OF VARIANTS HSAN1A TYR-133; TRP-133 AND ASP-144,
RP   CHARACTERIZATION OF VARIANT ALA-387, LACK OF ASSOCIATION OF VARIANT ALA-387
RP   WITH HSAN1A, AND INTERACTION WITH SPTLC2.
RX   PubMed=19132419; DOI=10.1007/s10048-008-0168-7;
RA   Hornemann T., Penno A., Richard S., Nicholson G., van Dijk F.S.,
RA   Rotthier A., Timmerman V., von Eckardstein A.;
RT   "A systematic comparison of all mutations in hereditary sensory neuropathy
RT   type I (HSAN I) reveals that the G387A mutation is not disease
RT   associated.";
RL   Neurogenetics 10:135-143(2009).
RN   [26]
RP   VARIANT HSAN1A PHE-331, CHARACTERIZATION OF VARIANTS HSAN1A TRP-133;
RP   PHE-331 AND VAL-352, AND SUBCELLULAR LOCATION.
RX   PubMed=21618344; DOI=10.1002/humu.21481;
RA   Rotthier A., Penno A., Rautenstrauss B., Auer-Grumbach M., Stettner G.M.,
RA   Asselbergh B., Van Hoof K., Sticht H., Levy N., Timmerman V., Hornemann T.,
RA   Janssens K.;
RT   "Characterization of two mutations in the SPTLC1 subunit of serine
RT   palmitoyltransferase associated with hereditary sensory and autonomic
RT   neuropathy type I.";
RL   Hum. Mutat. 32:E2211-E2225(2011).
RN   [27]
RP   VARIANT HSAN1A TRP-133, AND VARIANT GLY-310.
RX   PubMed=22302274; DOI=10.1007/s00415-011-6397-y;
RA   Davidson G.L., Murphy S.M., Polke J.M., Laura M., Salih M.A., Muntoni F.,
RA   Blake J., Brandner S., Davies N., Horvath R., Price S., Donaghy M.,
RA   Roberts M., Foulds N., Ramdharry G., Soler D., Lunn M.P., Manji H.,
RA   Davis M.B., Houlden H., Reilly M.M.;
RT   "Frequency of mutations in the genes associated with hereditary sensory and
RT   autonomic neuropathy in a UK cohort.";
RL   J. Neurol. 259:1673-1685(2012).
RN   [28]
RP   INVOLVEMENT IN HSAN1A, VARIANT HSAN1A TYR-331, AND CHARACTERIZATION OF
RP   VARIANT HSAN1A TYR-331.
RX   PubMed=23454272; DOI=10.1016/j.ejmg.2013.02.002;
RA   Auer-Grumbach M., Bode H., Pieber T.R., Schabhuettl M., Fischer D.,
RA   Seidl R., Graf E., Wieland T., Schuh R., Vacariu G., Grill F.,
RA   Timmerman V., Strom T.M., Hornemann T.;
RT   "Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a
RT   distinct syndromic phenotype.";
RL   Eur. J. Med. Genet. 56:266-269(2013).
RN   [29]
RP   VARIANT HSAN1A PHE-331.
RX   PubMed=24247255; DOI=10.3892/mmr.2013.1808;
RA   Suh B.C., Hong Y.B., Nakhro K., Nam S.H., Chung K.W., Choi B.O.;
RT   "Early-onset severe hereditary sensory and autonomic neuropathy type 1 with
RT   S331F SPTLC1 mutation.";
RL   Mol. Med. Report. 9:481-486(2014).
RN   [30]
RP   VARIANT HSAN1A ASP-144.
RX   PubMed=30420926; DOI=10.1155/2018/1898151;
RA   Ho K.W.D., Jerath N.U.;
RT   "V144D Mutation of SPTLC1 Can Present with Both Painful and Painless
RT   Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I.";
RL   Case Rep. Genet. 2018:1898151-1898151(2018).
RN   [31]
RP   INVOLVEMENT IN ALS27, AND VARIANTS ALS27 SER-20; LEU-39 DEL AND TYR-331.
RX   PubMed=34459874; DOI=10.1001/jamaneurol.2021.2598;
RG   FALS Sequencing Consortium;
RG   American Genome Center;
RG   International ALS Genomics Consortium;
RG   and ITALSGEN Consortium;
RA   Johnson J.O., Chia R., Miller D.E., Li R., Kumaran R., Abramzon Y.,
RA   Alahmady N., Renton A.E., Topp S.D., Gibbs J.R., Cookson M.R., Sabir M.S.,
RA   Dalgard C.L., Troakes C., Jones A.R., Shatunov A., Iacoangeli A.,
RA   Al Khleifat A., Ticozzi N., Silani V., Gellera C., Blair I.P.,
RA   Dobson-Stone C., Kwok J.B., Bonkowski E.S., Palvadeau R., Tienari P.J.,
RA   Morrison K.E., Shaw P.J., Al-Chalabi A., Brown R.H. Jr., Calvo A., Mora G.,
RA   Al-Saif H., Gotkine M., Leigh F., Chang I.J., Perlman S.J., Glass I.,
RA   Scott A.I., Shaw C.E., Basak A.N., Landers J.E., Chio A., Crawford T.O.,
RA   Smith B.N., Traynor B.J., Smith B.N., Ticozzi N., Fallini C., Gkazi A.S.,
RA   Topp S.D., Scotter E.L., Kenna K.P., Keagle P., Tiloca C., Vance C.,
RA   Troakes C., Colombrita C., King A., Pensato V., Castellotti B., Baas F.,
RA   Ten Asbroek A.L.M.A., McKenna-Yasek D., McLaughlin R.L., Polak M.,
RA   Asress S., Esteban-Perez J., Stevic Z., D'Alfonso S., Mazzini L.,
RA   Comi G.P., Del Bo R., Ceroni M., Gagliardi S., Querin G., Bertolin C.,
RA   van Rheenen W., Rademakers R., van Blitterswijk M., Lauria G., Duga S.,
RA   Corti S., Cereda C., Corrado L., Soraru G., Williams K.L., Nicholson G.A.,
RA   Blair I.P., Leblond-Manry C., Rouleau G.A., Hardiman O., Morrison K.E.,
RA   Veldink J.H., van den Berg L.H., Al-Chalabi A., Pall H., Shaw P.J.,
RA   Turner M.R., Talbot K., Taroni F., Garcia-Redondo A., Wu Z., Glass J.D.,
RA   Gellera C., Ratti A., Brown R.H. Jr., Silani V., Shaw C.E., Landers J.E.,
RA   Dalgard C.L., Adeleye A., Soltis A.R., Alba C., Viollet C., Bacikova D.,
RA   Hupalo D.N., Sukumar G., Pollard H.B., Wilkerson M.D., Martinez E.M.,
RA   Abramzon Y., Ahmed S., Arepalli S., Baloh R.H., Bowser R., Brady C.B.,
RA   Brice A., Broach J., Campbell R.H., Camu W., Chia R., Cooper-Knock J.,
RA   Ding J., Drepper C., Drory V.E., Dunckley T.L., Eicher J.D., England B.K.,
RA   Faghri F., Feldman E., Floeter M.K., Fratta P., Geiger J.T., Gerhard G.,
RA   Gibbs J.R., Gibson S.B., Glass J.D., Hardy J., Harms M.B.,
RA   Heiman-Patterson T.D., Hernandez D.G., Jansson L., Kirby J., Kowall N.W.,
RA   Laaksovirta H., Landeck N., Landi F., Le Ber I., Lumbroso S.,
RA   MacGowan D.J.L., Maragakis N.J., Mora G., Mouzat K., Murphy N.A.,
RA   Myllykangas L., Nalls M.A., Orrell R.W., Ostrow L.W., Pamphlett R.,
RA   Pickering-Brown S., Pioro E.P., Pletnikova O., Pliner H.A., Pulst S.M.,
RA   Ravits J.M., Renton A.E., Rivera A., Robberecht W., Rogaeva E.,
RA   Rollinson S., Rothstein J.D., Scholz S.W., Sendtner M., Shaw P.J.,
RA   Sidle K.C., Simmons Z., Singleton A.B., Smith N., Stone D.J., Tienari P.J.,
RA   Troncoso J.C., Valori M., Van Damme P., Van Deerlin V.M., Van Den Bosch L.,
RA   Zinman L., Landers J.E., Chio A., Traynor B.J., Angelocola S.M.,
RA   Ausiello F.P., Barberis M., Bartolomei I., Battistini S., Bersano E.,
RA   Bisogni G., Borghero G., Brunetti M., Cabona C., Calvo A., Canale F.,
RA   Canosa A., Cantisani T.A., Capasso M., Caponnetto C., Cardinali P.,
RA   Carrera P., Casale F., Chio A., Colletti T., Conforti F.L., Conte A.,
RA   Conti E., Corbo M., Cuccu S., Dalla Bella E., D'Errico E., DeMarco G.,
RA   Dubbioso R., Ferrarese C., Ferraro P.M., Filippi M., Fini N., Floris G.,
RA   Fuda G., Gallone S., Gianferrari G., Giannini F., Grassano M., Greco L.,
RA   Iazzolino B., Introna A., La Bella V., Lattante S., Lauria G., Liguori R.,
RA   Logroscino G., Logullo F.O., Lunetta C., Mandich P., Mandrioli J.,
RA   Manera U., Manganelli F., Marangi G., Marinou K., Marrosu M.G.,
RA   Martinelli I., Messina S., Moglia C., Mora G., Mosca L., Murru M.R.,
RA   Origone P., Passaniti C., Petrelli C., Petrucci A., Pozzi S., Pugliatti M.,
RA   Quattrini A., Ricci C., Riolo G., Riva N., Russo M., Sabatelli M.,
RA   Salamone P., Salivetto M., Salvi F., Santarelli M., Sbaiz L., Sideri R.,
RA   Simone I., Simonini C., Spataro R., Tanel R., Tedeschi G., Ticca A.,
RA   Torriello A., Tranquilli S., Tremolizzo L., Trojsi F., Vasta R.,
RA   Vacchiano V., Vita G., Volanti P., Zollino M., Zucchi E.;
RT   "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic
RT   Lateral Sclerosis.";
RL   JAMA Neurol. 78:1236-1248(2021).
RN   [32]
RP   INVOLVEMENT IN ALS27, VARIANTS ALS27 SER-20; PHE-23; LEU-39 DEL AND
RP   40-PHE-SER-41 DEL, CHARACTERIZATION OF VARIANTS ALS27 SER-20; PHE-23;
RP   LEU-39 DEL AND 40-PHE-SER-41 DEL, AND HOMEOSTATIC REGULATION BY ORMDL3 IN
RP   THE PRESENCE OF CERAMIDES.
RX   PubMed=34059824; DOI=10.1038/s41591-021-01346-1;
RA   Mohassel P., Donkervoort S., Lone M.A., Nalls M., Gable K., Gupta S.D.,
RA   Foley A.R., Hu Y., Saute J.A.M., Moreira A.L., Kok F., Introna A.,
RA   Logroscino G., Grunseich C., Nickolls A.R., Pourshafie N., Neuhaus S.B.,
RA   Saade D., Gangfuss A., Koelbel H., Piccus Z., Le Pichon C.E., Fiorillo C.,
RA   Ly C.V., Toepf A., Brady L., Specht S., Zidell A., Pedro H., Mittelmann E.,
RA   Thomas F.P., Chao K.R., Konersman C.G., Cho M.T., Brandt T., Straub V.,
RA   Connolly A.M., Schara U., Roos A., Tarnopolsky M., Hoeke A., Brown R.H.,
RA   Lee C.H., Hornemann T., Dunn T.M., Boennemann C.G.;
RT   "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid
RT   synthesis.";
RL   Nat. Med. 27:1197-1204(2021).
RN   [33]
RP   INVOLVEMENT IN ALS27, AND VARIANT ALS27 ARG-38.
RX   PubMed=36204986; DOI=10.1080/21678421.2022.2096409;
RA   Liu X., He J., Yu W., Fan D.;
RT   "A de novo c.113 T > C: p.L38R mutation of SPTLC1: case report of a girl
RT   with sporadic juvenile amyotrophic lateral sclerosis.";
RL   Amyotroph. Lateral Scler. Frontotemporal Degener. 23:634-637(2022).
CC   -!- FUNCTION: Component of the serine palmitoyltransferase multisubunit
CC       enzyme (SPT) that catalyzes the initial and rate-limiting step in
CC       sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA
CC       (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex
CC       is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this
CC       complex, the heterodimer with SPTLC2 or SPTLC3 forms the catalytic core
CC       (PubMed:19416851, PubMed:33558762, PubMed:36170811). The composition of
CC       the serine palmitoyltransferase (SPT) complex determines the substrate
CC       preference (PubMed:19416851, PubMed:33558762). The SPTLC1-SPTLC2-SPTSSA
CC       complex shows a strong preference for C16-CoA substrate, while the
CC       SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as
CC       substrates, with a slight preference for C14-CoA (PubMed:19416851,
CC       PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong
CC       preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB
CC       isozyme displays an ability to use a broader range of acyl-CoAs,
CC       without apparent preference (PubMed:19416851, PubMed:19648650,
CC       PubMed:33558761, PubMed:33558762). Required for adipocyte cell
CC       viability and metabolic homeostasis (By similarity).
CC       {ECO:0000250|UniProtKB:O35704, ECO:0000269|PubMed:19416851,
CC       ECO:0000269|PubMed:19648650, ECO:0000269|PubMed:33558761,
CC       ECO:0000269|PubMed:33558762, ECO:0000269|PubMed:36170811}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-serine + hexadecanoyl-CoA + H(+) = 3-oxosphinganine + CO2 +
CC         CoA; Xref=Rhea:RHEA:14761, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC         ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379,
CC         ChEBI:CHEBI:58299; EC=2.3.1.50;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14762;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=octadecanoyl-CoA + L-serine + H(+) = 3-oxoeicosasphinganine +
CC         CO2 + CoA; Xref=Rhea:RHEA:33683, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57394, ChEBI:CHEBI:65073;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33684;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=tetradecanoyl-CoA + L-serine + H(+) = 3-oxohexadecasphinganine
CC         + CO2 + CoA; Xref=Rhea:RHEA:35675, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57385, ChEBI:CHEBI:71007;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35676;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=dodecanoyl-CoA + L-serine + H(+) = 3-oxotetradecasphinganine +
CC         CO2 + CoA; Xref=Rhea:RHEA:35679, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57375, ChEBI:CHEBI:71008;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35680;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC   -!- COFACTOR:
CC       Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
CC         Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: SPT complex catalytic activity is negatively
CC       regulated by ORMDL proteins, including ORMDL3, in the presence of
CC       ceramides (PubMed:37308477). This mechanism allows to maintain ceramide
CC       levels at sufficient concentrations for the production of complex
CC       sphingolipids, but which prevents the accumulation of ceramides to
CC       levels that trigger apoptosis (Probable). {ECO:0000269|PubMed:37308477,
CC       ECO:0000305}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.75 mM for L-serine {ECO:0000269|PubMed:20504773};
CC         KM=0.3 mM for L-serine {ECO:0000269|PubMed:33558761};
CC         Vmax=1350 pmol/min/mg enzyme {ECO:0000269|PubMed:20504773};
CC   -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC       {ECO:0000269|PubMed:19416851}.
CC   -!- SUBUNIT: Component of the serine palmitoyltransferase (SPT) complex,
CC       which is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB
CC       (PubMed:19132419, PubMed:19416851, PubMed:33558761, PubMed:33558762,
CC       PubMed:37308477). The heterodimer consisting of SPTLC1 and
CC       SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or
CC       SPTSSB subunits determine substrate specificity (PubMed:33558762,
CC       PubMed:37308477). SPT also interacts with ORMDL proteins, especially
CC       ORMDL3, which negatively regulate SPT activity in the presence of
CC       ceramides (PubMed:20182505, PubMed:30700557, PubMed:33558762,
CC       PubMed:34059824, PubMed:37308477). Forms dimers of heterodimers with
CC       SPTLC2 (PubMed:33558761, PubMed:33558762). Interacts with RTN4 (isoform
CC       B) (By similarity). {ECO:0000250|UniProtKB:O35704,
CC       ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19416851,
CC       ECO:0000269|PubMed:20182505, ECO:0000269|PubMed:30700557,
CC       ECO:0000269|PubMed:33558761, ECO:0000269|PubMed:33558762,
CC       ECO:0000269|PubMed:34059824, ECO:0000269|PubMed:37308477}.
CC   -!- INTERACTION:
CC       O15269; Q8N138: ORMDL3; NbExp=6; IntAct=EBI-1044323, EBI-721750;
CC       O15269; O15270: SPTLC2; NbExp=5; IntAct=EBI-1044323, EBI-766136;
CC       O15269; Q9NUV7: SPTLC3; NbExp=3; IntAct=EBI-1044323, EBI-11614219;
CC       O15269; Q969W0: SPTSSA; NbExp=3; IntAct=EBI-1044323, EBI-723396;
CC       O15269-2; Q86SG2: ANKRD23; NbExp=3; IntAct=EBI-25912901, EBI-5661893;
CC       O15269-2; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-25912901, EBI-12891828;
CC       O15269-2; Q8IYM2: SLFN12; NbExp=3; IntAct=EBI-25912901, EBI-2822550;
CC       O15269-2; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-25912901, EBI-3942425;
CC       O15269-2; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-25912901, EBI-357085;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:21618344}; Single-pass membrane protein
CC       {ECO:0000250|UniProtKB:O35704}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=O15269-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O15269-2; Sequence=VSP_043127, VSP_043128;
CC   -!- TISSUE SPECIFICITY: Widely expressed. Not detected in small intestine.
CC       {ECO:0000269|PubMed:17023427}.
CC   -!- INDUCTION: Expression at protein level is highly increased in brains of
CC       patients with Alzheimer disease. No changes are observed at mRNA level.
CC       {ECO:0000269|PubMed:21994399}.
CC   -!- DOMAIN: The transmembrane domain is involved in the interaction with
CC       ORMDL3. {ECO:0000269|PubMed:33558762}.
CC   -!- PTM: Phosphorylation at Tyr-164 inhibits activity and promotes cell
CC       survival. {ECO:0000269|PubMed:23629659}.
CC   -!- DISEASE: Amyotrophic lateral sclerosis 27, juvenile (ALS27)
CC       [MIM:620285]: A form of amyotrophic lateral sclerosis, a
CC       neurodegenerative disorder affecting upper motor neurons in the brain
CC       and lower motor neurons in the brain stem and spinal cord, resulting in
CC       fatal paralysis. Sensory abnormalities are absent. The pathologic
CC       hallmarks of the disease include pallor of the corticospinal tract due
CC       to loss of motor neurons, presence of ubiquitin-positive inclusions
CC       within surviving motor neurons, and deposition of pathologic
CC       aggregates. The etiology of amyotrophic lateral sclerosis is likely to
CC       be multifactorial, involving both genetic and environmental factors.
CC       The disease is inherited in 5-10% of the cases. ALS27 is an autosomal
CC       dominant form manifesting as toe walking and gait abnormalities in
CC       early childhood. {ECO:0000269|PubMed:34059824,
CC       ECO:0000269|PubMed:34459874, ECO:0000269|PubMed:36204986,
CC       ECO:0000269|PubMed:37308477}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry. Variants associated with
CC       ALS27 tend to disrupt the normal homeostatic regulation of serine
CC       palmitoyltransferase (SPT) by ORMDL proteins, resulting in up-regulated
CC       SPT activity and elevated levels of canonical SPT products.
CC       {ECO:0000269|PubMed:34059824}.
CC   -!- DISEASE: Neuropathy, hereditary sensory and autonomic, 1A (HSAN1A)
CC       [MIM:162400]: A form of hereditary sensory and autonomic neuropathy, a
CC       genetically and clinically heterogeneous group of disorders
CC       characterized by degeneration of dorsal root and autonomic ganglion
CC       cells, and by prominent sensory abnormalities with a variable degree of
CC       motor and autonomic dysfunction. The neurological phenotype is often
CC       complicated by severe infections, osteomyelitis, and amputations.
CC       HSAN1A is an autosomal dominant axonal form with onset in the second or
CC       third decades. Initial symptoms are loss of pain, touch, heat, and cold
CC       sensation over the feet, followed by distal muscle wasting and
CC       weakness. Loss of pain sensation leads to chronic skin ulcers and
CC       distal amputations. {ECO:0000269|PubMed:11242114,
CC       ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702,
CC       ECO:0000269|PubMed:20504773, ECO:0000269|PubMed:21618344,
CC       ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:23454272,
CC       ECO:0000269|PubMed:24247255, ECO:0000269|PubMed:30420926}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry. Variants associated with HSAN1A tend to increase serine
CC       palmitoyltransferase (SPT) usage of alanine or glycine rather than
CC       serine, resulting in deoxysphingolipid synthesis. Deoxysphingolipids
CC       cannot be efficiently degraded by the cell machinery and cause cell
CC       toxicity. {ECO:0000305|PubMed:34059824}.
CC   -!- SIMILARITY: Belongs to the class-II pyridoxal-phosphate-dependent
CC       aminotransferase family. {ECO:0000305}.
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DR   EMBL; Y08685; CAA69941.1; -; mRNA.
DR   EMBL; AF286717; AAK29328.1; -; Genomic_DNA.
DR   EMBL; AF286703; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286704; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286705; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286706; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286707; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286708; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286709; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286710; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286711; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286712; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286713; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286714; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286715; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AF286716; AAK29328.1; JOINED; Genomic_DNA.
DR   EMBL; AK291546; BAF84235.1; -; mRNA.
DR   EMBL; AL391219; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL354751; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471089; EAW62804.1; -; Genomic_DNA.
DR   EMBL; BC007085; AAH07085.1; -; mRNA.
DR   CCDS; CCDS6692.1; -. [O15269-1]
DR   CCDS; CCDS6693.1; -. [O15269-2]
DR   RefSeq; NP_001268232.1; NM_001281303.1.
DR   RefSeq; NP_006406.1; NM_006415.4. [O15269-1]
DR   RefSeq; NP_847894.1; NM_178324.3. [O15269-2]
DR   PDB; 6M4N; EM; 3.80 A; A/E=1-473.
DR   PDB; 6M4O; EM; 3.40 A; B/S=1-473.
DR   PDB; 7CQI; EM; 3.20 A; C/S=1-473.
DR   PDB; 7CQK; EM; 3.30 A; C/S=1-473.
DR   PDB; 7K0I; EM; 3.30 A; A/D=1-473.
DR   PDB; 7K0J; EM; 3.10 A; A=1-473.
DR   PDB; 7K0K; EM; 2.60 A; A=1-473.
DR   PDB; 7K0L; EM; 3.40 A; A=1-473.
DR   PDB; 7K0M; EM; 2.90 A; A/E=1-473.
DR   PDB; 7K0N; EM; 3.10 A; A/E=1-473.
DR   PDB; 7K0O; EM; 3.10 A; A/E=1-473.
DR   PDB; 7K0P; EM; 3.10 A; A/E=1-473.
DR   PDB; 7K0Q; EM; 3.30 A; A=1-473.
DR   PDB; 7YIU; EM; 2.90 A; A/E=1-473.
DR   PDB; 7YIY; EM; 2.70 A; A/E=1-473.
DR   PDB; 7YJ1; EM; 3.10 A; A/E=1-473.
DR   PDB; 7YJ2; EM; 2.90 A; A/E=1-473.
DR   PDBsum; 6M4N; -.
DR   PDBsum; 6M4O; -.
DR   PDBsum; 7CQI; -.
DR   PDBsum; 7CQK; -.
DR   PDBsum; 7K0I; -.
DR   PDBsum; 7K0J; -.
DR   PDBsum; 7K0K; -.
DR   PDBsum; 7K0L; -.
DR   PDBsum; 7K0M; -.
DR   PDBsum; 7K0N; -.
DR   PDBsum; 7K0O; -.
DR   PDBsum; 7K0P; -.
DR   PDBsum; 7K0Q; -.
DR   PDBsum; 7YIU; -.
DR   PDBsum; 7YIY; -.
DR   PDBsum; 7YJ1; -.
DR   PDBsum; 7YJ2; -.
DR   AlphaFoldDB; O15269; -.
DR   EMDB; EMD-22598; -.
DR   EMDB; EMD-22599; -.
DR   EMDB; EMD-22600; -.
DR   EMDB; EMD-22601; -.
DR   EMDB; EMD-22602; -.
DR   EMDB; EMD-22604; -.
DR   EMDB; EMD-22605; -.
DR   EMDB; EMD-22606; -.
DR   EMDB; EMD-22608; -.
DR   EMDB; EMD-30079; -.
DR   EMDB; EMD-30080; -.
DR   EMDB; EMD-30081; -.
DR   EMDB; EMD-30082; -.
DR   EMDB; EMD-30441; -.
DR   EMDB; EMD-30442; -.
DR   EMDB; EMD-33864; -.
DR   EMDB; EMD-33866; -.
DR   EMDB; EMD-33868; -.
DR   EMDB; EMD-33869; -.
DR   SMR; O15269; -.
DR   BioGRID; 115809; 198.
DR   ComplexPortal; CPX-6663; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSA variant.
DR   ComplexPortal; CPX-6664; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSB variant.
DR   ComplexPortal; CPX-6665; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSA variant.
DR   ComplexPortal; CPX-6681; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSB variant.
DR   CORUM; O15269; -.
DR   DIP; DIP-45626N; -.
DR   FunCoup; O15269; 3163.
DR   IntAct; O15269; 137.
DR   MINT; O15269; -.
DR   STRING; 9606.ENSP00000262554; -.
DR   BindingDB; O15269; -.
DR   ChEMBL; CHEMBL1250343; -.
DR   DrugBank; DB00114; Pyridoxal phosphate.
DR   DrugBank; DB00133; Serine.
DR   GlyGen; O15269; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; O15269; -.
DR   MetOSite; O15269; -.
DR   PhosphoSitePlus; O15269; -.
DR   SwissPalm; O15269; -.
DR   BioMuta; SPTLC1; -.
DR   jPOST; O15269; -.
DR   MassIVE; O15269; -.
DR   PaxDb; 9606-ENSP00000262554; -.
DR   PeptideAtlas; O15269; -.
DR   ProteomicsDB; 48557; -. [O15269-1]
DR   ProteomicsDB; 48558; -. [O15269-2]
DR   Pumba; O15269; -.
DR   Antibodypedia; 2269; 395 antibodies from 37 providers.
DR   DNASU; 10558; -.
DR   Ensembl; ENST00000262554.7; ENSP00000262554.2; ENSG00000090054.17. [O15269-1]
DR   Ensembl; ENST00000337841.4; ENSP00000337635.4; ENSG00000090054.17. [O15269-2]
DR   Ensembl; ENST00000690139.1; ENSP00000510483.1; ENSG00000090054.17. [O15269-2]
DR   GeneID; 10558; -.
DR   KEGG; hsa:10558; -.
DR   MANE-Select; ENST00000262554.7; ENSP00000262554.2; NM_006415.4; NP_006406.1.
DR   UCSC; uc004arl.3; human. [O15269-1]
DR   AGR; HGNC:11277; -.
DR   ClinPGx; PA36106; -.
DR   CTD; 10558; -.
DR   DisGeNET; 10558; -.
DR   GeneCards; SPTLC1; -.
DR   GeneReviews; SPTLC1; -.
DR   HGNC; HGNC:11277; SPTLC1.
DR   HPA; ENSG00000090054; Low tissue specificity.
DR   MalaCards; SPTLC1; -.
DR   MIM; 162400; phenotype.
DR   MIM; 605712; gene.
DR   MIM; 620285; phenotype.
DR   OpenTargets; ENSG00000090054; -.
DR   Orphanet; 36386; Hereditary sensory and autonomic neuropathy type 1.
DR   Orphanet; 300605; Juvenile amyotrophic lateral sclerosis.
DR   VEuPathDB; HostDB:ENSG00000090054; -.
DR   eggNOG; KOG1358; Eukaryota.
DR   GeneTree; ENSGT00550000074872; -.
DR   HOGENOM; CLU_015846_0_1_1; -.
DR   InParanoid; O15269; -.
DR   OMA; LTKYGCG; -.
DR   OrthoDB; 3168162at2759; -.
DR   PAN-GO; O15269; 4 GO annotations based on evolutionary models.
DR   PhylomeDB; O15269; -.
DR   BioCyc; MetaCyc:HS01673-MONOMER; -.
DR   BRENDA; 2.3.1.50; 2681.
DR   PathwayCommons; O15269; -.
DR   Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR   SABIO-RK; O15269; -.
DR   SignaLink; O15269; -.
DR   SIGNOR; O15269; -.
DR   UniPathway; UPA00222; -.
DR   Agora; ENSG00000090054; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 10558; 265 hits in 1179 CRISPR screens.
DR   ChiTaRS; SPTLC1; human.
DR   GeneWiki; SPTLC1; -.
DR   GenomeRNAi; 10558; -.
DR   Pharos; O15269; Tchem.
DR   PRO; PR:O15269; -.
DR   Proteomes; UP000005640; Chromosome 9.
DR   RNAct; O15269; protein.
DR   Bgee; ENSG00000090054; Expressed in esophagus squamous epithelium and 210 other cell types or tissues.
DR   ExpressionAtlas; O15269; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0017059; C:serine palmitoyltransferase complex; IDA:UniProtKB.
DR   GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR   GO; GO:0004758; F:serine C-palmitoyltransferase activity; IDA:UniProtKB.
DR   GO; GO:0046513; P:ceramide biosynthetic process; IDA:MGI.
DR   GO; GO:1904504; P:positive regulation of lipophagy; IDA:MGI.
DR   GO; GO:1904649; P:regulation of fat cell apoptotic process; ISS:UniProtKB.
DR   GO; GO:0046511; P:sphinganine biosynthetic process; IEA:Ensembl.
DR   GO; GO:0030148; P:sphingolipid biosynthetic process; IDA:MGI.
DR   GO; GO:0006665; P:sphingolipid metabolic process; TAS:ProtInc.
DR   GO; GO:0006686; P:sphingomyelin biosynthetic process; IEA:Ensembl.
DR   GO; GO:0046512; P:sphingosine biosynthetic process; IDA:ComplexPortal.
DR   FunFam; 3.40.640.10:FF:000049; serine palmitoyltransferase 1 isoform X1; 1.
DR   Gene3D; 3.90.1150.10; Aspartate Aminotransferase, domain 1; 1.
DR   Gene3D; 3.40.640.10; Type I PLP-dependent aspartate aminotransferase-like (Major domain); 1.
DR   InterPro; IPR004839; Aminotransferase_I/II_large.
DR   InterPro; IPR050087; AON_synthase_class-II.
DR   InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR   InterPro; IPR015421; PyrdxlP-dep_Trfase_major.
DR   InterPro; IPR015422; PyrdxlP-dep_Trfase_small.
DR   PANTHER; PTHR13693; CLASS II AMINOTRANSFERASE/8-AMINO-7-OXONONANOATE SYNTHASE; 1.
DR   PANTHER; PTHR13693:SF2; SERINE PALMITOYLTRANSFERASE 1; 1.
DR   Pfam; PF00155; Aminotran_1_2; 1.
DR   SUPFAM; SSF53383; PLP-dependent transferases; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acyltransferase; Alternative splicing;
KW   Amyotrophic lateral sclerosis; Disease variant; Endoplasmic reticulum;
KW   Lipid metabolism; Membrane; Neurodegeneration; Neuropathy; Phosphoprotein;
KW   Proteomics identification; Pyridoxal phosphate; Reference proteome;
KW   Sphingolipid metabolism; Transferase; Transmembrane; Transmembrane helix.
FT   CHAIN           1..473
FT                   /note="Serine palmitoyltransferase 1"
FT                   /id="PRO_0000163853"
FT   TOPO_DOM        1..15
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        16..36
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        37..473
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          1..66
FT                   /note="Interaction with SPTLC2"
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MOD_RES         164
FT                   /note="Phosphotyrosine; by ABL"
FT                   /evidence="ECO:0000269|PubMed:23629659"
FT   VAR_SEQ         143
FT                   /note="D -> E (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_043127"
FT   VAR_SEQ         144..473
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_043128"
FT   VARIANT         20
FT                   /note="A -> S (in ALS27; the underlying nucleotide
FT                   substitution predominantly results in exon 2 skipping; in
FT                   patient's whole blood sample, only exon 2 deletion was
FT                   observed, but not the missense variant per se; when exon 2
FT                   deletion variant is expressed in induced pluripotent stem
FT                   cells (iPSC) differentiated into motor neuron-like cells,
FT                   increased production of sphinganine and ceramides is
FT                   observed; when exon 2 deletion variant is transfected into
FT                   HEK293 cells, decreased response to inhibition mediated by
FT                   ORMDL3 or ceramide is observed; dbSNP:rs879254294)"
FT                   /evidence="ECO:0000269|PubMed:34059824,
FT                   ECO:0000269|PubMed:34459874"
FT                   /id="VAR_088446"
FT   VARIANT         23
FT                   /note="Y -> F (in ALS27; increased production of
FT                   sphinganine and ceramides, when expressed in induced
FT                   pluripotent stem cells (iPSC) differentiated into motor
FT                   neuron-like cells; decreased response to inhibition
FT                   mediated by ORMDL3 and ceramide; no effect on the
FT                   interaction with ORMDL3; dbSNP:rs1554716504)"
FT                   /evidence="ECO:0000269|PubMed:34059824,
FT                   ECO:0000269|PubMed:37308477"
FT                   /id="VAR_088447"
FT   VARIANT         38
FT                   /note="L -> R (in ALS27; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:36204986"
FT                   /id="VAR_088448"
FT   VARIANT         39
FT                   /note="Missing (in ALS27; increased production of
FT                   sphinganine and ceramides, when expressed in induced
FT                   pluripotent stem cells (iPSC) differentiated into motor
FT                   neuron-like cells; decreased response to inhibition
FT                   mediated by ORMDL3 and ceramide; no effect on the
FT                   interaction with ORMDL3; dbSNP:rs1197928094)"
FT                   /evidence="ECO:0000269|PubMed:34059824,
FT                   ECO:0000269|PubMed:34459874"
FT                   /id="VAR_088449"
FT   VARIANT         40..41
FT                   /note="Missing (in ALS27; increased production of
FT                   sphinganine and ceramides, when expressed in induced
FT                   pluripotent stem cells (iPSC) differentiated into motor
FT                   neuron-like cells; decreased response to inhibition
FT                   mediated by ORMDL3 and ceramide; no effect on the
FT                   interaction with ORMDL3)"
FT                   /evidence="ECO:0000269|PubMed:34059824"
FT                   /id="VAR_088450"
FT   VARIANT         133
FT                   /note="C -> W (in HSAN1A; inactive in the heterodimeric SPT
FT                   complex; largely reduced canonical activity towards serine;
FT                   contrary to wild-type, uses alanine as substrate leading to
FT                   the formation of 1-deoxysphinganine (1-deoxySa); does not
FT                   affect the interaction with SPTLC2; dbSNP:rs119482082)"
FT                   /evidence="ECO:0000269|PubMed:11242114,
FT                   ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:20504773,
FT                   ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:22302274"
FT                   /id="VAR_011392"
FT   VARIANT         133
FT                   /note="C -> Y (in HSAN1A; reduced canonical activity
FT                   towards serine; does not affect the interaction with
FT                   SPTLC2; dbSNP:rs119482081)"
FT                   /evidence="ECO:0000269|PubMed:11242114,
FT                   ECO:0000269|PubMed:19132419"
FT                   /id="VAR_011393"
FT   VARIANT         144
FT                   /note="V -> D (in HSAN1A; reduced canonical activity
FT                   towards serine; does not affect the interaction with
FT                   SPTLC2; dbSNP:rs119482083)"
FT                   /evidence="ECO:0000269|PubMed:11242114,
FT                   ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:30420926"
FT                   /id="VAR_011394"
FT   VARIANT         151
FT                   /note="R -> L (in dbSNP:rs45461899)"
FT                   /evidence="ECO:0000269|PubMed:17060578"
FT                   /id="VAR_037889"
FT   VARIANT         239
FT                   /note="R -> W (in a breast cancer sample; somatic mutation;
FT                   dbSNP:rs542876370)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_036610"
FT   VARIANT         310
FT                   /note="A -> G (found in a patient with HSAN1A; uncertain
FT                   significance; dbSNP:rs768841574)"
FT                   /evidence="ECO:0000269|PubMed:22302274"
FT                   /id="VAR_068476"
FT   VARIANT         331
FT                   /note="S -> F (in HSAN1A; severe form with early onset;
FT                   reduced canonical activity towards serine and increased
FT                   production of deoxysphingolipids; no effect on subcellular
FT                   location at the endoplasmic reticulum; dbSNP:rs267607087)"
FT                   /evidence="ECO:0000269|PubMed:19651702,
FT                   ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:24247255"
FT                   /id="VAR_066245"
FT   VARIANT         331
FT                   /note="S -> Y (in ALS27 and HSAN1A; reduced canonical
FT                   activity towards serine and increased production of
FT                   deoxysphingolipids; dbSNP:rs267607087)"
FT                   /evidence="ECO:0000269|PubMed:23454272,
FT                   ECO:0000269|PubMed:34459874"
FT                   /id="VAR_073294"
FT   VARIANT         352
FT                   /note="A -> V (in HSAN1A; reduced canonical activity
FT                   towards serine and increased production of
FT                   deoxysphingolipids; no effect on subcellular location at
FT                   the endoplasmic reticulum; dbSNP:rs267607088)"
FT                   /evidence="ECO:0000269|PubMed:19651702,
FT                   ECO:0000269|PubMed:21618344"
FT                   /id="VAR_066246"
FT   VARIANT         387
FT                   /note="G -> A (does not affect catalytic activity towards
FT                   serine; does not affect the interaction with SPTLC2;
FT                   dbSNP:rs119482084)"
FT                   /evidence="ECO:0000269|PubMed:15037712,
FT                   ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702"
FT                   /id="VAR_037890"
FT   MUTAGEN         138
FT                   /note="F->A: Decreased catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         164
FT                   /note="Y->F: Increased serine palmitoyltransferase activity
FT                   and sphingolipid content."
FT                   /evidence="ECO:0000269|PubMed:23629659"
FT   MUTAGEN         337
FT                   /note="F->A: Strongly decreased catalytic activity with L-
FT                   serine and palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         338
FT                   /note="S->A: Decreased catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   HELIX           11..18
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           22..39
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           54..63
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           78..80
FT                   /evidence="ECO:0007829|PDB:7K0J"
FT   STRAND          85..87
FT                   /evidence="ECO:0007829|PDB:7YJ2"
FT   STRAND          90..97
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          99..103
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          108..110
FT                   /evidence="ECO:0007829|PDB:7K0J"
FT   HELIX           115..128
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          136..139
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           143..156
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          159..166
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           169..178
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          184..188
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           193..201
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          205..209
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           214..229
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           232..235
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          240..247
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            249..251
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           258..267
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          270..274
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            276..281
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          282..286
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           289..293
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           297..299
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          303..306
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          309..311
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          316..320
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           322..325
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            326..331
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           333..336
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           343..358
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           362..376
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            377..379
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          383..387
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          395..400
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           405..419
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           420..422
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           433..435
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          436..438
FT                   /evidence="ECO:0007829|PDB:6M4O"
FT   STRAND          443..445
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          450..452
FT                   /evidence="ECO:0007829|PDB:7YIU"
FT   HELIX           454..468
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            469..471
FT                   /evidence="ECO:0007829|PDB:7YIY"
SQ   SEQUENCE   473 AA;  52744 MW;  BA9E056A869D2EA2 CRC64;
     MATATEQWVL VEMVQALYEA PAYHLILEGI LILWIIRLLF SKTYKLQERS DLTVKEKEEL
     IEEWQPEPLV PPVPKDHPAL NYNIVSGPPS HKTVVNGKEC INFASFNFLG LLDNPRVKAA
     ALASLKKYGV GTCGPRGFYG TFDVHLDLED RLAKFMKTEE AIIYSYGFAT IASAIPAYSK
     RGDIVFVDRA ACFAIQKGLQ ASRSDIKLFK HNDMADLERL LKEQEIEDQK NPRKARVTRR
     FIVVEGLYMN TGTICPLPEL VKLKYKYKAR IFLEESLSFG VLGEHGRGVT EHYGINIDDI
     DLISANMENA LASIGGFCCG RSFVIDHQRL SGQGYCFSAS LPPLLAAAAI EALNIMEENP
     GIFAVLKEKC GQIHKALQGI SGLKVVGESL SPAFHLQLEE STGSREQDVR LLQEIVDQCM
     NRSIALTQAR YLEKEEKCLP PPSIRVVVTV EQTEEELERA ASTIKEVAQA VLL
//
ID   SPTC2_HUMAN             Reviewed;         562 AA.
AC   O15270; Q16685;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1998, sequence version 1.
DT   28-JAN-2026, entry version 211.
DE   RecName: Full=Serine palmitoyltransferase 2 {ECO:0000305};
DE            EC=2.3.1.50 {ECO:0000269|PubMed:19416851};
DE   AltName: Full=Long chain base biosynthesis protein 2;
DE            Short=LCB 2;
DE   AltName: Full=Long chain base biosynthesis protein 2a;
DE            Short=LCB2a {ECO:0000303|PubMed:19416851};
DE   AltName: Full=Serine-palmitoyl-CoA transferase 2;
DE            Short=SPT 2;
GN   Name=SPTLC2 {ECO:0000312|HGNC:HGNC:11278}; Synonyms=KIAA0526, LCB2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Pancreas;
RX   PubMed=9363775; DOI=10.1111/j.1432-1033.1997.00239.x;
RA   Weiss B., Stoffel W.;
RT   "Human and murine serine-palmitoyl-CoA transferase. Cloning, expression and
RT   characterization of the key enzyme in sphingolipid synthesis.";
RL   Eur. J. Biochem. 249:239-247(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   PubMed=9628581; DOI=10.1093/dnares/5.1.31;
RA   Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N.,
RA   Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. IX. The
RT   complete sequences of 100 new cDNA clones from brain which can code for
RT   large proteins in vitro.";
RL   DNA Res. 5:31-39(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12508121; DOI=10.1038/nature01348;
RA   Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA   Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA   Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA   Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA   Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA   Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA   Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA   Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA   Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA   Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA   Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA   Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA   Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA   Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA   Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA   Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA   Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA   Waterston R., Hood L., Weissenbach J.;
RT   "The DNA sequence and analysis of human chromosome 14.";
RL   Nature 421:601-607(2003).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lymph;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 60-562.
RC   TISSUE=Pancreatic islet;
RX   PubMed=8921873; DOI=10.1016/0378-1119(96)00309-5;
RA   Nagiec M.M., Lester R.L., Dickson R.C.;
RT   "Sphingolipid synthesis: identification and characterization of mammalian
RT   cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase.";
RL   Gene 177:237-241(1996).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 68-144.
RC   TISSUE=Pancreatic islet;
RX   PubMed=7506601; DOI=10.1093/hmg/2.11.1793;
RA   Takeda J., Yano H., Eng S., Zeng Y., Bell G.I.;
RT   "A molecular inventory of human pancreatic islets: sequence analysis of
RT   1000 cDNA clones.";
RL   Hum. Mol. Genet. 2:1793-1798(1993).
RN   [7]
RP   TISSUE SPECIFICITY.
RX   PubMed=17023427; DOI=10.1074/jbc.m608066200;
RA   Hornemann T., Richard S., Ruetti M.F., Wei Y., von Eckardstein A.;
RT   "Cloning and initial characterization of a new subunit for mammalian
RT   serine-palmitoyltransferase.";
RL   J. Biol. Chem. 281:37275-37281(2006).
RN   [8]
RP   FUNCTION.
RX   PubMed=19648650; DOI=10.1074/jbc.m109.023192;
RA   Hornemann T., Penno A., Ruetti M.F., Ernst D., Kivrak-Pfiffner F.,
RA   Rohrer L., von Eckardstein A.;
RT   "The SPTLC3 subunit of serine palmitoyltransferase generates short chain
RT   sphingoid bases.";
RL   J. Biol. Chem. 284:26322-26330(2009).
RN   [9]
RP   FUNCTION, CATALYTIC ACTIVITY, AND IDENTIFICATION IN THE SPT COMPLEX.
RX   PubMed=19416851; DOI=10.1073/pnas.0811269106;
RA   Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P., Eichler F.,
RA   Brown R.H. Jr., Harmon J.M., Dunn T.M.;
RT   "Identification of small subunits of mammalian serine palmitoyltransferase
RT   that confer distinct acyl-CoA substrate specificities.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:8186-8191(2009).
RN   [10]
RP   FUNCTION, VARIANTS HSAN1C MET-359; VAL-382 AND PHE-504, AND
RP   CHARACTERIZATION OF VARIANTS HSAN1C MET-359; VAL-382 AND PHE-504.
RX   PubMed=20920666; DOI=10.1016/j.ajhg.2010.09.010;
RA   Rotthier A., Auer-Grumbach M., Janssens K., Baets J., Penno A.,
RA   Almeida-Souza L., Van Hoof K., Jacobs A., De Vriendt E.,
RA   Schlotter-Weigel B., Loscher W., Vondracek P., Seeman P., De Jonghe P.,
RA   Van Dijck P., Jordanova A., Hornemann T., Timmerman V.;
RT   "Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause
RT   hereditary sensory and autonomic neuropathy type I.";
RL   Am. J. Hum. Genet. 87:513-522(2010).
RN   [11]
RP   FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=20504773; DOI=10.1074/jbc.m110.122259;
RA   Gable K., Gupta S.D., Han G., Niranjanakumari S., Harmon J.M., Dunn T.M.;
RT   "A disease-causing mutation in the active site of serine
RT   palmitoyltransferase causes catalytic promiscuity.";
RL   J. Biol. Chem. 285:22846-22852(2010).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [13]
RP   INDUCTION IN ALZHEIMER DISEASE.
RX   PubMed=21994399; DOI=10.1523/jneurosci.3883-11.2011;
RA   Geekiyanage H., Chan C.;
RT   "MicroRNA-137/181c regulates serine palmitoyltransferase and in turn
RT   amyloid beta, novel targets in sporadic Alzheimer's disease.";
RL   J. Neurosci. 31:14820-14830(2011).
RN   [14]
RP   REGULATION OF SPT COMPLEX ACTIVITY BY ORMDL PROTEINS IN THE PRESENCE OF
RP   CERAMIDES.
RX   PubMed=30700557; DOI=10.1074/jbc.ra118.007291;
RA   Davis D.L., Gable K., Suemitsu J., Dunn T.M., Wattenberg B.W.;
RT   "The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly
RT   regulated by ceramide: Reconstitution of SPT regulation in isolated
RT   membranes.";
RL   J. Biol. Chem. 294:5146-5156(2019).
RN   [15] {ECO:0007744|PDB:7K0I, ECO:0007744|PDB:7K0J, ECO:0007744|PDB:7K0K, ECO:0007744|PDB:7K0L, ECO:0007744|PDB:7K0M, ECO:0007744|PDB:7K0N, ECO:0007744|PDB:7K0O, ECO:0007744|PDB:7K0P, ECO:0007744|PDB:7K0Q}
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) IN COMPLEX WITH SPTLC1;
RP   SPTSSA AND ORMDL3, AND MUTAGENESIS OF ARG-302; ARG-304 AND ARG-305.
RX   PubMed=33558761; DOI=10.1038/s41594-020-00551-9;
RA   Wang Y., Niu Y., Zhang Z., Gable K., Gupta S.D., Somashekarappa N., Han G.,
RA   Zhao H., Myasnikov A.G., Kalathur R.C., Dunn T.M., Lee C.H.;
RT   "Structural insights into the regulation of human serine
RT   palmitoyltransferase complexes.";
RL   Nat. Struct. Mol. Biol. 28:240-248(2021).
RN   [16] {ECO:0007744|PDB:6M4N, ECO:0007744|PDB:6M4O, ECO:0007744|PDB:7CQI, ECO:0007744|PDB:7CQK}
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) IN COMPLEX WITH SPTLC1;
RP   SPTSSA AND ORMDL3, MUTAGENESIS OF TYR-122; LEU-126; ILE-130; TRP-134;
RP   TYR-176; SER-258; MET-320; THR-378; LYS-379; ILE-479 AND ARG-509, AND
RP   BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=33558762; DOI=10.1038/s41594-020-00553-7;
RA   Li S., Xie T., Liu P., Wang L., Gong X.;
RT   "Structural insights into the assembly and substrate selectivity of human
RT   SPT-ORMDL3 complex.";
RL   Nat. Struct. Mol. Biol. 28:249-257(2021).
RN   [17] {ECO:0007744|PDB:7YIU, ECO:0007744|PDB:7YIY, ECO:0007744|PDB:7YJ1, ECO:0007744|PDB:7YJ2}
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) IN COMPLEX WITH SPTLC1;
RP   SPTSSA AND ORMDL3, AND MUTAGENESIS OF TYR-122 AND ILE-503.
RX   PubMed=37308477; DOI=10.1038/s41467-023-39274-y;
RA   Xie T., Liu P., Wu X., Dong F., Zhang Z., Yue J., Mahawar U., Farooq F.,
RA   Vohra H., Fang Q., Liu W., Wattenberg B.W., Gong X.;
RT   "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid
RT   homeostasis.";
RL   Nat. Commun. 14:3475-3475(2023).
RN   [18]
RP   VARIANT HSAN1C PRO-182, CHARACTERIZATION OF VARIANT HSAN1C PRO-182, AND
RP   PATHOLOGICAL MECHANISM.
RX   PubMed=23658386; DOI=10.1212/wnl.0b013e318295d789;
RA   Murphy S.M., Ernst D., Wei Y., Laura M., Liu Y.T., Polke J., Blake J.,
RA   Winer J., Houlden H., Hornemann T., Reilly M.M.;
RT   "Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a
RT   novel mutation in SPTLC2.";
RL   Neurology 80:2106-2111(2013).
RN   [19]
RP   VARIANT HSAN1C TRP-183, AND CHARACTERIZATION OF VARIANT HSAN1C TRP-183.
RX   PubMed=26573920; DOI=10.1007/s12017-015-8379-1;
RA   Suriyanarayanan S., Auranen M., Toppila J., Paetau A., Shcherbii M.,
RA   Palin E., Wei Y., Lohioja T., Schlotter-Weigel B., Schoen U., Abicht A.,
RA   Rautenstrauss B., Tyynismaa H., Walter M.C., Hornemann T., Ylikallio E.;
RT   "The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory
RT   Neuropathy.";
RL   NeuroMolecular Med. 18:81-90(2016).
CC   -!- FUNCTION: Component of the serine palmitoyltransferase multisubunit
CC       enzyme (SPT) that catalyzes the initial and rate-limiting step in
CC       sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA
CC       (most commonly palmitoyl-CoA) to form long-chain bases
CC       (PubMed:19416851, PubMed:19648650, PubMed:20504773, PubMed:20920666).
CC       The SPT complex is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or
CC       SPTSSB. Within this complex, the heterodimer consisting of SPTLC1 and
CC       SPTLC2/SPTLC3 forms the catalytic core (PubMed:19416851). The
CC       composition of the serine palmitoyltransferase (SPT) complex determines
CC       the substrate preference (PubMed:19416851). The SPTLC1-SPTLC2-SPTSSA
CC       complex shows a strong preference for C16-CoA substrate, while the
CC       SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as
CC       substrates, with a slight preference for C14-CoA (PubMed:19416851,
CC       PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong
CC       preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB
CC       isozyme displays an ability to use a broader range of acyl-CoAs,
CC       without apparent preference (PubMed:19416851, PubMed:19648650). Crucial
CC       for adipogenesis (By similarity). {ECO:0000250|UniProtKB:P97363,
CC       ECO:0000269|PubMed:19416851, ECO:0000269|PubMed:19648650,
CC       ECO:0000269|PubMed:20504773, ECO:0000269|PubMed:20920666}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-serine + hexadecanoyl-CoA + H(+) = 3-oxosphinganine + CO2 +
CC         CoA; Xref=Rhea:RHEA:14761, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC         ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379,
CC         ChEBI:CHEBI:58299; EC=2.3.1.50;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=octadecanoyl-CoA + L-serine + H(+) = 3-oxoeicosasphinganine +
CC         CO2 + CoA; Xref=Rhea:RHEA:33683, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57394, ChEBI:CHEBI:65073;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33684;
CC         Evidence={ECO:0000269|PubMed:19416851};
CC   -!- COFACTOR:
CC       Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
CC         Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: SPT complex catalytic activity is negatively
CC       regulated by ORMDL proteins, including ORMDL3, in the presence of
CC       ceramides (PubMed:37308477). This mechanism allows to maintain ceramide
CC       levels at sufficient concentrations for the production of complex
CC       sphingolipids, but which prevents the accumulation of ceramides to
CC       levels that trigger apoptosis (Probable). {ECO:0000269|PubMed:37308477,
CC       ECO:0000305}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.75 mM for L-serine {ECO:0000269|PubMed:20504773};
CC         KM=0.3 mM for L-serine {ECO:0000269|PubMed:33558761};
CC         Vmax=1350 pmol/min/mg enzyme {ECO:0000269|PubMed:20504773};
CC   -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC   -!- SUBUNIT: Component of the serine palmitoyltransferase (SPT) complex,
CC       which is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB
CC       (PubMed:19416851). The heterodimer consisting of SPTLC1 and
CC       SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or
CC       SPTSSB subunits determine substrate specificity (PubMed:33558762,
CC       PubMed:37308477). SPT also interacts with ORMDL proteins, especially
CC       ORMDL3, which negatively regulate SPT activity in the presence of
CC       ceramides (PubMed:30700557, PubMed:33558762, PubMed:37308477). Forms
CC       dimers of heterodimers with SPTLC1 (PubMed:33558761, PubMed:33558762).
CC       {ECO:0000269|PubMed:19416851, ECO:0000269|PubMed:30700557,
CC       ECO:0000269|PubMed:33558761, ECO:0000269|PubMed:33558762,
CC       ECO:0000269|PubMed:37308477}.
CC   -!- INTERACTION:
CC       O15270; O15269: SPTLC1; NbExp=5; IntAct=EBI-766136, EBI-1044323;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:P97363}; Single-pass membrane protein
CC       {ECO:0000250|UniProtKB:P97363}.
CC   -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:17023427}.
CC   -!- INDUCTION: Expression at protein level is highly increased in brains of
CC       patients with Alzheimer disease. No changes are observed at mRNA level.
CC       {ECO:0000269|PubMed:21994399}.
CC   -!- DISEASE: Neuropathy, hereditary sensory and autonomic, 1C (HSAN1C)
CC       [MIM:613640]: A form of hereditary sensory and autonomic neuropathy, a
CC       genetically and clinically heterogeneous group of disorders
CC       characterized by degeneration of dorsal root and autonomic ganglion
CC       cells, and by prominent sensory abnormalities with a variable degree of
CC       motor and autonomic dysfunction. The neurological phenotype is often
CC       complicated by severe infections, osteomyelitis, and amputations.
CC       HSAN1C symptoms include loss of touch and vibration in the feet,
CC       dysesthesia and severe panmodal sensory loss in the upper and lower
CC       limbs, distal lower limb sensory loss with ulceration and
CC       osteomyelitis, and distal muscle weakness.
CC       {ECO:0000269|PubMed:20920666, ECO:0000269|PubMed:23658386,
CC       ECO:0000269|PubMed:26573920}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry. SPTLC2 disease mutations
CC       cause a shift in the substrate specificity of SPT resulting in the
CC       alternative use of L-alanine and L-glycine over its canonical substrate
CC       L-serine. This leads to the production of 1-deoxysphingolipids that
CC       cannot be correctly metabolized (PubMed:23658386).
CC       {ECO:0000269|PubMed:23658386, ECO:0000269|PubMed:26573920}.
CC   -!- SIMILARITY: Belongs to the class-II pyridoxal-phosphate-dependent
CC       aminotransferase family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA25452.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; Y08686; CAA69942.1; -; mRNA.
DR   EMBL; AB011098; BAA25452.2; ALT_INIT; mRNA.
DR   EMBL; AF111168; AAD09621.1; -; Genomic_DNA.
DR   EMBL; BC005123; AAH05123.1; -; mRNA.
DR   EMBL; U15555; AAC50871.1; -; mRNA.
DR   CCDS; CCDS9865.1; -.
DR   PIR; I38873; I38873.
DR   RefSeq; NP_004854.1; NM_004863.4.
DR   PDB; 6M4N; EM; 3.80 A; B/F=1-562.
DR   PDB; 6M4O; EM; 3.40 A; T=1-562.
DR   PDB; 7CQI; EM; 3.20 A; T=1-562.
DR   PDB; 7CQK; EM; 3.30 A; T=1-562.
DR   PDB; 7K0I; EM; 3.30 A; B/E=1-544.
DR   PDB; 7K0J; EM; 3.10 A; B=1-562.
DR   PDB; 7K0K; EM; 2.60 A; B=1-562.
DR   PDB; 7K0L; EM; 3.40 A; B=1-562.
DR   PDB; 7K0M; EM; 2.90 A; B/F=1-544.
DR   PDB; 7K0N; EM; 3.10 A; B/F=1-562.
DR   PDB; 7K0O; EM; 3.10 A; B/F=1-544.
DR   PDB; 7K0P; EM; 3.10 A; B/F=1-544.
DR   PDB; 7K0Q; EM; 3.30 A; B=1-562.
DR   PDB; 7YIU; EM; 2.90 A; B=1-562.
DR   PDB; 7YIY; EM; 2.70 A; B=1-562.
DR   PDB; 7YJ1; EM; 3.10 A; B=1-562.
DR   PDB; 7YJ2; EM; 2.90 A; B=1-562.
DR   PDBsum; 6M4N; -.
DR   PDBsum; 6M4O; -.
DR   PDBsum; 7CQI; -.
DR   PDBsum; 7CQK; -.
DR   PDBsum; 7K0I; -.
DR   PDBsum; 7K0J; -.
DR   PDBsum; 7K0K; -.
DR   PDBsum; 7K0L; -.
DR   PDBsum; 7K0M; -.
DR   PDBsum; 7K0N; -.
DR   PDBsum; 7K0O; -.
DR   PDBsum; 7K0P; -.
DR   PDBsum; 7K0Q; -.
DR   PDBsum; 7YIU; -.
DR   PDBsum; 7YIY; -.
DR   PDBsum; 7YJ1; -.
DR   PDBsum; 7YJ2; -.
DR   AlphaFoldDB; O15270; -.
DR   EMDB; EMD-22598; -.
DR   EMDB; EMD-22599; -.
DR   EMDB; EMD-22600; -.
DR   EMDB; EMD-22601; -.
DR   EMDB; EMD-22602; -.
DR   EMDB; EMD-22604; -.
DR   EMDB; EMD-22605; -.
DR   EMDB; EMD-22606; -.
DR   EMDB; EMD-22608; -.
DR   EMDB; EMD-30079; -.
DR   EMDB; EMD-30080; -.
DR   EMDB; EMD-30081; -.
DR   EMDB; EMD-30082; -.
DR   EMDB; EMD-30441; -.
DR   EMDB; EMD-30442; -.
DR   EMDB; EMD-33864; -.
DR   EMDB; EMD-33866; -.
DR   EMDB; EMD-33868; -.
DR   EMDB; EMD-33869; -.
DR   SMR; O15270; -.
DR   BioGRID; 114894; 156.
DR   ComplexPortal; CPX-6663; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSA variant.
DR   ComplexPortal; CPX-6664; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSB variant.
DR   CORUM; O15270; -.
DR   DIP; DIP-34604N; -.
DR   FunCoup; O15270; 832.
DR   IntAct; O15270; 79.
DR   MINT; O15270; -.
DR   STRING; 9606.ENSP00000216484; -.
DR   BindingDB; O15270; -.
DR   ChEMBL; CHEMBL1250344; -.
DR   DrugBank; DB00114; Pyridoxal phosphate.
DR   DrugBank; DB00133; Serine.
DR   GlyGen; O15270; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; O15270; -.
DR   PhosphoSitePlus; O15270; -.
DR   SwissPalm; O15270; -.
DR   BioMuta; SPTLC2; -.
DR   jPOST; O15270; -.
DR   MassIVE; O15270; -.
DR   PaxDb; 9606-ENSP00000216484; -.
DR   PeptideAtlas; O15270; -.
DR   ProteomicsDB; 48559; -.
DR   Pumba; O15270; -.
DR   Antibodypedia; 26092; 268 antibodies from 29 providers.
DR   DNASU; 9517; -.
DR   Ensembl; ENST00000216484.7; ENSP00000216484.2; ENSG00000100596.9.
DR   GeneID; 9517; -.
DR   KEGG; hsa:9517; -.
DR   MANE-Select; ENST00000216484.7; ENSP00000216484.2; NM_004863.4; NP_004854.1.
DR   UCSC; uc001xub.4; human.
DR   AGR; HGNC:11278; -.
DR   ClinPGx; PA36107; -.
DR   CTD; 9517; -.
DR   DisGeNET; 9517; -.
DR   GeneCards; SPTLC2; -.
DR   HGNC; HGNC:11278; SPTLC2.
DR   HPA; ENSG00000100596; Low tissue specificity.
DR   MalaCards; SPTLC2; -.
DR   MIM; 605713; gene.
DR   MIM; 613640; phenotype.
DR   OpenTargets; ENSG00000100596; -.
DR   Orphanet; 36386; Hereditary sensory and autonomic neuropathy type 1.
DR   VEuPathDB; HostDB:ENSG00000100596; -.
DR   eggNOG; KOG1357; Eukaryota.
DR   GeneTree; ENSGT00940000155786; -.
DR   HOGENOM; CLU_015846_7_1_1; -.
DR   InParanoid; O15270; -.
DR   OMA; QPRANGC; -.
DR   OrthoDB; 65434at2759; -.
DR   PAN-GO; O15270; 4 GO annotations based on evolutionary models.
DR   PhylomeDB; O15270; -.
DR   BioCyc; MetaCyc:HS02117-MONOMER; -.
DR   BRENDA; 2.3.1.50; 2681.
DR   PathwayCommons; O15270; -.
DR   Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR   SABIO-RK; O15270; -.
DR   SignaLink; O15270; -.
DR   UniPathway; UPA00222; -.
DR   Agora; ENSG00000100596; -.
DR   BioGRID-ORCS; 9517; 105 hits in 1178 CRISPR screens.
DR   ChiTaRS; SPTLC2; human.
DR   GeneWiki; SPTLC2; -.
DR   GenomeRNAi; 9517; -.
DR   Pharos; O15270; Tchem.
DR   PRO; PR:O15270; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; O15270; protein.
DR   Bgee; ENSG00000100596; Expressed in corpus callosum and 194 other cell types or tissues.
DR   ExpressionAtlas; O15270; baseline and differential.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0017059; C:serine palmitoyltransferase complex; IDA:UniProtKB.
DR   GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR   GO; GO:0004758; F:serine C-palmitoyltransferase activity; IDA:UniProtKB.
DR   GO; GO:0060612; P:adipose tissue development; ISS:UniProtKB.
DR   GO; GO:0046513; P:ceramide biosynthetic process; IDA:MGI.
DR   GO; GO:1904504; P:positive regulation of lipophagy; IDA:MGI.
DR   GO; GO:0046511; P:sphinganine biosynthetic process; IEA:Ensembl.
DR   GO; GO:0030148; P:sphingolipid biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0006686; P:sphingomyelin biosynthetic process; IEA:Ensembl.
DR   GO; GO:0046512; P:sphingosine biosynthetic process; IDA:ComplexPortal.
DR   CDD; cd06454; KBL_like; 1.
DR   FunFam; 3.90.1150.10:FF:000004; 2-amino-3-ketobutyrate coenzyme A ligase; 1.
DR   FunFam; 3.40.640.10:FF:000047; serine palmitoyltransferase 2 isoform X1; 1.
DR   Gene3D; 3.90.1150.10; Aspartate Aminotransferase, domain 1; 1.
DR   Gene3D; 3.40.640.10; Type I PLP-dependent aspartate aminotransferase-like (Major domain); 1.
DR   InterPro; IPR001917; Aminotrans_II_pyridoxalP_BS.
DR   InterPro; IPR004839; Aminotransferase_I/II_large.
DR   InterPro; IPR050087; AON_synthase_class-II.
DR   InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR   InterPro; IPR015421; PyrdxlP-dep_Trfase_major.
DR   InterPro; IPR015422; PyrdxlP-dep_Trfase_small.
DR   PANTHER; PTHR13693; CLASS II AMINOTRANSFERASE/8-AMINO-7-OXONONANOATE SYNTHASE; 1.
DR   PANTHER; PTHR13693:SF79; SERINE PALMITOYLTRANSFERASE 2; 1.
DR   Pfam; PF00155; Aminotran_1_2; 1.
DR   SUPFAM; SSF53383; PLP-dependent transferases; 1.
DR   PROSITE; PS00599; AA_TRANSFER_CLASS_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acyltransferase; Disease variant; Endoplasmic reticulum;
KW   Lipid metabolism; Membrane; Neurodegeneration; Neuropathy;
KW   Proteomics identification; Pyridoxal phosphate; Reference proteome;
KW   Sphingolipid metabolism; Transferase; Transmembrane; Transmembrane helix.
FT   CHAIN           1..562
FT                   /note="Serine palmitoyltransferase 2"
FT                   /id="PRO_0000163858"
FT   TRANSMEM        67..87
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         379
FT                   /note="N6-(pyridoxal phosphate)lysine"
FT                   /evidence="ECO:0000250"
FT   VARIANT         182
FT                   /note="A -> P (in HSAN1C; reduced activity with L-serine as
FT                   substrate; increased activity toward L-alanine resulting in
FT                   the accumulation of 1-deoxy-sphinganine;
FT                   dbSNP:rs864621998)"
FT                   /evidence="ECO:0000269|PubMed:23658386"
FT                   /id="VAR_069525"
FT   VARIANT         183
FT                   /note="R -> W (in HSAN1C; late onset; slightly increased
FT                   activity with L-serine as substrate; highly increased
FT                   activity toward L-alanine resulting in the accumulation of
FT                   1-deoxy-sphinganine; dbSNP:rs775437084)"
FT                   /evidence="ECO:0000269|PubMed:26573920"
FT                   /id="VAR_081286"
FT   VARIANT         359
FT                   /note="V -> M (in HSAN1C; partial loss of normal activity
FT                   as measured by reduced formation of sphinganine; affects
FT                   enzymatic affinity resulting in the accumulation of the
FT                   alternative metabolite 1-deoxy-sphinganine;
FT                   dbSNP:rs267607090)"
FT                   /evidence="ECO:0000269|PubMed:20920666"
FT                   /id="VAR_064798"
FT   VARIANT         382
FT                   /note="G -> V (in HSAN1C; complete loss of normal activity
FT                   as measured by lack of formation of sphinganine; affects
FT                   enzymatic affinity resulting in the accumulation of the
FT                   alternative metabolite 1-deoxy-sphinganine;
FT                   dbSNP:rs267607089)"
FT                   /evidence="ECO:0000269|PubMed:20920666"
FT                   /id="VAR_064799"
FT   VARIANT         504
FT                   /note="I -> F (in HSAN1C; partial loss of normal activity
FT                   as measured by reduced formation of sphinganine; affects
FT                   enzymatic affinity resulting in the accumulation of the
FT                   alternative metabolite 1-deoxy-sphinganine;
FT                   dbSNP:rs267607091)"
FT                   /evidence="ECO:0000269|PubMed:20920666"
FT                   /id="VAR_064800"
FT   MUTAGEN         122
FT                   /note="Y->A: Decreased catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates. Does not affect the negative
FT                   regulation by OMRDL3 and ceramides."
FT                   /evidence="ECO:0000269|PubMed:33558762,
FT                   ECO:0000269|PubMed:37308477"
FT   MUTAGEN         126
FT                   /note="L->W: Some decrease in catalytic activity with L-
FT                   serine and palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         130
FT                   /note="I->W: Loss of catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         134
FT                   /note="W->A: Loss of catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         176
FT                   /note="Y->A: Loss of catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         258
FT                   /note="S->R: Loss of catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         302
FT                   /note="R->A: Reduces the dimerization propensity with
FT                   SPTLC1; reduces the dimerization propensity with SPTLC1;
FT                   when associated with A-305. Does not impair enzymatic
FT                   activity; when associated with A-304 and A-305."
FT                   /evidence="ECO:0000269|PubMed:33558761"
FT   MUTAGEN         304
FT                   /note="R->A: Reduces the dimerization propensity with
FT                   SPTLC1; when associated with A-302 and A-304. Does not
FT                   impair enzymatic activity; when associated with A-302 and
FT                   A-304."
FT                   /evidence="ECO:0000269|PubMed:33558761"
FT   MUTAGEN         305
FT                   /note="R->A: Reduces the dimerization propensity with
FT                   SPTLC1; when associated with A-302 and A-304. Does not
FT                   impair enzymatic activity; when associated with A-302 and
FT                   A-304."
FT                   /evidence="ECO:0000269|PubMed:33558761"
FT   MUTAGEN         320
FT                   /note="M->Q: Decreased catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         378
FT                   /note="T->A: Decreased catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         379
FT                   /note="K->A: Loss of catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         479
FT                   /note="I->W: Loss of catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   MUTAGEN         503
FT                   /note="I->R: Loss of negative regulation by OMRDL3 and
FT                   ceramides."
FT                   /evidence="ECO:0000269|PubMed:37308477"
FT   MUTAGEN         509
FT                   /note="R->A: Loss of catalytic activity with L-serine and
FT                   palmitoyl-CoA as substrates."
FT                   /evidence="ECO:0000269|PubMed:33558762"
FT   CONFLICT        61..64
FT                   /note="EAFE -> TLAR (in Ref. 5; AAC50871)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        436..562
FT                   /note="KECVQQLAENTRYFRRRLKEMGFIIYGNEDSPVVPLMLYMPAKIGAFGREML
FT                   KRNIGVVVVGFPATPIIESRARFCLSAAHTKEILDTALKEIDEVGDLLQLKYSRHRLVP
FT                   LLDRPFDETTYEETED -> NGITIHEVVQTRNTYHRFSPLSPVFSHQCLWIMLP (in
FT                   Ref. 5; AAC50871)"
FT                   /evidence="ECO:0000305"
FT   STRAND          50..52
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          54..57
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           68..91
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            92..94
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          100..102
FT                   /evidence="ECO:0007829|PDB:7CQI"
FT   HELIX           106..108
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          109..111
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            117..120
FT                   /evidence="ECO:0007829|PDB:7YJ2"
FT   HELIX           121..125
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           127..129
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           131..133
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          137..140
FT                   /evidence="ECO:0007829|PDB:7CQI"
FT   STRAND          143..152
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          154..159
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          161..172
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           178..180
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          184..186
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           187..198
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          204..206
FT                   /evidence="ECO:0007829|PDB:7CQI"
FT   TURN            207..210
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           214..227
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          229..234
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           238..243
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           246..248
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          254..259
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           264..273
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          276..280
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           285..298
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            301..303
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          308..318
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            319..322
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           327..336
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          340..344
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            346..351
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          352..356
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           358..362
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           367..369
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          371..383
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          386..390
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           392..401
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           403..407
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           413..427
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            428..430
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          431..433
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           434..454
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            455..457
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          467..472
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   HELIX           476..488
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          494..496
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            498..500
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   TURN            503..505
FT                   /evidence="ECO:0007829|PDB:6M4O"
FT   STRAND          507..511
FT                   /evidence="ECO:0007829|PDB:7YIY"
FT   STRAND          513..515
FT                   /evidence="ECO:0007829|PDB:7CQI"
FT   HELIX           518..535
FT                   /evidence="ECO:0007829|PDB:7YIY"
SQ   SEQUENCE   562 AA;  62924 MW;  0C1AA1E233DE36F1 CRC64;
     MRPEPGGCCC RRTVRANGCV ANGEVRNGYV RSSAAAAAAA AAGQIHHVTQ NGGLYKRPFN
     EAFEETPMLV AVLTYVGYGV LTLFGYLRDF LRYWRIEKCH HATEREEQKD FVSLYQDFEN
     FYTRNLYMRI RDNWNRPICS VPGARVDIME RQSHDYNWSF KYTGNIIKGV INMGSYNYLG
     FARNTGSCQE AAAKVLEEYG AGVCSTRQEI GNLDKHEELE ELVARFLGVE AAMAYGMGFA
     TNSMNIPALV GKGCLILSDE LNHASLVLGA RLSGATIRIF KHNNMQSLEK LLKDAIVYGQ
     PRTRRPWKKI LILVEGIYSM EGSIVRLPEV IALKKKYKAY LYLDEAHSIG ALGPTGRGVV
     EYFGLDPEDV DVMMGTFTKS FGASGGYIGG KKELIDYLRT HSHSAVYATS LSPPVVEQII
     TSMKCIMGQD GTSLGKECVQ QLAENTRYFR RRLKEMGFII YGNEDSPVVP LMLYMPAKIG
     AFGREMLKRN IGVVVVGFPA TPIIESRARF CLSAAHTKEI LDTALKEIDE VGDLLQLKYS
     RHRLVPLLDR PFDETTYEET ED
//
ID   SQSTM_HUMAN             Reviewed;         440 AA.
AC   Q13501; A6NFN7; B2R661; B3KUW5; Q13446; Q9BUV7; Q9BVS6; Q9UEU1;
DT   11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   28-JAN-2026, entry version 237.
DE   RecName: Full=Sequestosome-1 {ECO:0000305};
DE   AltName: Full=EBI3-associated protein of 60 kDa {ECO:0000303|PubMed:8551575};
DE            Short=EBIAP;
DE            Short=p60 {ECO:0000303|PubMed:8551575};
DE   AltName: Full=Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa {ECO:0000303|PubMed:8650207};
DE   AltName: Full=Ubiquitin-binding protein p62 {ECO:0000303|PubMed:8650207};
DE            Short=p62 {ECO:0000303|PubMed:30266909};
GN   Name=SQSTM1 {ECO:0000303|PubMed:16286508, ECO:0000312|HGNC:HGNC:11280};
GN   Synonyms=ORCA, OSIL;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606 {ECO:0000312|Proteomes:UP000005640};
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 345-361 AND
RP   394-411, AND INTERACTION WITH EBI3.
RC   TISSUE=B-cell;
RX   PubMed=8551575; DOI=10.1128/jvi.70.2.1143-1153.1996;
RA   Devergne O., Hummel M., Koeppen H., Le Beau M.M., Nathanson E.C., Kieff E.,
RA   Birkenbach M.;
RT   "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr
RT   virus infection in B lymphocytes.";
RL   J. Virol. 70:1143-1153(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 51-96; 184-187;
RP   213-217; 239-264 AND 268-281, TISSUE SPECIFICITY, INTERACTION WITH LCK, AND
RP   MUTAGENESIS OF TYR-9.
RC   TISSUE=Cervix carcinoma;
RX   PubMed=8650207; DOI=10.1073/pnas.93.12.5991;
RA   Joung I., Strominger J.L., Shin J.;
RT   "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck
RT   SH2 domain.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:5991-5995(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Caudate nucleus, and Trachea;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15372022; DOI=10.1038/nature02919;
RA   Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA   Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA   She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA   Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA   Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA   Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA   Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA   Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA   Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA   Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA   Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA   Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA   Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT   "The DNA sequence and comparative analysis of human chromosome 5.";
RL   Nature 431:268-274(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Pancreas, Placenta, Skin, and Uterus;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, AND INDUCTION.
RX   PubMed=9762895; DOI=10.1016/s0014-5793(98)01021-7;
RA   Vadlamudi R.K., Shin J.;
RT   "Genomic structure and promoter analysis of the p62 gene encoding a non-
RT   proteasomal multiubiquitin chain binding protein.";
RL   FEBS Lett. 435:138-142(1998).
RN   [7]
RP   PROTEIN SEQUENCE OF 51-60; 166-174 AND 379-388.
RX   PubMed=10362795; DOI=10.1016/s0002-9440(10)65426-0;
RA   Stumptner C., Heid H., Fuchsbichler A., Hauser H., Mischinger H.-J.,
RA   Zatloukal K., Denk H.;
RT   "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma.
RT   Demonstration of p62 as major constituent.";
RL   Am. J. Pathol. 154:1701-1710(1999).
RN   [8]
RP   INTERACTION WITH LCK AND RASA1.
RX   PubMed=8618896; DOI=10.1073/pnas.92.26.12338;
RA   Park I., Chung J., Walsh C.T., Yun Y., Strominger J.L., Shin J.;
RT   "Phosphotyrosine-independent binding of a 62-kDa protein to the src
RT   homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of
RT   Ser-59 in the lck unique N-terminal region.";
RL   Proc. Natl. Acad. Sci. U.S.A. 92:12338-12342(1995).
RN   [9]
RP   INTERACTION WITH UBIQUITIN.
RX   PubMed=8702753; DOI=10.1074/jbc.271.34.20235;
RA   Vadlamudi R.K., Joung I., Strominger J.L., Shin J.;
RT   "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck,
RT   belongs to a new class of ubiquitin-binding proteins.";
RL   J. Biol. Chem. 271:20235-20237(1996).
RN   [10]
RP   INTERACTION WITH NR2F2.
RX   PubMed=8910285; DOI=10.1074/jbc.271.44.27197;
RA   Marcus S.L., Winrow C.J., Capone J.P., Rachubinski R.A.;
RT   "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone
RT   receptor.";
RL   J. Biol. Chem. 271:27197-27200(1996).
RN   [11]
RP   INTERACTION WITH PRKCI AND PRKCZ, AND SUBCELLULAR LOCATION.
RX   PubMed=9566925; DOI=10.1128/mcb.18.5.3069;
RA   Sanchez P., De Carcer G., Sandoval I.V., Moscat J., Diaz-Meco M.T.;
RT   "Localization of atypical protein kinase C isoforms into lysosome-targeted
RT   endosomes through interaction with p62.";
RL   Mol. Cell. Biol. 18:3069-3080(1998).
RN   [12]
RP   INTERACTION WITH RIPK1; PRKCZ; PRKCI; IKBKB; TRADD AND TNFRSF1A, AND
RP   FUNCTION.
RX   PubMed=10356400; DOI=10.1093/emboj/18.11.3044;
RA   Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.;
RT   "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB
RT   activation.";
RL   EMBO J. 18:3044-3053(1999).
RN   [13]
RP   INTERACTION WITH MAPKAPK5, AND SUBCELLULAR LOCATION.
RX   PubMed=10708586; DOI=10.1006/bbrc.2000.2333;
RA   Sudo T., Maruyama M., Osada H.;
RT   "p62 functions as a p38 MAP kinase regulator.";
RL   Biochem. Biophys. Res. Commun. 269:521-525(2000).
RN   [14]
RP   INTERACTION WITH TRAF6 AND RIPK1, DOMAIN, AND FUNCTION.
RX   PubMed=10747026; DOI=10.1093/emboj/19.7.1576;
RA   Sanz L., Diaz-Meco M.T., Nakano H., Moscat J.;
RT   "The atypical PKC-interacting protein p62 channels NF-kappaB activation by
RT   the IL-1-TRAF6 pathway.";
RL   EMBO J. 19:1576-1586(2000).
RN   [15]
RP   INTERACTION WITH NTRK1; TRAF6; NGFR AND PRKCZ, AND FUNCTION.
RX   PubMed=11244088; DOI=10.1074/jbc.c000869200;
RA   Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A.,
RA   Moscat J.;
RT   "The atypical protein kinase C-interacting protein p62 is a scaffold for
RT   NF-kappaB activation by nerve growth factor.";
RL   J. Biol. Chem. 276:7709-7712(2001).
RN   [16]
RP   SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=11786419; DOI=10.1016/s0002-9440(10)64369-6;
RA   Zatloukal K., Stumptner C., Fuchsbichler A., Heid H., Schnoelzer M.,
RA   Kenner L., Kleinert R., Prinz M., Aguzzi A., Denk H.;
RT   "p62 Is a common component of cytoplasmic inclusions in protein aggregation
RT   diseases.";
RL   Am. J. Pathol. 160:255-263(2002).
RN   [17]
RP   INTERACTION WITH PAWR AND PRKCZ.
RX   PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0;
RA   Chang S., Kim J.H., Shin J.;
RT   "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4-
RT   induced PKCzeta inhibition.";
RL   FEBS Lett. 510:57-61(2002).
RN   [18]
RP   SUBCELLULAR LOCATION.
RX   PubMed=11981755; DOI=10.1053/jhep.2002.32674;
RA   Stumptner C., Fuchsbichler A., Heid H., Zatloukal K., Denk H.;
RT   "Mallory body -- a disease-associated type of sequestosome.";
RL   Hepatology 35:1053-1062(2002).
RN   [19]
RP   INTERACTION WITH NTRK1; NTRK2 AND NTRK3, SUBCELLULAR LOCATION, AND
RP   FUNCTION.
RX   PubMed=12471037; DOI=10.1074/jbc.m208468200;
RA   Geetha T., Wooten M.W.;
RT   "Association of the atypical protein kinase C-interacting protein p62/ZIP
RT   with nerve growth factor receptor TrkA regulates receptor trafficking and
RT   Erk5 signaling.";
RL   J. Biol. Chem. 278:4730-4739(2003).
RN   [20]
RP   INTERACTION WITH PRKCI; PRKCZ; MAP2K5 AND NBR1, DOMAIN, MUTAGENESIS OF
RP   LYS-7; LYS-13; 21-ARG-ARG-22; TYR-67; ASP-69; ASP-71; ASP-73; ASP-80 AND
RP   GLU-82, AND DIMERIZATION.
RX   PubMed=12813044; DOI=10.1074/jbc.m303221200;
RA   Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A.,
RA   Michaelsen E., Bjoerkoey G., Johansen T.;
RT   "Interaction codes within the family of mammalian Phox and Bem1p domain-
RT   containing proteins.";
RL   J. Biol. Chem. 278:34568-34581(2003).
RN   [21]
RP   INTERACTION WITH PRKCZ, DOMAIN, OLIGOMERIZATION, AND MUTAGENESIS OF LYS-7;
RP   ASP-69 AND ASP-73.
RX   PubMed=12887891; DOI=10.1016/s1097-2765(03)00246-6;
RA   Wilson M.I., Gill D.J., Perisic O., Quinn M.T., Williams R.L.;
RT   "PB1 domain-mediated heterodimerization in NADPH oxidase and signaling
RT   complexes of atypical protein kinase C with Par6 and p62.";
RL   Mol. Cell 12:39-50(2003).
RN   [22]
RP   INDUCTION.
RX   PubMed=12700667; DOI=10.1038/sj.onc.1206325;
RA   Thompson H.G.R., Harris J.W., Wold B.J., Lin F., Brody J.P.;
RT   "p62 overexpression in breast tumors and regulation by prostate-derived Ets
RT   factor in breast cancer cells.";
RL   Oncogene 22:2322-2333(2003).
RN   [23]
RP   SUBCELLULAR LOCATION.
RX   PubMed=15158159; DOI=10.1016/j.brainres.2004.03.029;
RA   Nakaso K., Yoshimoto Y., Nakano T., Takeshima T., Fukuhara Y., Yasui K.,
RA   Araga S., Yanagawa T., Ishii T., Nakashima K.;
RT   "Transcriptional activation of p62/A170/ZIP during the formation of the
RT   aggregates: possible mechanisms and the role in Lewy body formation in
RT   Parkinson's disease.";
RL   Brain Res. 1012:42-51(2004).
RN   [24]
RP   INTERACTION WITH TRAF6; PSMC2 AND PSMD4, DOMAIN, MUTAGENESIS OF LEU-398;
RP   PHE-406; LEU-413; LEU-417 AND ILE-431, AND FUNCTION.
RX   PubMed=15340068; DOI=10.1128/mcb.24.18.8055-8068.2004;
RA   Seibenhener M.L., Babu J.R., Geetha T., Wong H.C., Krishna N.R.,
RA   Wooten M.W.;
RT   "Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in
RT   ubiquitin proteasome degradation.";
RL   Mol. Cell. Biol. 24:8055-8068(2004).
RN   [25]
RP   FUNCTION.
RX   PubMed=16079148; DOI=10.1074/jbc.c500237200;
RA   Wooten M.W., Geetha T., Seibenhener M.L., Babu J.R., Diaz-Meco M.T.,
RA   Moscat J.;
RT   "The p62 scaffold regulates nerve growth factor-induced NF-kappaB
RT   activation by influencing TRAF6 polyubiquitination.";
RL   J. Biol. Chem. 280:35625-35629(2005).
RN   [26]
RP   FUNCTION, SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, INTERACTION WITH
RP   MAP1LC3B, POSSIBLE PROTECTIVE ROLE IN HD, AND MUTAGENESIS OF ASP-69 AND
RP   ILE-431.
RX   PubMed=16286508; DOI=10.1083/jcb.200507002;
RA   Bjorkoy G., Lamark T., Brech A., Outzen H., Perander M., Overvatn A.,
RA   Stenmark H., Johansen T.;
RT   "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a
RT   protective effect on huntingtin-induced cell death.";
RL   J. Cell Biol. 171:603-614(2005).
RN   [27]
RP   INTERACTION WITH MAPT, DOMAIN, SUBCELLULAR LOCATION, AND FUNCTION.
RX   PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x;
RA   Babu J.R., Geetha T., Wooten M.W.;
RT   "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal
RT   degradation.";
RL   J. Neurochem. 94:192-203(2005).
RN   [28]
RP   INTERACTION WITH AJUBA AND LIMD1.
RX   PubMed=15870274; DOI=10.1128/mcb.25.10.4010-4022.2005;
RA   Feng Y., Longmore G.D.;
RT   "The LIM protein Ajuba influences interleukin-1-induced NF-kappaB
RT   activation by affecting the assembly and activity of the protein kinase
RT   Czeta/p62/TRAF6 signaling complex.";
RL   Mol. Cell. Biol. 25:4010-4022(2005).
RN   [29]
RP   INDUCTION, AND FUNCTION.
RX   PubMed=15911346; DOI=10.1016/j.mcn.2005.02.011;
RA   Wang Z., Figueiredo-Pereira M.E.;
RT   "Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of
RT   ubiquitinated proteins induced by prostaglandin J2 without reducing its
RT   neurotoxicity.";
RL   Mol. Cell. Neurosci. 29:222-231(2005).
RN   [30]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-148, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=15592455; DOI=10.1038/nbt1046;
RA   Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA   Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT   "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL   Nat. Biotechnol. 23:94-101(2005).
RN   [31]
RP   INTERACTION WITH NBR1 AND TRIM55, PHOSPHORYLATION, DOMAIN, AND FUNCTION.
RX   PubMed=15802564; DOI=10.1126/science.1110463;
RA   Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E.,
RA   Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G.,
RA   Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L., Ehler E.,
RA   Udd B., Gautel M.;
RT   "The kinase domain of titin controls muscle gene expression and protein
RT   turnover.";
RL   Science 308:1599-1603(2005).
RN   [32]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-332, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA   Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT   networks.";
RL   Cell 127:635-648(2006).
RN   [33]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=16964243; DOI=10.1038/nbt1240;
RA   Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT   "A probability-based approach for high-throughput protein phosphorylation
RT   analysis and site localization.";
RL   Nat. Biotechnol. 24:1285-1292(2006).
RN   [34]
RP   FUNCTION, INTERACTION WITH GABARAP; GABARAPL1; GABARAPL2; MAP1LC3A AND
RP   MAP1LC3B, AND MUTAGENESIS OF 323-GLU-GLU-324; SER-332; 335-ASP--ASP-337;
RP   TRP-338 AND SER-342.
RX   PubMed=17580304; DOI=10.1074/jbc.m702824200;
RA   Pankiv S., Clausen T.H., Lamark T., Brech A., Bruun J.A., Outzen H.,
RA   Overvatn A., Bjorkoy G., Johansen T.;
RT   "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of
RT   ubiquitinated protein aggregates by autophagy.";
RL   J. Biol. Chem. 282:24131-24145(2007).
RN   [35]
RP   PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION).
RX   PubMed=24331465; DOI=10.1016/j.chom.2013.11.003;
RA   Barnett T.C., Liebl D., Seymour L.M., Gillen C.M., Lim J.Y., Larock C.N.,
RA   Davies M.R., Schulz B.L., Nizet V., Teasdale R.D., Walker M.J.;
RT   "The globally disseminated M1T1 clone of group A Streptococcus evades
RT   autophagy for intracellular replication.";
RL   Cell Host Microbe 14:675-682(2013).
RN   [36]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [37]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272;
RP   SER-328; SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [38]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [39]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [40]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-355 AND SER-361, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [41]
RP   FUNCTION, INTERACTION WITH WDFY3, AND SUBCELLULAR LOCATION.
RX   PubMed=20168092; DOI=10.4161/auto.6.3.11226;
RA   Clausen T.H., Lamark T., Isakson P., Finley K., Larsen K.B., Brech A.,
RA   Overvatn A., Stenmark H., Bjorkoy G., Simonsen A., Johansen T.;
RT   "p62/SQSTM1 and ALFY interact to facilitate the formation of p62
RT   bodies/ALIS and their degradation by autophagy.";
RL   Autophagy 6:330-344(2010).
RN   [42]
RP   INTERACTION WITH KEAP1.
RX   PubMed=20495340; DOI=10.4161/auto.6.5.12189;
RA   Fan W., Tang Z., Chen D., Moughon D., Ding X., Chen S., Zhu M., Zhong Q.;
RT   "Keap1 facilitates p62-mediated ubiquitin aggregate clearance via
RT   autophagy.";
RL   Autophagy 6:614-621(2010).
RN   [43]
RP   FUNCTION, INTERACTION WITH KEAP1, INDUCTION, AND MUTAGENESIS OF ASP-347;
RP   THR-350; GLY-351 AND GLU-352.
RX   PubMed=20452972; DOI=10.1074/jbc.m110.118976;
RA   Jain A., Lamark T., Sjoettem E., Larsen K.B., Awuh J.A., Oevervatn A.,
RA   McMahon M., Hayes J.D., Johansen T.;
RT   "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a
RT   positive feedback loop by inducing antioxidant response element-driven gene
RT   transcription.";
RL   J. Biol. Chem. 285:22576-22591(2010).
RN   [44]
RP   INTERACTION WITH FHOD3.
RX   PubMed=21149568; DOI=10.1083/jcb.201005060;
RA   Iskratsch T., Lange S., Dwyer J., Kho A.L., dos Remedios C., Ehler E.;
RT   "Formin follows function: a muscle-specific isoform of FHOD3 is regulated
RT   by CK2 phosphorylation and promotes myofibril maintenance.";
RL   J. Cell Biol. 191:1159-1172(2010).
RN   [45]
RP   INTERACTION WITH TRIM5, AND SUBCELLULAR LOCATION.
RX   PubMed=20357094; DOI=10.1128/jvi.02412-09;
RA   O'Connor C., Pertel T., Gray S., Robia S.L., Bakowska J.C., Luban J.,
RA   Campbell E.M.;
RT   "p62/sequestosome-1 associates with and sustains the expression of
RT   retroviral restriction factor TRIM5alpha.";
RL   J. Virol. 84:5997-6006(2010).
RN   [46]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; SER-207; SER-249;
RP   SER-266; SER-272 AND SER-332, AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [47]
RP   INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228;
RP   LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425.
RX   PubMed=22084127; DOI=10.1001/archneurol.2011.250;
RA   Fecto F., Yan J., Vemula S.P., Liu E., Yang Y., Chen W., Zheng J.G.,
RA   Shi Y., Siddique N., Arrat H., Donkervoort S., Ajroud-Driss S., Sufit R.L.,
RA   Heller S.L., Deng H.X., Siddique T.;
RT   "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.";
RL   Arch. Neurol. 68:1440-1446(2011).
RN   [48]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [49]
RP   IDENTIFICATION IN A COMPLEX WITH ZFAND5 AND UBIQUITIN, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=21923101; DOI=10.1021/bi201137e;
RA   Garner T.P., Strachan J., Shedden E.C., Long J.E., Cavey J.R., Shaw B.,
RA   Layfield R., Searle M.S.;
RT   "Independent interactions of ubiquitin-binding domains in a ubiquitin-
RT   mediated ternary complex.";
RL   Biochemistry 50:9076-9087(2011).
RN   [50]
RP   FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-24; SER-207;
RP   THR-269; SER-272; SER-282; SER-332; SER-366 AND SER-403, AND MUTAGENESIS OF
RP   SER-403.
RX   PubMed=22017874; DOI=10.1016/j.molcel.2011.07.039;
RA   Matsumoto G., Wada K., Okuno M., Kurosawa M., Nukina N.;
RT   "Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic
RT   clearance of ubiquitinated proteins.";
RL   Mol. Cell 44:279-289(2011).
RN   [51]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-272, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA   Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA   Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT   "System-wide temporal characterization of the proteome and phosphoproteome
RT   of human embryonic stem cell differentiation.";
RL   Sci. Signal. 4:RS3-RS3(2011).
RN   [52]
RP   FUNCTION.
RX   PubMed=22622177; DOI=10.4161/auto.19381;
RA   Taillebourg E., Gregoire I., Viargues P., Jacomin A.C., Thevenon D.,
RA   Faure M., Fauvarque M.O.;
RT   "The deubiquitinating enzyme USP36 controls selective autophagy activation
RT   by ubiquitinated proteins.";
RL   Autophagy 8:767-779(2012).
RN   [53]
RP   INTERACTION WITH TRIM13, AND SUBCELLULAR LOCATION.
RX   PubMed=22178386; DOI=10.1016/j.bbamcr.2011.11.015;
RA   Tomar D., Singh R., Singh A.K., Pandya C.D., Singh R.;
RT   "TRIM13 regulates ER stress induced autophagy and clonogenic ability of the
RT   cells.";
RL   Biochim. Biophys. Acta 1823:316-326(2012).
RN   [54]
RP   INTERACTION WITH MAP1LC3A.
RX   PubMed=22421968; DOI=10.1038/cdd.2012.30;
RA   Seillier M., Peuget S., Gayet O., Gauthier C., N'guessan P., Monte M.,
RA   Carrier A., Iovanna J.L., Dusetti N.J.;
RT   "TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins
RT   through the LC3-interacting region (LIR) and promotes autophagy-dependent
RT   cell death.";
RL   Cell Death Differ. 19:1525-1535(2012).
RN   [55]
RP   INTERACTION WITH TRIM50, AND SUBCELLULAR LOCATION.
RX   PubMed=22792322; DOI=10.1371/journal.pone.0040440;
RA   Fusco C., Micale L., Egorov M., Monti M., D'Addetta E.V., Augello B.,
RA   Cozzolino F., Calcagni A., Fontana A., Polishchuk R.S., Didelot G.,
RA   Reymond A., Pucci P., Merla G.;
RT   "The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes
RT   the sequestration and clearance of ubiquitinated proteins into the
RT   aggresome.";
RL   PLoS ONE 7:E40440-E40440(2012).
RN   [56]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, ACETYLATION [LARGE SCALE
RP   ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE [LARGE
RP   SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS]
RP   (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [57]
RP   FUNCTION.
RX   PubMed=24128730; DOI=10.4161/auto.26085;
RA   Isakson P., Lystad A.H., Breen K., Koster G., Stenmark H., Simonsen A.;
RT   "TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody
RT   ring degradation by selective autophagy.";
RL   Autophagy 9:1955-1964(2013).
RN   [58]
RP   INTERACTION WITH SESN1 AND SESN2.
RX   PubMed=23274085; DOI=10.1016/j.cmet.2012.12.002;
RA   Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E.,
RA   Kang D., Rhee S.G.;
RT   "Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation
RT   of Keap1 and prevent oxidative liver damage.";
RL   Cell Metab. 17:73-84(2013).
RN   [59]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272;
RP   SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [60]
RP   INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; VAL-381; LEU-387 AND
RP   LEU-392.
RX   PubMed=24042580; DOI=10.1001/jamaneurol.2013.3849;
RG   French Clinical and Genetic Research Network on FTD/FTD-ALS;
RA   Le Ber I., Camuzat A., Guerreiro R., Bouya-Ahmed K., Bras J., Nicolas G.,
RA   Gabelle A., Didic M., De Septenville A., Millecamps S., Lenglet T.,
RA   Latouche M., Kabashi E., Campion D., Hannequin D., Hardy J., Brice A.;
RT   "SQSTM1 mutations in French patients with frontotemporal dementia or
RT   frontotemporal dementia with amyotrophic lateral sclerosis.";
RL   JAMA Neurol. 70:1403-1410(2013).
RN   [61]
RP   LIR MOTIF.
RX   PubMed=23908376; DOI=10.1242/jcs.126128;
RA   Birgisdottir A.B., Lamark T., Johansen T.;
RT   "The LIR motif - crucial for selective autophagy.";
RL   J. Cell Sci. 126:3237-3247(2013).
RN   [62]
RP   INTERACTION WITH MAP1LC3B.
RX   PubMed=24089205; DOI=10.1038/nature12606;
RA   Tang Z., Lin M.G., Stowe T.R., Chen S., Zhu M., Stearns T., Franco B.,
RA   Zhong Q.;
RT   "Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar
RT   satellites.";
RL   Nature 502:254-257(2013).
RN   [63]
RP   FUNCTION, INTERACTION WITH TNS2 AND IRS1, AND DEVELOPMENTAL STAGE.
RX   PubMed=25101860; DOI=10.1016/j.cellsig.2014.07.033;
RA   Koh A., Park D., Jeong H., Lee J., Lee M.N., Suh P.G., Ryu S.H.;
RT   "Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated
RT   sequestration and degradation.";
RL   Cell. Signal. 26:2470-2480(2014).
RN   [64]
RP   INTERACTION WITH TRIM5.
RX   PubMed=25127057; DOI=10.1016/j.devcel.2014.06.013;
RA   Mandell M.A., Jain A., Arko-Mensah J., Chauhan S., Kimura T., Dinkins C.,
RA   Silvestri G., Munch J., Kirchhoff F., Simonsen A., Wei Y., Levine B.,
RA   Johansen T., Deretic V.;
RT   "TRIM proteins regulate autophagy and can target autophagic substrates by
RT   direct recognition.";
RL   Dev. Cell 30:394-409(2014).
RN   [65]
RP   INTERACTION WITH SESN2 AND ULK1, AND PHOSPHORYLATION AT SER-403 BY ULK1.
RX   PubMed=25040165; DOI=10.1111/febs.12905;
RA   Ro S.H., Semple I.A., Park H., Park H., Park H.W., Kim M., Kim J.S.,
RA   Lee J.H.;
RT   "Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of
RT   p62/sequestosome-1.";
RL   FEBS J. 281:3816-3827(2014).
RN   [66]
RP   INTERACTION WITH GABARAP, AND MUTAGENESIS OF TRP-338.
RX   PubMed=24668264; DOI=10.1002/embr.201338003;
RA   Lystad A.H., Ichimura Y., Takagi K., Yang Y., Pankiv S., Kanegae Y.,
RA   Kageyama S., Suzuki M., Saito I., Mizushima T., Komatsu M., Simonsen A.;
RT   "Structural determinants in GABARAP required for the selective binding and
RT   recruitment of ALFY to LC3B-positive structures.";
RL   EMBO Rep. 15:557-565(2014).
RN   [67]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-176; SER-233; SER-306
RP   AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [68]
RP   INTERACTION WITH UBD.
RX   PubMed=25422469; DOI=10.1073/pnas.1403383111;
RA   Theng S.S., Wang W., Mah W.C., Chan C., Zhuo J., Gao Y., Qin H., Lim L.,
RA   Chong S.S., Song J., Lee C.G.;
RT   "Disruption of FAT10-MAD2 binding inhibits tumor progression.";
RL   Proc. Natl. Acad. Sci. U.S.A. 111:E5282-E5291(2014).
RN   [69]
RP   DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH NU214.
RX   PubMed=20851865; DOI=10.3324/haematol.2010.029769;
RA   Gorello P., La Starza R., Di Giacomo D., Messina M., Puzzolo M.C.,
RA   Crescenzi B., Santoro A., Chiaretti S., Mecucci C.;
RT   "SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic
RT   leukemia.";
RL   Haematologica 95:2161-2163(2010).
RN   [70]
RP   INVOLVEMENT IN FTDALS3, AND VARIANT FTDALS3 LYS-238 DEL.
RX   PubMed=25114083; DOI=10.3233/jad-141512;
RA   Boutoleau-Bretonniere C., Camuzat A., Le Ber I., Bouya-Ahmed K.,
RA   Guerreiro R., Deruet A.L., Evrard C., Bras J., Lamy E., Auffray-Calvier E.,
RA   Pallardy A., Hardy J., Brice A., Derkinderen P., Vercelletto M.;
RT   "A phenotype of atypical apraxia of speech in a family carrying SQSTM1
RT   mutation.";
RL   J. Alzheimers Dis. 43:625-630(2015).
RN   [71]
RP   FUNCTION, AND INTERACTION WITH PEX5.
RX   PubMed=26344566; DOI=10.1038/ncb3230;
RA   Zhang J., Tripathi D.N., Jing J., Alexander A., Kim J., Powell R.T.,
RA   Dere R., Tait-Mulder J., Lee J.H., Paull T.T., Pandita R.K., Charaka V.K.,
RA   Pandita T.K., Kastan M.B., Walker C.L.;
RT   "ATM functions at the peroxisome to induce pexophagy in response to ROS.";
RL   Nat. Cell Biol. 17:1259-1269(2015).
RN   [72]
RP   INVOLVEMENT IN DMRV.
RX   PubMed=26208961; DOI=10.1212/wnl.0000000000001864;
RA   Bucelli R.C., Arhzaouy K., Pestronk A., Pittman S.K., Rojas L., Sue C.M.,
RA   Evilae A., Hackman P., Udd B., Harms M.B., Weihl C.C.;
RT   "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles.";
RL   Neurology 85:665-674(2015).
RN   [73]
RP   INVOLVEMENT IN NADGP.
RX   PubMed=27545679; DOI=10.1016/j.ajhg.2016.06.026;
RA   Haack T.B., Ignatius E., Calvo-Garrido J., Iuso A., Isohanni P.,
RA   Maffezzini C., Loennqvist T., Suomalainen A., Gorza M., Kremer L.S.,
RA   Graf E., Hartig M., Berutti R., Paucar M., Svenningsson P., Stranneheim H.,
RA   Brandberg G., Wedell A., Kurian M.A., Hayflick S.A., Venco P., Tiranti V.,
RA   Strom T.M., Dichgans M., Horvath R., Holinski-Feder E., Freyer C.,
RA   Meitinger T., Prokisch H., Senderek J., Wredenberg A., Carroll C.J.,
RA   Klopstock T.;
RT   "Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset
RT   neurodegeneration with ataxia, dystonia, and gaze palsy.";
RL   Am. J. Hum. Genet. 99:735-743(2016).
RN   [74]
RP   FUNCTION, AND UBIQUITINATION.
RX   PubMed=27368102; DOI=10.1016/j.cell.2016.05.078;
RA   Jongsma M.L., Berlin I., Wijdeven R.H., Janssen L., Janssen G.M.,
RA   Garstka M.A., Janssen H., Mensink M., van Veelen P.A., Spaapen R.M.,
RA   Neefjes J.;
RT   "An ER-associated pathway defines endosomal architecture for controlled
RT   cargo transport.";
RL   Cell 166:152-166(2016).
RN   [75]
RP   INTERACTION WITH TRIM11.
RX   PubMed=27498865; DOI=10.1016/j.celrep.2016.07.019;
RA   Liu T., Tang Q., Liu K., Xie W., Liu X., Wang H., Wang R.F., Cui J.;
RT   "TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent
RT   selective autophagy.";
RL   Cell Rep. 16:1988-2002(2016).
RN   [76]
RP   UBIQUITINATION, AND FUNCTION.
RX   PubMed=27880896; DOI=10.1016/j.celrep.2016.11.005;
RA   Heath R.J., Goel G., Baxt L.A., Rush J.S., Mohanan V., Paulus G.L.C.,
RA   Jani V., Lassen K.G., Xavier R.J.;
RT   "RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial
RT   Autophagy.";
RL   Cell Rep. 17:2183-2194(2016).
RN   [77]
RP   FUNCTION, UBIQUITINATION AT LYS-420, AND MUTAGENESIS OF LYS-420.
RX   PubMed=28380357; DOI=10.1016/j.celrep.2017.03.030;
RA   Lee Y., Chou T.F., Pittman S.K., Keith A.L., Razani B., Weihl C.C.;
RT   "Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain
RT   ubiquitination.";
RL   Cell Rep. 19:188-202(2017).
RN   [78]
RP   DOMAIN, AND UBIQUITINATION.
RX   PubMed=28322253; DOI=10.1038/cr.2017.40;
RA   Peng H., Yang J., Li G., You Q., Han W., Li T., Gao D., Xie X., Lee B.H.,
RA   Du J., Hou J., Zhang T., Rao H., Huang Y., Li Q., Zeng R., Hui L., Wang H.,
RA   Xia Q., Zhang X., He Y., Komatsu M., Dikic I., Finley D., Hu R.;
RT   "Ubiquitylation of p62/sequestosome1 activates its autophagy receptor
RT   function and controls selective autophagy upon ubiquitin stress.";
RL   Cell Res. 27:657-674(2017).
RN   [79]
RP   SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-435, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=28112733; DOI=10.1038/nsmb.3366;
RA   Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA   Nielsen M.L.;
RT   "Site-specific mapping of the human SUMO proteome reveals co-modification
RT   with phosphorylation.";
RL   Nat. Struct. Mol. Biol. 24:325-336(2017).
RN   [80]
RP   FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-403, MUTAGENESIS OF
RP   SER-403, AND CHARACTERIZATION OF VARIANTS PDB3 THR-404 AND SER-411.
RX   PubMed=29507397; DOI=10.1038/s41422-018-0017-7;
RA   Sun D., Wu R., Zheng J., Li P., Yu L.;
RT   "Polyubiquitin chain-induced p62 phase separation drives autophagic cargo
RT   segregation.";
RL   Cell Res. 28:405-415(2018).
RN   [81]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=29343546; DOI=10.15252/embj.201798308;
RA   Zaffagnini G., Savova A., Danieli A., Romanov J., Tremel S., Ebner M.,
RA   Peterbauer T., Sztacho M., Trapannone R., Tarafder A.K., Sachse C.,
RA   Martens S.;
RT   "p62 filaments capture and present ubiquitinated cargos for autophagy.";
RL   EMBO J. 37:0-0(2018).
RN   [82]
RP   INTERACTION WITH TRIM16.
RX   PubMed=30143514; DOI=10.15252/embj.201798358;
RA   Jena K.K., Kolapalli S.P., Mehto S., Nath P., Das B., Sahoo P.K., Ahad A.,
RA   Syed G.H., Raghav S.K., Senapati S., Chauhan S., Chauhan S.;
RT   "TRIM16 controls assembly and degradation of protein aggregates by
RT   modulating the p62-NRF2 axis and autophagy.";
RL   EMBO J. 37:0-0(2018).
RN   [83]
RP   INTERACTION WITH LRRC25.
RX   PubMed=29288164; DOI=10.15252/embj.201796781;
RA   Du Y., Duan T., Feng Y., Liu Q., Lin M., Cui J., Wang R.F.;
RT   "LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I
RT   for autophagic degradation.";
RL   EMBO J. 37:351-366(2018).
RN   [84]
RP   FUNCTION, INTERACTION WITH WDR81, AND DOMAIN.
RX   PubMed=28404643; DOI=10.1083/jcb.201608039;
RA   Liu X., Li Y., Wang X., Xing R., Liu K., Gan Q., Tang C., Gao Z., Jian Y.,
RA   Luo S., Guo W., Yang C.;
RT   "The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote
RT   aggrephagy.";
RL   J. Cell Biol. 216:1301-1320(2017).
RN   [85]
RP   INTERACTION WITH TRIM23.
RX   PubMed=28871090; DOI=10.1038/s41564-017-0017-2;
RA   Sparrer K.M.J., Gableske S., Zurenski M.A., Parker Z.M., Full F.,
RA   Baumgart G.J., Kato J., Pacheco-Rodriguez G., Liang C., Pornillos O.,
RA   Moss J., Vaughan M., Gack M.U.;
RT   "TRIM23 mediates virus-induced autophagy via activation of TBK1.";
RL   Nat. Microbiol. 2:1543-1557(2017).
RN   [86]
RP   FUNCTION, PHOSPHORYLATION AT SER-403, AND MUTAGENESIS OF SER-403.
RX   PubMed=29496741; DOI=10.15252/embj.201797858;
RA   Prabakaran T., Bodda C., Krapp C., Zhang B.C., Christensen M.H., Sun C.,
RA   Reinert L., Cai Y., Jensen S.B., Skouboe M.K., Nyengaard J.R.,
RA   Thompson C.B., Lebbink R.J., Sen G.C., van Loo G., Nielsen R., Komatsu M.,
RA   Nejsum L.N., Jakobsen M.R., Gyrd-Hansen M., Paludan S.R.;
RT   "Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent
RT   autophagy pathway activated by TBK1.";
RL   EMBO J. 37:0-0(2018).
RN   [87]
RP   INTERACTION WITH USP12.
RX   PubMed=30266909; DOI=10.1038/s41467-018-05653-z;
RA   Aron R., Pellegrini P., Green E.W., Maddison D.C., Opoku-Nsiah K.,
RA   Oliveira A.O., Wong J.S., Daub A.C., Giorgini F., Muchowski P.,
RA   Finkbeiner S.;
RT   "Deubiquitinase Usp12 functions noncatalytically to induce autophagy and
RT   confer neuroprotection in models of Huntington's disease.";
RL   Nat. Commun. 9:3191-3191(2018).
RN   [88]
RP   FUNCTION, SUBCELLULAR LOCATION, DOMAIN, ACETYLATION AT LYS-420 AND LYS-435,
RP   AND MUTAGENESIS OF LYS-420 AND LYS-435.
RX   PubMed=31857589; DOI=10.1038/s41467-019-13718-w;
RA   You Z., Jiang W.X., Qin L.Y., Gong Z., Wan W., Li J., Wang Y., Zhang H.,
RA   Peng C., Zhou T., Tang C., Liu W.;
RT   "Requirement for p62 acetylation in the aggregation of ubiquitylated
RT   proteins under nutrient stress.";
RL   Nat. Commun. 10:5792-5792(2019).
RN   [89]
RP   INTERACTION WITH ECSIT.
RX   PubMed=31281713; DOI=10.4110/in.2019.19.e16;
RA   Kim M.J., Min Y., Kwon J., Son J., Im J.S., Shin J., Lee K.Y.;
RT   "p62 Negatively Regulates TLR4 Signaling via Functional Regulation of the
RT   TRAF6-ECSIT Complex.";
RL   Immune Netw. 19:e16-e16(2019).
RN   [90]
RP   INTERACTION WITH CYLD.
RX   PubMed=32185393; DOI=10.1093/brain/awaa039;
RA   Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G.,
RA   Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T.,
RA   Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K.,
RA   Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A.,
RA   Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M.,
RA   Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N.,
RA   Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P.,
RA   Kwok J.B.;
RT   "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral
RT   sclerosis.";
RL   Brain 143:783-799(2020).
RN   [91]
RP   FUNCTION, AND INTERACTION WITH MOAP1.
RX   PubMed=33393215; DOI=10.15252/embr.202050854;
RA   Tan C.T., Chang H.C., Zhou Q., Yu C., Fu N.Y., Sabapathy K., Yu V.C.;
RT   "MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and
RT   suppresses Nrf2 signaling.";
RL   EMBO Rep. 22:e50854-e50854(2021).
RN   [92]
RP   FUNCTION, AND UBIQUITINATION AT LYS-435.
RX   PubMed=33472082; DOI=10.1016/j.celrep.2020.108659;
RA   Cremer T., Jongsma M.L.M., Trulsson F., Vertegaal A.C.O., Neefjes J.,
RA   Berlin I.;
RT   "The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal
RT   control over the endolysosomal pathway.";
RL   Cell Rep. 34:108659-108659(2021).
RN   [93]
RP   FUNCTION, AND DEUBIQUITINATION BY EPSTEIN-BARR VIRUS PROTEIN BPLF1
RP   (MICROBIAL INFECTION).
RX   PubMed=33509017; DOI=10.1080/15548627.2021.1874660;
RA   Ylae-Anttila P., Gupta S., Masucci M.G.;
RT   "The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit
RT   selective autophagy.";
RL   Autophagy 17:3461-3474(2021).
RN   [94]
RP   SUBCELLULAR LOCATION, INTERACTION WITH TAX1BP1, AND FUNCTION.
RX   PubMed=34471133; DOI=10.1038/s41467-021-25572-w;
RA   Turco E., Savova A., Gere F., Ferrari L., Romanov J., Schuschnig M.,
RA   Martens S.;
RT   "Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin
RT   condensate formation and autophagy initiation.";
RL   Nat. Commun. 12:5212-5212(2021).
RN   [95]
RP   INTERACTION WITH ASB6.
RX   PubMed=34164402; DOI=10.3389/fcell.2021.684885;
RA   Gong L., Wang K., Wang M., Hu R., Li H., Gao D., Lin M.;
RT   "CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to
RT   Regulate Cell Proliferation and Autophagy.";
RL   Front. Cell Dev. Biol. 9:684885-684885(2021).
RN   [96]
RP   FUNCTION.
RX   PubMed=34893540; DOI=10.1073/pnas.2107993118;
RA   Heo A.J., Kim S.B., Ji C.H., Han D., Lee S.J., Lee S.H., Lee M.J.,
RA   Lee J.S., Ciechanover A., Kim B.Y., Kwon Y.T.;
RT   "The N-terminal cysteine is a dual sensor of oxygen and oxidative stress.";
RL   Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021).
RN   [97]
RP   FUNCTION, AND INTERACTION WITH GRB2.
RX   PubMed=35831301; DOI=10.1038/s41420-022-01106-1;
RA   Hou B., Huang H., Li Y., Liang J., Xi Z., Jiang X., Liu L., Li E.;
RT   "Grb2 interacts with necrosome components and is involved in rasfonin-
RT   induced necroptosis.";
RL   Cell. Death. Discov. 8:319-319(2022).
RN   [98]
RP   FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-349; SER-403 AND
RP   SER-407, AND MUTAGENESIS OF SER-349; THR-350 AND 403-SER--SER-407.
RX   PubMed=37306101; DOI=10.15252/embj.2022113349;
RA   Ikeda R., Noshiro D., Morishita H., Takada S., Kageyama S., Fujioka Y.,
RA   Funakoshi T., Komatsu-Hirota S., Arai R., Ryzhii E., Abe M., Koga T.,
RA   Motohashi H., Nakao M., Sakimura K., Horii A., Waguri S., Ichimura Y.,
RA   Noda N.N., Komatsu M.;
RT   "Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox-
RT   independent stress response.";
RL   EMBO J. 42:e113349-e113349(2023).
RN   [99]
RP   FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-289 AND CYS-290, AND
RP   MUTAGENESIS OF 289-CYS-CYS-290.
RX   PubMed=37802024; DOI=10.1016/j.molcel.2023.09.004;
RA   Huang X., Yao J., Liu L., Chen J., Mei L., Huangfu J., Luo D., Wang X.,
RA   Lin C., Chen X., Yang Y., Ouyang S., Wei F., Wang Z., Zhang S., Xiang T.,
RA   Neculai D., Sun Q., Kong E., Tate E.W., Yang A.;
RT   "S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in
RT   mammalian autophagy.";
RL   Mol. Cell 83:3485-3501(2023).
RN   [100]
RP   INTERACTION WITH WDR83.
RX   PubMed=38103557; DOI=10.1016/j.molcel.2023.11.023;
RA   Abudu Y.P., Kournoutis A., Brenne H.B., Lamark T., Johansen T.;
RT   "MORG1 limits mTORC1 signaling by inhibiting Rag GTPases.";
RL   Mol. Cell 0:0-0(2023).
RN   [101]
RP   STRUCTURE BY NMR OF 387-436, CHARACTERIZATION OF VARIANT LEU-392, AND
RP   DOMAIN.
RX   PubMed=12857745; DOI=10.1074/jbc.m307416200;
RA   Ciani B., Layfield R., Cavey J.R., Sheppard P.W., Searle M.S.;
RT   "Structure of the ubiquitin-associated domain of p62 (SQSTM1) and
RT   implications for mutations that cause Paget's disease of bone.";
RL   J. Biol. Chem. 278:37409-37412(2003).
RN   [102]
RP   STRUCTURE BY NMR OF 387-436, AND INTERACTION WITH UBIQUITIN.
RX   PubMed=18083707; DOI=10.1074/jbc.m704973200;
RA   Long J., Gallagher T.R., Cavey J.R., Sheppard P.W., Ralston S.H.,
RA   Layfield R., Searle M.S.;
RT   "Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a
RT   novel conformational switch.";
RL   J. Biol. Chem. 283:5427-5440(2008).
RN   [103]
RP   STRUCTURE BY NMR OF 387-436.
RX   PubMed=17932931; DOI=10.1002/prot.21692;
RA   Evans C.L., Long J.E., Gallagher T.R., Hirst J.D., Searle M.S.;
RT   "Conformation and dynamics of the three-helix bundle UBA domain of p62 from
RT   experiment and simulation.";
RL   Proteins 71:227-240(2008).
RN   [104]
RP   STRUCTURE BY NMR OF 387-436, SUBUNIT, FUNCTION, MUTAGENESIS OF GLU-409 AND
RP   GLY-410, AND CHARACTERIZATION OF VARIANT PDB3 ARG-425.
RX   PubMed=19931284; DOI=10.1016/j.jmb.2009.11.032;
RA   Long J., Garner T.P., Pandya M.J., Craven C.J., Chen P., Shaw B.,
RA   Williamson M.P., Layfield R., Searle M.S.;
RT   "Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and
RT   regulates NF-kappaB signalling.";
RL   J. Mol. Biol. 396:178-194(2010).
RN   [105]
RP   VARIANT PDB3 LEU-392, AND VARIANTS VAL-117 AND GLN-274.
RX   PubMed=11992264; DOI=10.1086/340731;
RA   Laurin N., Brown J.P., Morissette J., Raymond V.;
RT   "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in
RT   Paget disease of bone.";
RL   Am. J. Hum. Genet. 70:1582-1588(2002).
RN   [106]
RP   VARIANT PDB3 LEU-392.
RX   PubMed=12374763; DOI=10.1093/hmg/11.22.2735;
RA   Hocking L.J., Lucas G.J.A., Daroszewska A., Mangion J., Olavesen M.,
RA   Cundy T., Nicholson G.C., Ward L., Bennett S.T., Wuyts W., Van Hul W.,
RA   Ralston S.H.;
RT   "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and
RT   sporadic Paget's disease.";
RL   Hum. Mol. Genet. 11:2735-2739(2002).
RN   [107]
RP   VARIANT PDB3 LEU-387.
RX   PubMed=14584883; DOI=10.1359/jbmr.2003.18.10.1748;
RA   Johnson-Pais T.L., Wisdom J.H., Weldon K.S., Cody J.D., Hansen M.F.,
RA   Singer F.R., Leach R.J.;
RT   "Three novel mutations in SQSTM1 identified in familial Paget's disease of
RT   bone.";
RL   J. Bone Miner. Res. 18:1748-1753(2003).
RN   [108]
RP   VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425.
RX   PubMed=15146436; DOI=10.1002/art.20224;
RA   Eekhoff E.W.M., Karperien M., Houtsma D., Zwinderman A.H., Dragoiescu C.,
RA   Kneppers A.L.J., Papapoulos S.E.;
RT   "Familial Paget's disease in The Netherlands: occurrence, identification of
RT   new mutations in the sequestosome 1 gene, and their clinical
RT   associations.";
RL   Arthritis Rheum. 50:1650-1654(2004).
RN   [109]
RP   VARIANT PDB3 LEU-392.
RX   PubMed=15207768; DOI=10.1016/j.bone.2004.01.010;
RA   Good D.A., Busfield F., Fletcher B.H., Lovelock P.K., Duffy D.L.,
RA   Kesting J.B., Andersen J., Shaw J.T.E.;
RT   "Identification of SQSTM1 mutations in familial Paget's disease in
RT   Australian pedigrees.";
RL   Bone 35:277-282(2004).
RN   [110]
RP   VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425.
RX   PubMed=15125799; DOI=10.1359/jbmr.040203;
RA   Falchetti A., Di Stefano M., Marini F., Del Monte F., Mavilia C.,
RA   Strigoli D., De Feo M.L., Isaia G., Masi L., Amedei A., Cioppi F.,
RA   Ghinoi V., Maddali Bongi S., Di Fede G., Sferrazza C., Rini G.B.,
RA   Melchiorre D., Matucci-Cerinic M., Brandi M.L.;
RT   "Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an
RT   Italian series of patients affected by Paget's disease of bone (PDB).";
RL   J. Bone Miner. Res. 19:1013-1017(2004).
RN   [111]
RP   VARIANTS PDB3 VAL-404; SER-411 AND ARG-425, AND CHARACTERIZATION OF
RP   VARIANTS VAL-404; SER-411 AND ARG-425.
RX   PubMed=15176995; DOI=10.1359/jbmr.0403015;
RA   Hocking L.J., Lucas G.J.A., Daroszewska A., Cundy T., Nicholson G.C.,
RA   Donath J., Walsh J.P., Finlayson C., Cavey J.R., Ciani B., Sheppard P.W.,
RA   Searle M.S., Layfield R., Ralston S.H.;
RT   "Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype
RT   phenotype correlation, functional analysis, and structural consequences.";
RL   J. Bone Miner. Res. 19:1122-1127(2004).
RN   [112]
RP   VARIANT GLU-238, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=17488105; DOI=10.1021/pr0700908;
RA   Bunger M.K., Cargile B.J., Sevinsky J.R., Deyanova E., Yates N.A.,
RA   Hendrickson R.C., Stephenson J.L. Jr.;
RT   "Detection and validation of non-synonymous coding SNPs from orthogonal
RT   analysis of shotgun proteomics data.";
RL   J. Proteome Res. 6:2331-2340(2007).
RN   [113]
RP   INVOLVEMENT IN FTDALS3, VARIANTS FTDALS3 VAL-16; VAL-33; GLU-80; MET-90;
RP   TRP-107; ASN-129; CYS-212; VAL-219; PRO-226; LEU-228; THR-232; LYS-238 DEL;
RP   ASN-258; CYS-321; GLY-329; LEU-348; LEU-387; LEU-392 AND PRO-430, AND
RP   VARIANTS VAL-17; ARG-103; GLN-107; TYR-108; HIS-110; VAL-117; SER-118;
RP   GLY-119; SER-125; CYS-139; ILE-153; LEU-180; HIS-217; GLU-238;
RP   265-SER-ARG-266 DELINS SER-ARG; ASP-274; ILE-278; VAL-308; LYS-319; GLY-334
RP   DEL; THR-349 AND LEU-439.
RX   PubMed=24899140; DOI=10.1007/s00401-014-1298-7;
RA   van der Zee J., Van Langenhove T., Kovacs G.G., Dillen L., Deschamps W.,
RA   Engelborghs S., Matej R., Vandenbulcke M., Sieben A., Dermaut B., Smets K.,
RA   Van Damme P., Merlin C., Laureys A., Van Den Broeck M., Mattheijssens M.,
RA   Peeters K., Benussi L., Binetti G., Ghidoni R., Borroni B., Padovani A.,
RA   Archetti S., Pastor P., Razquin C., Ortega-Cubero S., Hernandez I.,
RA   Boada M., Ruiz A., de Mendonca A., Miltenberger-Miltenyi G., do Couto F.S.,
RA   Sorbi S., Nacmias B., Bagnoli S., Graff C., Chiang H.H., Thonberg H.,
RA   Perneczky R., Diehl-Schmid J., Alexopoulos P., Frisoni G.B., Bonvicini C.,
RA   Synofzik M., Maetzler W., vom Hagen J.M., Schoels L., Haack T.B.,
RA   Strom T.M., Prokisch H., Dols-Icardo O., Clarimon J., Lleo A., Santana I.,
RA   Almeida M.R., Santiago B., Heneka M.T., Jessen F., Ramirez A.,
RA   Sanchez-Valle R., Llado A., Gelpi E., Sarafov S., Tournev I., Jordanova A.,
RA   Parobkova E., Fabrizi G.M., Testi S., Salmon E., Stroebel T., Santens P.,
RA   Robberecht W., De Jonghe P., Martin J.J., Cras P., Vandenberghe R.,
RA   De Deyn P.P., Cruts M., Sleegers K., Van Broeckhoven C.;
RT   "Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar
RT   degeneration.";
RL   Acta Neuropathol. 128:397-410(2014).
CC   -!- FUNCTION: Molecular adapter required for selective macroautophagy
CC       (aggrephagy) by acting as a bridge between polyubiquitinated proteins
CC       and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508,
CC       PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177,
CC       PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397,
CC       PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540,
CC       PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the
CC       recruitment of ubiquitinated cargo proteins to autophagosomes via
CC       multiple domains that bridge proteins and organelles in different steps
CC       (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730,
CC       PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540,
CC       PubMed:37802024). SQSTM1 first mediates the assembly and removal of
CC       ubiquitinated proteins by undergoing liquid-liquid phase separation
CC       upon binding to ubiquitinated proteins via its UBA domain, leading to
CC       the formation of insoluble cytoplasmic inclusions, known as p62 bodies
CC       (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730,
CC       PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024).
CC       SQSTM1 then interacts with ATG8 family proteins on autophagosomes via
CC       its LIR motif, leading to p62 body recruitment to autophagosomes,
CC       followed by autophagic clearance of ubiquitinated proteins
CC       (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177,
CC       PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself
CC       degraded along with its ubiquitinated cargos (PubMed:16286508,
CC       PubMed:17580304, PubMed:37802024). Also required to recruit
CC       ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092).
CC       Also involved in autophagy of peroxisomes (pexophagy) in response to
CC       reactive oxygen species (ROS) by acting as a bridge between
CC       ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts
CC       as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1:
CC       interaction inactivates the BCR(KEAP1) complex by sequestering the
CC       complex in inclusion bodies, promoting nuclear accumulation of
CC       NFE2L2/NRF2 and subsequent expression of cytoprotective genes
CC       (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101).
CC       Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to
CC       autophagosomes (PubMed:29496741). Involved in endosome organization by
CC       retaining vesicles in the perinuclear cloud: following ubiquitination
CC       by RNF26, attracts specific vesicle-associated adapters, forming a
CC       molecular bridge that restrains cognate vesicles in the perinuclear
CC       region and organizes the endosomal pathway for efficient cargo
CC       transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2
CC       into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal
CC       degradation (PubMed:25101860). May regulate the activation of NFKB1 by
CC       TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400,
CC       PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148,
CC       PubMed:19931284). May play a role in titin/TTN downstream signaling in
CC       muscle cells (PubMed:15802564). Adapter that mediates the interaction
CC       between TRAF6 and CYLD (By similarity). {ECO:0000250|UniProtKB:Q64337,
CC       ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026,
CC       ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037,
CC       ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564,
CC       ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362,
CC       ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508,
CC       ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284,
CC       ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20452972,
CC       ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22622177,
CC       ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:25101860,
CC       ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27368102,
CC       ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:28404643,
CC       ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29496741,
CC       ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589,
CC       ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:33472082,
CC       ECO:0000269|PubMed:33509017, ECO:0000269|PubMed:34471133,
CC       ECO:0000269|PubMed:34893540, ECO:0000269|PubMed:35831301,
CC       ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}.
CC   -!- SUBUNIT: Homooligomer or heterooligomer; may form homotypic arrays
CC       (PubMed:12887891, PubMed:19931284). Dimerization interferes with
CC       ubiquitin binding (PubMed:19931284). Component of a ternary complex
CC       with PAWR and PRKCZ (PubMed:11755531). Forms a complex with JUB/Ajuba,
CC       PRKCZ and TRAF6 (PubMed:15870274). Identified in a complex with TRAF6
CC       and CYLD (By similarity). Identified in a heterotrimeric complex with
CC       ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the
CC       same ubiquitin molecule (PubMed:21923101). Interacts (via LIR motif)
CC       with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members,
CC       including GABARAP, GABARAPL1 and GABARAPL2; these interactions are
CC       necessary for the recruitment MAP1 LC3 family members to inclusion
CC       bodies containing polyubiquitinated protein aggregates and for their
CC       degradation by autophagy (PubMed:16286508, PubMed:17580304,
CC       PubMed:22421968, PubMed:24089205, PubMed:24668264). Interacts directly
CC       with PRKCI and PRKCZ (PubMed:10356400, PubMed:12813044,
CC       PubMed:12887891, PubMed:9566925). Interacts with EBI3, LCK, RASA1,
CC       NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5 (PubMed:10708586,
CC       PubMed:11244088, PubMed:12471037, PubMed:8551575, PubMed:8618896,
CC       PubMed:8650207, PubMed:8910285). Upon TNF stimulation, interacts with
CC       RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF-
CC       R1/TNFRSF1A, TRADD and RIPK1 (PubMed:10747026). Interacts with the
CC       proteasome subunits PSMD4 and PSMC2 (PubMed:15340068). Interacts with
CC       TRAF6 (PubMed:10747026). Interacts with 'Lys-63'-linked
CC       polyubiquitinated MAPT/TAU (PubMed:15953362). Interacts with FHOD3
CC       (PubMed:21149568). Interacts with CYLD (PubMed:32185393). Interacts
CC       with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085,
CC       PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with
CC       UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct
CC       and regulates the interaction of SQSTM1 with ubiquitinated proteins
CC       (PubMed:28404643). Interacts with WDFY3; this interaction is required
CC       to recruit WDFY3 to cytoplasmic bodies and to PML bodies
CC       (PubMed:20168092). Interacts with LRRC25 (PubMed:29288164). Interacts
CC       with STING1; leading to relocalization of STING1 to autophagosomes
CC       (PubMed:29496741). Interacts (when phosphorylated at Ser-349) with
CC       KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex
CC       by sequestering KEAP1 in inclusion bodies, promoting its degradation
CC       (PubMed:20452972, PubMed:20495340, PubMed:37306101). Interacts with
CC       MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester
CC       KEAP1 (PubMed:33393215). Interacts with GBP1 (By similarity). Interacts
CC       with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5;
CC       specifically binds PEX5 ubiquitinated at 'Lys-209' in response to
CC       reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1
CC       domain) with TNS2; the interaction leads to sequestration of TNS2 in
CC       cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and
CC       proteasomal degradation (PubMed:25101860). Interacts with IRS1; the
CC       interaction is disrupted by the presence of tensin TNS2
CC       (PubMed:25101860). Interacts with TRIM5 (PubMed:20357094,
CC       PubMed:25127057). Interacts with TRIM11 (when ubiquitinated); promoting
CC       AIM2 recruitment to autophagosomes and autophagy-dependent degradation
CC       of AIM2 (PubMed:27498865). Interacts with TRIM13 (PubMed:22178386).
CC       Interacts with TRIM16 (PubMed:30143514). Interacts with TRIM23
CC       (PubMed:28871090). Interacts with TRIM50 (PubMed:22792322). Interacts
CC       with TRIM55 (PubMed:15802564). Interacts with ECSIT; this interaction
CC       inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT
CC       complex (PubMed:31281713). Interacts with GABRR1, GABRR2 and GABRR3 (By
CC       similarity). Interacts with WDR83 (PubMed:38103557). Interacts with
CC       GRB2 (PubMed:35831301). Interacts with USP12; the interaction is
CC       independent of USP12 deubiquitinase activity and may be involved in
CC       regulation of autophagic flux (PubMed:30266909). Interacts with ASB6
CC       (PubMed:34164402). {ECO:0000250|UniProtKB:O08623,
CC       ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400,
CC       ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:10747026,
CC       ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:11755531,
CC       ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:12813044,
CC       ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:15340068,
CC       ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15870274,
CC       ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508,
CC       ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284,
CC       ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094,
CC       ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:20495340,
CC       ECO:0000269|PubMed:21149568, ECO:0000269|PubMed:21923101,
CC       ECO:0000269|PubMed:22178386, ECO:0000269|PubMed:22421968,
CC       ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:23274085,
CC       ECO:0000269|PubMed:24089205, ECO:0000269|PubMed:24668264,
CC       ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25101860,
CC       ECO:0000269|PubMed:25127057, ECO:0000269|PubMed:25422469,
CC       ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27498865,
CC       ECO:0000269|PubMed:28404643, ECO:0000269|PubMed:28871090,
CC       ECO:0000269|PubMed:29288164, ECO:0000269|PubMed:29496741,
CC       ECO:0000269|PubMed:30143514, ECO:0000269|PubMed:30266909,
CC       ECO:0000269|PubMed:31281713, ECO:0000269|PubMed:32185393,
CC       ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:34164402,
CC       ECO:0000269|PubMed:34471133, ECO:0000269|PubMed:35831301,
CC       ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:38103557,
CC       ECO:0000269|PubMed:8551575, ECO:0000269|PubMed:8618896,
CC       ECO:0000269|PubMed:8650207, ECO:0000269|PubMed:8910285,
CC       ECO:0000269|PubMed:9566925}.
CC   -!- INTERACTION:
CC       Q13501; P05067: APP; NbExp=6; IntAct=EBI-307104, EBI-77613;
CC       Q13501; P54253: ATXN1; NbExp=4; IntAct=EBI-307104, EBI-930964;
CC       Q13501; O95817: BAG3; NbExp=3; IntAct=EBI-307104, EBI-747185;
CC       Q13501; Q16543: CDC37; NbExp=8; IntAct=EBI-307104, EBI-295634;
CC       Q13501; P57739: CLDN2; NbExp=4; IntAct=EBI-307104, EBI-751440;
CC       Q13501; P34972: CNR2; NbExp=5; IntAct=EBI-307104, EBI-2835940;
CC       Q13501; Q15038: DAZAP2; NbExp=4; IntAct=EBI-307104, EBI-724310;
CC       Q13501; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-307104, EBI-25840445;
CC       Q13501; O14682: ENC1; NbExp=7; IntAct=EBI-307104, EBI-6425462;
CC       Q13501; Q2V2M9: FHOD3; NbExp=6; IntAct=EBI-307104, EBI-6395541;
CC       Q13501; Q2V2M9-4: FHOD3; NbExp=4; IntAct=EBI-307104, EBI-6395505;
CC       Q13501; O95166: GABARAP; NbExp=17; IntAct=EBI-307104, EBI-712001;
CC       Q13501; Q9H0R8: GABARAPL1; NbExp=18; IntAct=EBI-307104, EBI-746969;
CC       Q13501; P60520: GABARAPL2; NbExp=25; IntAct=EBI-307104, EBI-720116;
CC       Q13501; P0DMV8: HSPA1A; NbExp=3; IntAct=EBI-307104, EBI-11052499;
CC       Q13501; P42858: HTT; NbExp=11; IntAct=EBI-307104, EBI-466029;
CC       Q13501; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-307104, EBI-81279;
CC       Q13501; Q14145: KEAP1; NbExp=21; IntAct=EBI-307104, EBI-751001;
CC       Q13501; Q5S007: LRRK2; NbExp=18; IntAct=EBI-307104, EBI-5323863;
CC       Q13501; Q9UDY8: MALT1; NbExp=2; IntAct=EBI-307104, EBI-1047372;
CC       Q13501; Q9H492: MAP1LC3A; NbExp=16; IntAct=EBI-307104, EBI-720768;
CC       Q13501; Q9GZQ8: MAP1LC3B; NbExp=31; IntAct=EBI-307104, EBI-373144;
CC       Q13501; Q9BXW4: MAP1LC3C; NbExp=8; IntAct=EBI-307104, EBI-2603996;
CC       Q13501; Q13163: MAP2K5; NbExp=5; IntAct=EBI-307104, EBI-307294;
CC       Q13501; Q14596: NBR1; NbExp=7; IntAct=EBI-307104, EBI-742698;
CC       Q13501; Q9BPW8: NIPSNAP1; NbExp=3; IntAct=EBI-307104, EBI-307125;
CC       Q13501; P04629: NTRK1; NbExp=2; IntAct=EBI-307104, EBI-1028226;
CC       Q13501; Q96CV9: OPTN; NbExp=7; IntAct=EBI-307104, EBI-748974;
CC       Q13501; P50542-3: PEX5; NbExp=2; IntAct=EBI-307104, EBI-12181987;
CC       Q13501; Q9UGJ0: PRKAG2; NbExp=3; IntAct=EBI-307104, EBI-2959705;
CC       Q13501; P41743: PRKCI; NbExp=11; IntAct=EBI-307104, EBI-286199;
CC       Q13501; Q12923: PTPN13; NbExp=2; IntAct=EBI-307104, EBI-355227;
CC       Q13501; P54725: RAD23A; NbExp=3; IntAct=EBI-307104, EBI-746453;
CC       Q13501; P58004: SESN2; NbExp=9; IntAct=EBI-307104, EBI-3939642;
CC       Q13501; Q96B97: SH3KBP1; NbExp=4; IntAct=EBI-307104, EBI-346595;
CC       Q13501; P84022: SMAD3; NbExp=3; IntAct=EBI-307104, EBI-347161;
CC       Q13501; P37840: SNCA; NbExp=3; IntAct=EBI-307104, EBI-985879;
CC       Q13501; Q13501: SQSTM1; NbExp=10; IntAct=EBI-307104, EBI-307104;
CC       Q13501; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-307104, EBI-357085;
CC       Q13501; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-307104, EBI-359276;
CC       Q13501; P07437: TUBB; NbExp=4; IntAct=EBI-307104, EBI-350864;
CC       Q13501; P0CG48: UBC; NbExp=5; IntAct=EBI-307104, EBI-3390054;
CC       Q13501; P11473: VDR; NbExp=4; IntAct=EBI-307104, EBI-286357;
CC       Q13501; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-307104, EBI-11141397;
CC       Q13501; Q8IZQ1: WDFY3; NbExp=7; IntAct=EBI-307104, EBI-1569256;
CC       Q13501; P19544-6: WT1; NbExp=3; IntAct=EBI-307104, EBI-11745701;
CC       Q13501; P17028: ZNF24; NbExp=3; IntAct=EBI-307104, EBI-707773;
CC       Q13501; A8K2U6; NbExp=3; IntAct=EBI-307104, EBI-25877771;
CC       Q13501; P38182: ATG8; Xeno; NbExp=3; IntAct=EBI-307104, EBI-2684;
CC       Q13501; Q9Z2X8: Keap1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-647110;
CC       Q13501; P12709: PGI1; Xeno; NbExp=3; IntAct=EBI-307104, EBI-7238;
CC       Q13501; P28700: Rxra; Xeno; NbExp=3; IntAct=EBI-307104, EBI-346715;
CC       Q13501; O70405: Ulk1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-8390771;
CC       Q13501; P12504: vif; Xeno; NbExp=2; IntAct=EBI-307104, EBI-779991;
CC   -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, autophagosome
CC       {ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508,
CC       ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:20168092,
CC       ECO:0000269|PubMed:37802024}. Preautophagosomal structure
CC       {ECO:0000269|PubMed:34471133}. Cytoplasm, cytosol
CC       {ECO:0000269|PubMed:11786419, ECO:0000269|PubMed:11981755,
CC       ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094,
CC       ECO:0000269|PubMed:21923101, ECO:0000269|PubMed:22017874,
CC       ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:29343546,
CC       ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589,
CC       ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. Nucleus, PML
CC       body {ECO:0000269|PubMed:20168092}. Late endosome
CC       {ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:9566925}. Lysosome
CC       {ECO:0000269|PubMed:9566925}. Nucleus {ECO:0000269|PubMed:10708586}.
CC       Endoplasmic reticulum {ECO:0000269|PubMed:22178386}. Cytoplasm,
CC       myofibril, sarcomere {ECO:0000250|UniProtKB:O08623}. Note=In cardiac
CC       muscle, localizes to the sarcomeric band (By similarity). Localizes to
CC       cytoplasmic membraneless inclusion bodies, known as p62 bodies,
CC       containing polyubiquitinated protein aggregates (PubMed:11786419,
CC       PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397,
CC       PubMed:31857589, PubMed:37306101, PubMed:37802024). In
CC       neurodegenerative diseases, detected in Lewy bodies in Parkinson
CC       disease, neurofibrillary tangles in Alzheimer disease, and HTT
CC       aggregates in Huntington disease (PubMed:15158159). In protein
CC       aggregate diseases of the liver, found in large amounts in Mallory
CC       bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in
CC       hepatocellular carcinoma, and in SERPINA1 aggregates (PubMed:11981755).
CC       Enriched in Rosenthal fibers of pilocytic astrocytoma
CC       (PubMed:11786419). In the cytoplasm, observed in both membrane-free
CC       ubiquitin-containing protein aggregates (sequestosomes) and membrane-
CC       surrounded autophagosomes (PubMed:15953362, PubMed:17580304).
CC       Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum
CC       (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies
CC       (PubMed:20357094). When nuclear export is blocked by treatment with
CC       leptomycin B, accumulates in PML bodies (PubMed:20168092).
CC       {ECO:0000250|UniProtKB:O08623, ECO:0000269|PubMed:11786419,
CC       ECO:0000269|PubMed:11981755, ECO:0000269|PubMed:15158159,
CC       ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:17580304,
CC       ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094,
CC       ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22178386,
CC       ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29507397,
CC       ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:37306101,
CC       ECO:0000269|PubMed:37802024}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q13501-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q13501-2; Sequence=VSP_015841;
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC       {ECO:0000269|PubMed:8650207}.
CC   -!- DEVELOPMENTAL STAGE: During myogenesis, there is a marked increase in
CC       levels in fully differentiated myotubes compared to undifferentiated
CC       myoblasts. {ECO:0000269|PubMed:25101860}.
CC   -!- INDUCTION: By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at
CC       protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is
CC       directly activated by NFE2L2/NRF2; creating a positive feedback loop
CC       (PubMed:20452972). {ECO:0000269|PubMed:12700667,
CC       ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:20452972,
CC       ECO:0000269|PubMed:9762895}.
CC   -!- DOMAIN: The UBA domain binds specifically 'Lys-63'-linked polyubiquitin
CC       chains of polyubiquitinated substrates (PubMed:12857745,
CC       PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the
CC       interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains
CC       are necessary and sufficient for the localization into the ubiquitin-
CC       containing inclusion bodies (PubMed:15802564).
CC       {ECO:0000269|PubMed:12857745, ECO:0000269|PubMed:15340068,
CC       ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28322253,
CC       ECO:0000269|PubMed:31857589}.
CC   -!- DOMAIN: The PB1 domain mediates homooligomerization and interactions
CC       with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044,
CC       PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and
CC       UBA domains are necessary and sufficient for the localization into the
CC       ubiquitin-containing inclusion bodies (PubMed:15802564).
CC       {ECO:0000269|PubMed:12813044, ECO:0000269|PubMed:12887891,
CC       ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28404643}.
CC   -!- DOMAIN: The ZZ-type zinc finger mediates the interaction with RIPK1.
CC       {ECO:0000269|PubMed:10747026}.
CC   -!- DOMAIN: The LIR (LC3-interacting region) motif mediates the interaction
CC       with ATG8 family proteins. {ECO:0000269|PubMed:23908376}.
CC   -!- PTM: Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer
CC       interface and increases binding affinity to ubiquitinated proteins (By
CC       similarity). Phosphorylation at Ser-407 also primes for subsequent
CC       phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403
CC       by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing
CC       the affinity between the UBA domain and polyubiquitin chains
CC       (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1
CC       is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by
CC       TBK1, leading to promote relocalization of 'Lys-63'-linked
CC       ubiquitinated STING1 to autophagosomes (PubMed:29496741).
CC       Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and
CC       inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear
CC       accumulation and expression of phase II detoxifying enzymes
CC       (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564).
CC       {ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:15802564,
CC       ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:25040165,
CC       ECO:0000269|PubMed:29496741, ECO:0000269|PubMed:37306101}.
CC   -!- PTM: Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1
CC       attracts specific vesicle-associated adapters, forming a molecular
CC       bridge that restrains cognate vesicles in the perinuclear region and
CC       organizes the endosomal pathway for efficient cargo transport
CC       (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3
CC       increases its ability to bind polyubiquitin chains by destabilizing the
CC       UBA dimer interface (PubMed:28322253). Deubiquitination by USP15
CC       releases target vesicles for fast transport into the cell periphery
CC       (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420,
CC       increasing SQSTM1 sequestering activity and promoting its degradation
CC       (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked
CC       polyubiquitination leading to xenophagic targeting of bacteria and
CC       inhibition of their replication (PubMed:27880896).
CC       {ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:27880896,
CC       ECO:0000269|PubMed:28322253, ECO:0000269|PubMed:28380357,
CC       ECO:0000269|PubMed:33472082}.
CC   -!- PTM: Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity
CC       by destabilizing the UBA dimer interface and increases binding affinity
CC       to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6
CC       (PubMed:31857589). {ECO:0000269|PubMed:31857589}.
CC   -!- PTM: Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for
CC       efficient autophagic degradation of SQSTM1-cargo complexes by promoting
CC       affinity for ATG8 proteins and recruitment of p62 bodies to
CC       autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290
CC       by LYPLA1 (PubMed:37802024). {ECO:0000269|PubMed:37802024}.
CC   -!- PTM: (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading
CC       to its degradation (PubMed:24331465). Degradation by SpeB prevents
CC       autophagy, promoting to S.pyogenes intracellular replication
CC       (PubMed:24331465). {ECO:0000269|PubMed:24331465}.
CC   -!- PTM: (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1;
CC       leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1-
CC       positive structures. {ECO:0000269|PubMed:33509017}.
CC   -!- DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of
CC       bone remodeling characterized by increased bone turnover affecting one
CC       or more sites throughout the skeleton, primarily the axial skeleton.
CC       Osteoclastic overactivity followed by compensatory osteoblastic
CC       activity leads to a structurally disorganized mosaic of bone (woven
CC       bone), which is mechanically weaker, larger, less compact, more
CC       vascular, and more susceptible to fracture than normal adult lamellar
CC       bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763,
CC       ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799,
CC       ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995,
CC       ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284,
CC       ECO:0000269|PubMed:29507397}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Note=In a cell model for Huntington disease (HD), appears to
CC       form a shell surrounding aggregates of mutant HTT that may protect
CC       cells from apoptosis, possibly by recruiting autophagosomal components
CC       to the polyubiquitinated protein aggregates.
CC       {ECO:0000269|PubMed:16286508}.
CC   -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
CC       (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by
CC       frontotemporal dementia and/or amyotrophic lateral sclerosis in
CC       affected individuals. There is high intrafamilial variation.
CC       Frontotemporal dementia is characterized by frontal and temporal lobe
CC       atrophy associated with neuronal loss, gliosis, and dementia. Patients
CC       exhibit progressive changes in social, behavioral, and/or language
CC       function. Amyotrophic lateral sclerosis is characterized by the death
CC       of motor neurons in the brain, brainstem, and spinal cord, resulting in
CC       fatal paralysis. Some FTDALS3 patients may also develop Paget disease
CC       of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580,
CC       ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy,
CC       childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder
CC       characterized by gait abnormalities, ataxia, dysarthria, dystonia,
CC       vertical gaze palsy, and cognitive decline. Disease onset is in
CC       childhood or adolescence. NADGP transmission pattern is consistent with
CC       autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}.
CC       Note=The disease is caused by variants affecting the gene represented
CC       in this entry.
CC   -!- DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An
CC       autosomal dominant myopathy with adult onset, characterized by muscle
CC       weakness of the distal upper and lower limbs, walking difficulties, and
CC       proximal weakness of the shoulder girdle muscles. Muscle biopsy shows
CC       rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is
CC       caused by variants affecting the gene represented in this entry.
CC   -!- DISEASE: Note=A chromosomal aberration involving SQSTM1 is found in a
CC       form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34)
CC       with NUP214. {ECO:0000269|PubMed:20851865}.
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DR   EMBL; U41806; AAA93299.1; -; mRNA.
DR   EMBL; U46751; AAC52070.1; -; mRNA.
DR   EMBL; AK098077; BAG53577.1; -; mRNA.
DR   EMBL; AK312451; BAG35358.1; -; mRNA.
DR   EMBL; AC008393; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC000951; AAH00951.1; -; mRNA.
DR   EMBL; BC001874; AAH01874.1; -; mRNA.
DR   EMBL; BC003139; AAH03139.1; -; mRNA.
DR   EMBL; BC017222; AAH17222.1; -; mRNA.
DR   EMBL; BC019111; AAH19111.1; -; mRNA.
DR   EMBL; AF060494; AAC64516.1; -; Genomic_DNA.
DR   CCDS; CCDS34317.1; -. [Q13501-1]
DR   CCDS; CCDS47355.1; -. [Q13501-2]
DR   RefSeq; NP_001135770.1; NM_001142298.2. [Q13501-2]
DR   RefSeq; NP_001135771.1; NM_001142299.2. [Q13501-2]
DR   RefSeq; NP_003891.1; NM_003900.5. [Q13501-1]
DR   PDB; 1Q02; NMR; -; A=387-436.
DR   PDB; 2JY7; NMR; -; A=387-436.
DR   PDB; 2JY8; NMR; -; A=387-436.
DR   PDB; 2K0B; NMR; -; X=387-436.
DR   PDB; 2KNV; NMR; -; A/B=387-436.
DR   PDB; 4MJS; X-ray; 2.50 A; B/D/F/H/J/L/N/P/R/T/V/X=3-102.
DR   PDB; 4UF8; EM; 10.90 A; A/B/C/I=3-102.
DR   PDB; 4UF9; EM; 10.30 A; A/B/D=1-122.
DR   PDB; 5YP7; X-ray; 1.42 A; A/D=126-180.
DR   PDB; 5YP8; X-ray; 1.45 A; A/B=126-180.
DR   PDB; 5YPA; X-ray; 2.50 A; A/B=126-180.
DR   PDB; 5YPB; X-ray; 2.90 A; A/B/C/D=126-180.
DR   PDB; 5YPC; X-ray; 1.96 A; A/B/C/D=126-180.
DR   PDB; 5YPE; X-ray; 2.85 A; A/B/C/D=126-180.
DR   PDB; 5YPF; X-ray; 2.95 A; A/B/C/D=126-180.
DR   PDB; 5YPG; X-ray; 2.20 A; A/B=126-180.
DR   PDB; 5YPH; X-ray; 1.63 A; A/B=126-180.
DR   PDB; 6JM4; X-ray; 3.20 A; A/B/C/D=1-102.
DR   PDB; 6KHZ; X-ray; 2.80 A; A/B/C/D=125-169.
DR   PDB; 6MIU; X-ray; 1.90 A; A/B=120-171.
DR   PDB; 6MJ7; X-ray; 1.41 A; A=120-171.
DR   PDB; 6TGY; EM; 3.50 A; A=1-122.
DR   PDB; 6TH3; EM; 4.00 A; A/B/C=1-122.
DR   PDB; 7R1O; X-ray; 2.20 A; AAA/BBB/CCC/DDD=120-172.
DR   PDBsum; 1Q02; -.
DR   PDBsum; 2JY7; -.
DR   PDBsum; 2JY8; -.
DR   PDBsum; 2K0B; -.
DR   PDBsum; 2KNV; -.
DR   PDBsum; 4MJS; -.
DR   PDBsum; 4UF8; -.
DR   PDBsum; 4UF9; -.
DR   PDBsum; 5YP7; -.
DR   PDBsum; 5YP8; -.
DR   PDBsum; 5YPA; -.
DR   PDBsum; 5YPB; -.
DR   PDBsum; 5YPC; -.
DR   PDBsum; 5YPE; -.
DR   PDBsum; 5YPF; -.
DR   PDBsum; 5YPG; -.
DR   PDBsum; 5YPH; -.
DR   PDBsum; 6JM4; -.
DR   PDBsum; 6KHZ; -.
DR   PDBsum; 6MIU; -.
DR   PDBsum; 6MJ7; -.
DR   PDBsum; 6TGY; -.
DR   PDBsum; 6TH3; -.
DR   PDBsum; 7R1O; -.
DR   AlphaFoldDB; Q13501; -.
DR   BMRB; Q13501; -.
DR   EMDB; EMD-10501; -.
DR   EMDB; EMD-10502; -.
DR   EMDB; EMD-2936; -.
DR   EMDB; EMD-2937; -.
DR   SMR; Q13501; -.
DR   BioGRID; 114397; 1356.
DR   CORUM; Q13501; -.
DR   DIP; DIP-34443N; -.
DR   ELM; Q13501; -.
DR   FunCoup; Q13501; 2230.
DR   IntAct; Q13501; 311.
DR   MINT; Q13501; -.
DR   STRING; 9606.ENSP00000374455; -.
DR   BindingDB; Q13501; -.
DR   ChEMBL; CHEMBL4295816; -.
DR   GuidetoPHARMACOLOGY; 3213; -.
DR   MoonDB; Q13501; Predicted.
DR   GlyGen; Q13501; 2 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; Q13501; -.
DR   PhosphoSitePlus; Q13501; -.
DR   SwissPalm; Q13501; -.
DR   BioMuta; SQSTM1; -.
DR   DMDM; 74735628; -.
DR   jPOST; Q13501; -.
DR   MassIVE; Q13501; -.
DR   PaxDb; 9606-ENSP00000374455; -.
DR   PeptideAtlas; Q13501; -.
DR   ProteomicsDB; 59496; -. [Q13501-1]
DR   ProteomicsDB; 59497; -. [Q13501-2]
DR   Pumba; Q13501; -.
DR   Antibodypedia; 761; 1362 antibodies from 49 providers.
DR   DNASU; 8878; -.
DR   YCharOS; Q13501; Tested 18 antibodies from 6 manufacturers.
DR   Ensembl; ENST00000360718.5; ENSP00000353944.5; ENSG00000161011.21. [Q13501-2]
DR   Ensembl; ENST00000389805.9; ENSP00000374455.4; ENSG00000161011.21. [Q13501-1]
DR   Ensembl; ENST00000640444.2; ENSP00000491834.2; ENSG00000284099.3. [Q13501-1]
DR   Ensembl; ENST00000643389.2; ENSP00000495843.2; ENSG00000284099.3. [Q13501-1]
DR   GeneID; 8878; -.
DR   KEGG; hsa:8878; -.
DR   MANE-Select; ENST00000389805.9; ENSP00000374455.4; NM_003900.5; NP_003891.1.
DR   UCSC; uc003mkw.5; human. [Q13501-1]
DR   AGR; HGNC:11280; -.
DR   ClinPGx; PA36109; -.
DR   CTD; 8878; -.
DR   DisGeNET; 8878; -.
DR   GeneCards; SQSTM1; -.
DR   HGNC; HGNC:11280; SQSTM1.
DR   HPA; ENSG00000161011; Tissue enhanced (skeletal).
DR   MalaCards; SQSTM1; -.
DR   MIM; 167250; phenotype.
DR   MIM; 601530; gene.
DR   MIM; 616437; phenotype.
DR   MIM; 617145; phenotype.
DR   MIM; 617158; phenotype.
DR   OpenTargets; ENSG00000161011; -.
DR   Orphanet; 803; Amyotrophic lateral sclerosis.
DR   Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR   Orphanet; 603; Distal myopathy, Welander type.
DR   Orphanet; 275872; Frontotemporal dementia with motor neuron disease.
DR   VEuPathDB; HostDB:ENSG00000161011; -.
DR   eggNOG; KOG4582; Eukaryota.
DR   GeneTree; ENSGT00390000002781; -.
DR   HOGENOM; CLU_038011_1_0_1; -.
DR   InParanoid; Q13501; -.
DR   OMA; NCNGWLT; -.
DR   OrthoDB; 441278at2759; -.
DR   PAN-GO; Q13501; 7 GO annotations based on evolutionary models.
DR   PhylomeDB; Q13501; -.
DR   PathwayCommons; Q13501; -.
DR   Reactome; R-HSA-205043; NRIF signals cell death from the nucleus.
DR   Reactome; R-HSA-209543; p75NTR recruits signalling complexes.
DR   Reactome; R-HSA-209560; NF-kB is activated and signals survival.
DR   Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy.
DR   Reactome; R-HSA-8951664; Neddylation.
DR   Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR   Reactome; R-HSA-9664873; Pexophagy.
DR   Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants.
DR   Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway.
DR   Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2.
DR   SignaLink; Q13501; -.
DR   SIGNOR; Q13501; -.
DR   Agora; ENSG00000161011; -.
DR   BioGRID-ORCS; 8878; 28 hits in 1166 CRISPR screens.
DR   CD-CODE; 1822EB5E; Synthetic Condensate 000092.
DR   CD-CODE; 5D6181E1; Synthetic Condensate 000293.
DR   CD-CODE; 718A9EC3; P62 body.
DR   CD-CODE; 98C8800A; Synthetic Condensate 000338.
DR   CD-CODE; B5B9A610; PML body.
DR   CD-CODE; DEE660B4; Stress granule.
DR   CD-CODE; EF6CBD8C; Synthetic Condensate 000070.
DR   CD-CODE; F17BA747; P62 cluster.
DR   CD-CODE; F5639AB0; Synthetic Condensate 000096.
DR   ChiTaRS; SQSTM1; human.
DR   EvolutionaryTrace; Q13501; -.
DR   GeneWiki; Sequestosome_1; -.
DR   GenomeRNAi; 8878; -.
DR   Pharos; Q13501; Tbio.
DR   PRO; PR:Q13501; -.
DR   Proteomes; UP000005640; Chromosome 5.
DR   RNAct; Q13501; protein.
DR   Bgee; ENSG00000161011; Expressed in right adrenal gland cortex and 177 other cell types or tissues.
DR   ExpressionAtlas; Q13501; baseline and differential.
DR   GO; GO:0016235; C:aggresome; IBA:GO_Central.
DR   GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005776; C:autophagosome; IDA:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0016234; C:inclusion body; IDA:UniProtKB.
DR   GO; GO:0043232; C:intracellular membraneless organelle; IDA:UniProtKB.
DR   GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0097413; C:Lewy body; IEA:Ensembl.
DR   GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0000932; C:P-body; IDA:UniProtKB.
DR   GO; GO:0000407; C:phagophore assembly site; IEA:UniProtKB-SubCell.
DR   GO; GO:0016605; C:PML body; IDA:UniProtKB.
DR   GO; GO:0030017; C:sarcomere; IEA:UniProtKB-SubCell.
DR   GO; GO:0097225; C:sperm midpiece; IEA:Ensembl.
DR   GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0035255; F:ionotropic glutamate receptor binding; ISS:ARUK-UCL.
DR   GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB.
DR   GO; GO:0140693; F:molecular condensate scaffold activity; IDA:UniProtKB.
DR   GO; GO:0140313; F:molecular sequestering activity; IDA:UniProt.
DR   GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB.
DR   GO; GO:0005080; F:protein kinase C binding; IPI:UniProtKB.
DR   GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB.
DR   GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR   GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProtKB.
DR   GO; GO:0030971; F:receptor tyrosine kinase binding; TAS:ProtInc.
DR   GO; GO:0042169; F:SH2 domain binding; IDA:UniProtKB.
DR   GO; GO:0035591; F:signaling adaptor activity; IDA:UniProtKB.
DR   GO; GO:0038023; F:signaling receptor activity; IDA:UniProt.
DR   GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB.
DR   GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB.
DR   GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0035973; P:aggrephagy; IDA:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0006914; P:autophagy; IDA:UniProtKB.
DR   GO; GO:0000422; P:autophagy of mitochondrion; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0070342; P:brown fat cell proliferation; IEA:Ensembl.
DR   GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR   GO; GO:0033554; P:cellular response to stress; IDA:UniProt.
DR   GO; GO:0016197; P:endosomal transport; TAS:UniProtKB.
DR   GO; GO:0007032; P:endosome organization; IDA:UniProtKB.
DR   GO; GO:0097009; P:energy homeostasis; IEA:Ensembl.
DR   GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR   GO; GO:0008104; P:intracellular protein localization; TAS:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB.
DR   GO; GO:0016236; P:macroautophagy; IDA:UniProtKB.
DR   GO; GO:0140694; P:membraneless organelle assembly; IDA:UniProtKB.
DR   GO; GO:0000423; P:mitophagy; IGI:ParkinsonsUK-UCL.
DR   GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB.
DR   GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:UniProt.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0000425; P:pexophagy; IDA:UniProtKB.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR   GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt.
DR   GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:ARUK-UCL.
DR   GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; TAS:UniProtKB.
DR   GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB.
DR   GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl.
DR   GO; GO:1905719; P:protein localization to perinuclear region of cytoplasm; IDA:UniProtKB.
DR   GO; GO:0071211; P:protein targeting to vacuole involved in autophagy; IDA:UniProtKB.
DR   GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB.
DR   GO; GO:0010821; P:regulation of mitochondrion organization; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0061635; P:regulation of protein complex stability; IDA:UniProtKB.
DR   GO; GO:0046578; P:regulation of Ras protein signal transduction; NAS:UniProtKB.
DR   GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR   GO; GO:0098780; P:response to mitochondrial depolarisation; IGI:ParkinsonsUK-UCL.
DR   GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl.
DR   GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc.
DR   CDD; cd06402; PB1_p62; 1.
DR   CDD; cd14320; UBA_SQSTM; 1.
DR   CDD; cd02340; ZZ_NBR1_like; 1.
DR   DisProt; DP01111; -.
DR   FunFam; 1.10.8.10:FF:000034; Sequestosome 1; 1.
DR   FunFam; 3.10.20.90:FF:000169; Sequestosome 1; 1.
DR   FunFam; 3.30.60.90:FF:000012; Sequestosome 1; 1.
DR   Gene3D; 3.30.60.90; -; 1.
DR   Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1.
DR   Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1.
DR   IDEAL; IID00383; -.
DR   InterPro; IPR052260; Autophagy_Rcpt_SigReg.
DR   InterPro; IPR053793; PB1-like.
DR   InterPro; IPR000270; PB1_dom.
DR   InterPro; IPR034866; PB1_p62.
DR   InterPro; IPR033741; SQSTM_UBA.
DR   InterPro; IPR015940; UBA.
DR   InterPro; IPR009060; UBA-like_sf.
DR   InterPro; IPR000433; Znf_ZZ.
DR   InterPro; IPR043145; Znf_ZZ_sf.
DR   PANTHER; PTHR15090; SEQUESTOSOME 1-RELATED; 1.
DR   PANTHER; PTHR15090:SF0; SEQUESTOSOME-1; 1.
DR   Pfam; PF00564; PB1; 1.
DR   Pfam; PF16577; UBA_5; 1.
DR   Pfam; PF00569; ZZ; 1.
DR   SMART; SM00666; PB1; 1.
DR   SMART; SM00165; UBA; 1.
DR   SMART; SM00291; ZnF_ZZ; 1.
DR   SUPFAM; SSF54277; CAD & PB1 domains; 1.
DR   SUPFAM; SSF57850; RING/U-box; 1.
DR   SUPFAM; SSF46934; UBA-like; 1.
DR   PROSITE; PS51745; PB1; 1.
DR   PROSITE; PS50030; UBA; 1.
DR   PROSITE; PS01357; ZF_ZZ_1; 1.
DR   PROSITE; PS50135; ZF_ZZ_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing;
KW   Amyotrophic lateral sclerosis; Apoptosis; Autophagy; Cytoplasm;
KW   Cytoplasmic vesicle; Differentiation; Direct protein sequencing;
KW   Disease variant; Endoplasmic reticulum; Endosome; Immunity;
KW   Isopeptide bond; Lipoprotein; Lysosome; Metal-binding; Neurodegeneration;
KW   Nucleus; Palmitate; Phosphoprotein; Proteomics identification;
KW   Reference proteome; Ubl conjugation; Zinc; Zinc-finger.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:22814378"
FT   CHAIN           2..440
FT                   /note="Sequestosome-1"
FT                   /id="PRO_0000072176"
FT   DOMAIN          3..102
FT                   /note="PB1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01081"
FT   DOMAIN          389..434
FT                   /note="UBA"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT   ZN_FING         123..173
FT                   /note="ZZ-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   REGION          2..50
FT                   /note="Interaction with LCK"
FT                   /evidence="ECO:0000269|PubMed:8650207"
FT   REGION          43..107
FT                   /note="Interaction with PRKCZ and dimerization"
FT                   /evidence="ECO:0000250|UniProtKB:O08623"
FT   REGION          50..80
FT                   /note="Interaction with PAWR"
FT                   /evidence="ECO:0000269|PubMed:11755531"
FT   REGION          122..224
FT                   /note="Interaction with GABRR3"
FT                   /evidence="ECO:0000250|UniProtKB:O08623"
FT   REGION          170..220
FT                   /note="LIM protein-binding (LB)"
FT   REGION          196..235
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          264..390
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          269..440
FT                   /note="Interaction with NTRK1"
FT                   /evidence="ECO:0000250|UniProtKB:O08623"
FT   REGION          321..342
FT                   /note="MAP1LC3B-binding"
FT                   /evidence="ECO:0000269|PubMed:17580304"
FT   REGION          347..352
FT                   /note="Interaction with KEAP1"
FT                   /evidence="ECO:0000269|PubMed:20452972"
FT   MOTIF           228..233
FT                   /note="TRAF6-binding"
FT   MOTIF           336..341
FT                   /note="LIR"
FT   COMPBIAS        283..296
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        310..324
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        337..347
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        351..373
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         128
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   BINDING         131
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   BINDING         142
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   BINDING         145
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   BINDING         151
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   BINDING         154
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   BINDING         160
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   BINDING         163
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT   SITE            252..253
FT                   /note="Breakpoint for translocation to form the NUP214-
FT                   SQSTM1 fusion protein"
FT                   /evidence="ECO:0000269|PubMed:20851865"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:22814378"
FT   MOD_RES         24
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0007744|PubMed:24275569"
FT   MOD_RES         148
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0007744|PubMed:15592455"
FT   MOD_RES         170
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT   MOD_RES         176
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         207
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0007744|PubMed:20068231"
FT   MOD_RES         233
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         249
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:20068231"
FT   MOD_RES         266
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:20068231"
FT   MOD_RES         269
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163"
FT   MOD_RES         272
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT   MOD_RES         282
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:22017874"
FT   MOD_RES         306
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         328
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         332
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT   MOD_RES         349
FT                   /note="Phosphoserine; by ULK1"
FT                   /evidence="ECO:0000269|PubMed:37306101"
FT   MOD_RES         355
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         361
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         365
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q64337"
FT   MOD_RES         366
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163,
FT                   ECO:0007744|PubMed:24275569"
FT   MOD_RES         403
FT                   /note="Phosphoserine; by CK2, ULK1 and TBK1"
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:29496741,
FT                   ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:37306101"
FT   MOD_RES         407
FT                   /note="Phosphoserine; by ULK1"
FT                   /evidence="ECO:0000269|PubMed:37306101"
FT   MOD_RES         420
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:31857589"
FT   MOD_RES         435
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:31857589"
FT   LIPID           289
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:37802024"
FT   LIPID           290
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:37802024"
FT   CROSSLNK        91
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:27880896"
FT   CROSSLNK        189
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:27880896"
FT   CROSSLNK        420
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000269|PubMed:28380357"
FT   CROSSLNK        435
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2); alternate"
FT                   /evidence="ECO:0000269|PubMed:33472082,
FT                   ECO:0007744|PubMed:28112733"
FT   VAR_SEQ         1..84
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:15489334"
FT                   /id="VSP_015841"
FT   VARIANT         16
FT                   /note="A -> V (in FTDALS3; dbSNP:rs1554162295)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073899"
FT   VARIANT         17
FT                   /note="A -> V (in dbSNP:rs141502868)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073900"
FT   VARIANT         33
FT                   /note="A -> V (in FTDALS3; dbSNP:rs200396166)"
FT                   /evidence="ECO:0000269|PubMed:22084127,
FT                   ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073901"
FT   VARIANT         80
FT                   /note="D -> E (in FTDALS3; dbSNP:rs148366738)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073902"
FT   VARIANT         90
FT                   /note="V -> M (in FTDALS3; dbSNP:rs181263868)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073903"
FT   VARIANT         103
FT                   /note="K -> R (in dbSNP:rs748170760)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073904"
FT   VARIANT         107
FT                   /note="R -> Q"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073905"
FT   VARIANT         107
FT                   /note="R -> W (in FTDALS3; dbSNP:rs771903158)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073906"
FT   VARIANT         108
FT                   /note="D -> Y"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073907"
FT   VARIANT         110
FT                   /note="R -> H (in dbSNP:rs1267306593)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073908"
FT   VARIANT         117
FT                   /note="A -> V (in dbSNP:rs147810437)"
FT                   /evidence="ECO:0000269|PubMed:11992264,
FT                   ECO:0000269|PubMed:24899140"
FT                   /id="VAR_023590"
FT   VARIANT         118
FT                   /note="P -> S (in dbSNP:rs200152247)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073909"
FT   VARIANT         119
FT                   /note="R -> G (in dbSNP:rs548787835)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073910"
FT   VARIANT         125
FT                   /note="N -> S (in dbSNP:rs769325755)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073911"
FT   VARIANT         129
FT                   /note="D -> N (in FTDALS3; dbSNP:rs753212399)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073912"
FT   VARIANT         139
FT                   /note="R -> C (in dbSNP:rs750256905)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073913"
FT   VARIANT         153
FT                   /note="V -> I (in FTDALS3; dbSNP:rs145056421)"
FT                   /evidence="ECO:0000269|PubMed:22084127,
FT                   ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073914"
FT   VARIANT         180
FT                   /note="S -> L (in dbSNP:rs1582008478)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073915"
FT   VARIANT         212
FT                   /note="R -> C (in FTDALS3; dbSNP:rs201263163)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073916"
FT   VARIANT         217
FT                   /note="R -> H (in dbSNP:rs761822261)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073917"
FT   VARIANT         219
FT                   /note="G -> V (in FTDALS3)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073918"
FT   VARIANT         226
FT                   /note="S -> P (in FTDALS3; dbSNP:rs765200636)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073919"
FT   VARIANT         228
FT                   /note="P -> L (in FTDALS3; dbSNP:rs151191977)"
FT                   /evidence="ECO:0000269|PubMed:22084127,
FT                   ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073920"
FT   VARIANT         232
FT                   /note="P -> T (in FTDALS3; dbSNP:rs1225746517)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073921"
FT   VARIANT         238
FT                   /note="K -> E (confirmed at protein level;
FT                   dbSNP:rs11548633)"
FT                   /evidence="ECO:0000269|PubMed:17488105,
FT                   ECO:0000269|PubMed:24899140"
FT                   /id="VAR_068915"
FT   VARIANT         238
FT                   /note="Missing (in FTDALS3)"
FT                   /evidence="ECO:0000269|PubMed:22084127,
FT                   ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083"
FT                   /id="VAR_073922"
FT   VARIANT         258
FT                   /note="D -> N (in FTDALS3; dbSNP:rs774986849)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073923"
FT   VARIANT         265..266
FT                   /note="RS -> SR"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073924"
FT   VARIANT         274
FT                   /note="E -> D (in dbSNP:rs55793208)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_061707"
FT   VARIANT         274
FT                   /note="E -> Q"
FT                   /evidence="ECO:0000269|PubMed:11992264"
FT                   /id="VAR_023591"
FT   VARIANT         278
FT                   /note="T -> I (in dbSNP:rs200445838)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073925"
FT   VARIANT         308
FT                   /note="A -> V (in dbSNP:rs541356917)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073926"
FT   VARIANT         318
FT                   /note="S -> P (in FTDALS3)"
FT                   /evidence="ECO:0000269|PubMed:22084127"
FT                   /id="VAR_073927"
FT   VARIANT         319
FT                   /note="E -> K (in dbSNP:rs61748794)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073928"
FT   VARIANT         321
FT                   /note="R -> C (in FTDALS3; likely benign;
FT                   dbSNP:rs140226523)"
FT                   /evidence="ECO:0000269|PubMed:22084127,
FT                   ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073929"
FT   VARIANT         329
FT                   /note="D -> G (in FTDALS3; dbSNP:rs148294622)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073930"
FT   VARIANT         334
FT                   /note="Missing"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073931"
FT   VARIANT         348
FT                   /note="P -> L (in FTDALS3; dbSNP:rs772889843)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073932"
FT   VARIANT         349
FT                   /note="S -> T (in dbSNP:rs774512680)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073933"
FT   VARIANT         370
FT                   /note="S -> P (in FTDALS3; dbSNP:rs143956614)"
FT                   /evidence="ECO:0000269|PubMed:22084127"
FT                   /id="VAR_073934"
FT   VARIANT         381
FT                   /note="A -> V (in FTDALS3; dbSNP:rs772122047)"
FT                   /evidence="ECO:0000269|PubMed:24042580"
FT                   /id="VAR_073935"
FT   VARIANT         387
FT                   /note="P -> L (in PDB3 and FTDALS3; dbSNP:rs776749939)"
FT                   /evidence="ECO:0000269|PubMed:14584883,
FT                   ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140"
FT                   /id="VAR_023592"
FT   VARIANT         392
FT                   /note="P -> L (in PDB3 and FTDALS3; no effect on
FT                   polyubiquitin-binding; dbSNP:rs104893941)"
FT                   /evidence="ECO:0000269|PubMed:11992264,
FT                   ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:12857745,
FT                   ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436,
FT                   ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:22084127,
FT                   ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140"
FT                   /id="VAR_023593"
FT   VARIANT         399
FT                   /note="S -> P (in PDB3; dbSNP:rs1561609625)"
FT                   /evidence="ECO:0000269|PubMed:15146436"
FT                   /id="VAR_023594"
FT   VARIANT         404
FT                   /note="M -> T (in PDB3; decreased ability to undergo
FT                   liquid-liquid phase separation and formation of p62 body;
FT                   dbSNP:rs1247551175)"
FT                   /evidence="ECO:0000269|PubMed:15146436,
FT                   ECO:0000269|PubMed:29507397"
FT                   /id="VAR_023595"
FT   VARIANT         404
FT                   /note="M -> V (in PDB3; loss of polyubiquitin-binding;
FT                   dbSNP:rs771966860)"
FT                   /evidence="ECO:0000269|PubMed:15125799,
FT                   ECO:0000269|PubMed:15176995"
FT                   /id="VAR_023596"
FT   VARIANT         411
FT                   /note="G -> S (in PDB3 and FTDALS3; no effect on
FT                   polyubiquitin-binding; decreased ability to undergo liquid-
FT                   liquid phase separation and formation of p62 body;
FT                   dbSNP:rs143511494)"
FT                   /evidence="ECO:0000269|PubMed:15176995,
FT                   ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:29507397"
FT                   /id="VAR_023597"
FT   VARIANT         425
FT                   /note="G -> R (in PDB3 and FTDALS3; loss of polyubiquitin-
FT                   binding and increased activation of NF-kappa-B;
FT                   dbSNP:rs757212984)"
FT                   /evidence="ECO:0000269|PubMed:15125799,
FT                   ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995,
FT                   ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:22084127"
FT                   /id="VAR_023598"
FT   VARIANT         430
FT                   /note="T -> P (in FTDALS3; dbSNP:rs770118706)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073936"
FT   VARIANT         439
FT                   /note="P -> L (in dbSNP:rs199854262)"
FT                   /evidence="ECO:0000269|PubMed:24899140"
FT                   /id="VAR_073937"
FT   MUTAGEN         7
FT                   /note="K->A: Loss of interactions with PRKCZ, PRCKI and
FT                   NBR1. Loss of dimerization; when associated with A-69."
FT                   /evidence="ECO:0000269|PubMed:12813044,
FT                   ECO:0000269|PubMed:12887891"
FT   MUTAGEN         9
FT                   /note="Y->F: No effect on interaction with LCK."
FT                   /evidence="ECO:0000269|PubMed:8650207"
FT   MUTAGEN         13
FT                   /note="K->A: No effect on interaction with PRKCI."
FT                   /evidence="ECO:0000269|PubMed:12813044"
FT   MUTAGEN         21..22
FT                   /note="RR->AA: Loss of interaction with PRKCI. Alters
FT                   dimerization."
FT                   /evidence="ECO:0000269|PubMed:12813044"
FT   MUTAGEN         67
FT                   /note="Y->A: No effect on interaction with PRKCZ."
FT                   /evidence="ECO:0000269|PubMed:12813044"
FT   MUTAGEN         69
FT                   /note="D->A: No effect on interactions with PRKCZ, PRKCI
FT                   and NBR1. Loss of localization in cytoplasmic inclusion
FT                   bodies. Loss of dimerization; when associated with A-7."
FT                   /evidence="ECO:0000269|PubMed:12813044,
FT                   ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:16286508"
FT   MUTAGEN         71
FT                   /note="D->A: No effect on interaction with PRKCI."
FT                   /evidence="ECO:0000269|PubMed:12813044"
FT   MUTAGEN         73
FT                   /note="D->A: No effect on interactions with PRKCZ and
FT                   PRKCI."
FT                   /evidence="ECO:0000269|PubMed:12813044,
FT                   ECO:0000269|PubMed:12887891"
FT   MUTAGEN         80
FT                   /note="D->A: No effect on interaction with PRKCI."
FT                   /evidence="ECO:0000269|PubMed:12813044"
FT   MUTAGEN         82
FT                   /note="E->A: No effect on interaction with PRKCI."
FT                   /evidence="ECO:0000269|PubMed:12813044"
FT   MUTAGEN         289..290
FT                   /note="CC->SS: Abolished palmitoylation."
FT                   /evidence="ECO:0000269|PubMed:37802024"
FT   MUTAGEN         323..324
FT                   /note="EE->AA: No effect on MAP1LC3B-binding."
FT                   /evidence="ECO:0000269|PubMed:17580304"
FT   MUTAGEN         332
FT                   /note="S->A: No effect on MAP1LC3B-binding."
FT                   /evidence="ECO:0000269|PubMed:17580304"
FT   MUTAGEN         335..337
FT                   /note="DDD->ADA: 75% decrease in MAP1LC3B-binding."
FT                   /evidence="ECO:0000269|PubMed:17580304"
FT   MUTAGEN         338
FT                   /note="W->A: Strong decrease in MAP1LC3B-binding, disrupts
FT                   interaction with GABARAP."
FT                   /evidence="ECO:0000269|PubMed:17580304,
FT                   ECO:0000269|PubMed:24668264"
FT   MUTAGEN         342
FT                   /note="S->A: No effect on MAP1LC3B-binding."
FT                   /evidence="ECO:0000269|PubMed:17580304"
FT   MUTAGEN         347
FT                   /note="D->A: Strongly decreased interaction with KEAP1."
FT                   /evidence="ECO:0000269|PubMed:20452972"
FT   MUTAGEN         349
FT                   /note="S->A: Impaired phosphorylation by ULK1, leading to
FT                   decreased p62 body formation."
FT                   /evidence="ECO:0000269|PubMed:37306101"
FT   MUTAGEN         350
FT                   /note="T->A: Strongly decreased interaction with KEAP1."
FT                   /evidence="ECO:0000269|PubMed:20452972,
FT                   ECO:0000269|PubMed:37306101"
FT   MUTAGEN         351
FT                   /note="G->A: Strongly decreased interaction with KEAP1."
FT                   /evidence="ECO:0000269|PubMed:20452972"
FT   MUTAGEN         352
FT                   /note="E->A: Strongly decreased interaction with KEAP1."
FT                   /evidence="ECO:0000269|PubMed:20452972"
FT   MUTAGEN         398
FT                   /note="L->V: No effect on polyubiquitin-binding."
FT                   /evidence="ECO:0000269|PubMed:15340068"
FT   MUTAGEN         403..407
FT                   /note="SMGFS->EMGFE: Mimics phosphorylation; increased
FT                   phosphorylation at S-349."
FT                   /evidence="ECO:0000269|PubMed:37306101"
FT   MUTAGEN         403
FT                   /note="S->A: Abolished phosphorylation by CK2, leading to
FT                   decreased affinity for ubiquitinated proteins. Abolished
FT                   ability to promote relocalization of 'Lys-63'-linked
FT                   ubiquitinated STING1 to autophagosomes."
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0000269|PubMed:29496741"
FT   MUTAGEN         403
FT                   /note="S->E: Mimmics phosphorylation; increased affinity
FT                   for ubiquitinated proteins, leading to increased p62 body
FT                   formation and autophagic degradation."
FT                   /evidence="ECO:0000269|PubMed:22017874,
FT                   ECO:0000269|PubMed:29507397"
FT   MUTAGEN         406
FT                   /note="F->V: Loss of polyubiquitin-binding."
FT                   /evidence="ECO:0000269|PubMed:15340068"
FT   MUTAGEN         409
FT                   /note="E->K: Decreased activation of NF-kappa-B."
FT                   /evidence="ECO:0000269|PubMed:19931284"
FT   MUTAGEN         410
FT                   /note="G->K: Decreased activation of NF-kappa-B."
FT                   /evidence="ECO:0000269|PubMed:19931284"
FT   MUTAGEN         413
FT                   /note="L->V: No effect on polyubiquitin-binding."
FT                   /evidence="ECO:0000269|PubMed:15340068"
FT   MUTAGEN         417
FT                   /note="L->V: Loss of polyubiquitin-binding."
FT                   /evidence="ECO:0000269|PubMed:15340068"
FT   MUTAGEN         420
FT                   /note="K->Q: Mimics acetylation; leading to increased
FT                   ability to bind ubiquitinated proteins; when associated
FT                   with Q-435."
FT                   /evidence="ECO:0000269|PubMed:31857589"
FT   MUTAGEN         420
FT                   /note="K->R: Decreased ubiquitination by the BCR(KEAP1)
FT                   complex, leading to decreased sequestering activity.
FT                   Strongly reduced acetylation; when associated with R-435."
FT                   /evidence="ECO:0000269|PubMed:28380357,
FT                   ECO:0000269|PubMed:31857589"
FT   MUTAGEN         431
FT                   /note="I->V: Partial loss of polyubiquitin-binding. Loss of
FT                   localization to cytoplasmic inclusion bodies."
FT                   /evidence="ECO:0000269|PubMed:15340068,
FT                   ECO:0000269|PubMed:16286508"
FT   MUTAGEN         435
FT                   /note="K->Q: Mimics acetylation; leading to increased
FT                   ability to bind ubiquitinated proteins; when associated
FT                   with Q-420."
FT                   /evidence="ECO:0000269|PubMed:31857589"
FT   MUTAGEN         435
FT                   /note="K->R: Strongly reduced acetylation; when associated
FT                   with R-420."
FT                   /evidence="ECO:0000269|PubMed:31857589"
FT   CONFLICT        321
FT                   /note="R -> A (in Ref. 1; AAA93299)"
FT                   /evidence="ECO:0000305"
FT   STRAND          5..10
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   STRAND          13..15
FT                   /evidence="ECO:0007829|PDB:6TGY"
FT   STRAND          19..24
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   STRAND          36..39
FT                   /evidence="ECO:0007829|PDB:6TGY"
FT   HELIX           43..54
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   STRAND          62..64
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   STRAND          66..68
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   STRAND          74..76
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   HELIX           80..88
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   STRAND          92..101
FT                   /evidence="ECO:0007829|PDB:4MJS"
FT   STRAND          120..122
FT                   /evidence="ECO:0007829|PDB:6MJ7"
FT   TURN            129..131
FT                   /evidence="ECO:0007829|PDB:6MJ7"
FT   STRAND          132..134
FT                   /evidence="ECO:0007829|PDB:6KHZ"
FT   STRAND          139..147
FT                   /evidence="ECO:0007829|PDB:6MJ7"
FT   HELIX           152..156
FT                   /evidence="ECO:0007829|PDB:6MJ7"
FT   TURN            157..162
FT                   /evidence="ECO:0007829|PDB:6MJ7"
FT   STRAND          165..168
FT                   /evidence="ECO:0007829|PDB:6MJ7"
FT   STRAND          388..390
FT                   /evidence="ECO:0007829|PDB:2JY7"
FT   HELIX           392..402
FT                   /evidence="ECO:0007829|PDB:1Q02"
FT   TURN            403..405
FT                   /evidence="ECO:0007829|PDB:2JY7"
FT   STRAND          409..411
FT                   /evidence="ECO:0007829|PDB:2JY7"
FT   HELIX           412..419
FT                   /evidence="ECO:0007829|PDB:1Q02"
FT   TURN            420..422
FT                   /evidence="ECO:0007829|PDB:1Q02"
FT   HELIX           424..431
FT                   /evidence="ECO:0007829|PDB:1Q02"
FT   STRAND          432..434
FT                   /evidence="ECO:0007829|PDB:2JY8"
FT   INIT_MET        Q13501-2:1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:22814378"
FT   MOD_RES         Q13501-2:2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:22814378"
SQ   SEQUENCE   440 AA;  47687 MW;  462D94C171F337CD CRC64;
     MASLTVKAYL LGKEDAAREI RRFSFCCSPE PEAEAEAAAG PGPCERLLSR VAALFPALRP
     GGFQAHYRDE DGDLVAFSSD EELTMAMSYV KDDIFRIYIK EKKECRRDHR PPCAQEAPRN
     MVHPNVICDG CNGPVVGTRY KCSVCPDYDL CSVCEGKGLH RGHTKLAFPS PFGHLSEGFS
     HSRWLRKVKH GHFGWPGWEM GPPGNWSPRP PRAGEARPGP TAESASGPSE DPSVNFLKNV
     GESVAAALSP LGIEVDIDVE HGGKRSRLTP VSPESSSTEE KSSSQPSSCC SDPSKPGGNV
     EGATQSLAEQ MRKIALESEG RPEEQMESDN CSGGDDDWTH LSSKEVDPST GELQSLQMPE
     SEGPSSLDPS QEGPTGLKEA ALYPHLPPEA DPRLIESLSQ MLSMGFSDEG GWLTRLLQTK
     NYDIGAALDT IQYSKHPPPL
//
ID   TNR21_HUMAN             Reviewed;         655 AA.
AC   O75509; B2RDI9; Q0D2P5; Q96D86;
DT   27-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1998, sequence version 1.
DT   28-JAN-2026, entry version 210.
DE   RecName: Full=Tumor necrosis factor receptor superfamily member 21;
DE   AltName: Full=Death receptor 6;
DE   AltName: CD_antigen=CD358;
DE   Flags: Precursor;
GN   Name=TNFRSF21; Synonyms=DR6; ORFNames=UNQ437/PRO868;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND INTERACTION
RP   WITH TRADD.
RX   PubMed=9714541; DOI=10.1016/s0014-5793(98)00791-1;
RA   Pan G., Bauer J.H., Haridas V., Wang S., Liu D., Yu G., Vincenz C.,
RA   Aggarwal B.B., Ni J., Dixit V.M.;
RT   "Identification and functional characterization of DR6, a novel death
RT   domain-containing TNF receptor.";
RL   FEBS Lett. 431:351-356(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=12975309; DOI=10.1101/gr.1293003;
RA   Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA   Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA   Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA   Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA   Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA   Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA   Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA   Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT   "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT   identify novel human secreted and transmembrane proteins: a bioinformatics
RT   assessment.";
RL   Genome Res. 13:2265-2270(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Placenta;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=14574404; DOI=10.1038/nature02055;
RA   Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA   Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA   Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA   Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA   Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA   Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA   Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA   Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA   Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA   French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA   Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA   Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA   Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA   Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA   Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA   Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA   Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA   Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA   Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA   Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA   Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA   Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA   Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA   Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA   Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA   West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA   Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA   Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA   Rogers J., Beck S.;
RT   "The DNA sequence and analysis of human chromosome 6.";
RL   Nature 425:805-811(2003).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, Colon, and Eye;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-82; ASN-141; ASN-252; ASN-257;
RP   ASN-278 AND ASN-289, MUTAGENESIS OF ASN-82; ASN-141; ASN-252; ASN-257;
RP   ASN-278 AND ASN-289, INDUCTION BY TNF, AND PALMITOYLATION AT CYS-368.
RX   PubMed=19654028; DOI=10.1016/j.bbamcr.2009.07.008;
RA   Klima M., Zajedova J., Doubravska L., Andera L.;
RT   "Functional analysis of the posttranslational modifications of the death
RT   receptor 6.";
RL   Biochim. Biophys. Acta 1793:1579-1587(2009).
RN   [8]
RP   FUNCTION, AND TISSUE SPECIFICITY.
RX   PubMed=21725297; DOI=10.1038/nm.2373;
RA   Mi S., Lee X., Hu Y., Ji B., Shao Z., Yang W., Huang G., Walus L.,
RA   Rhodes K., Gong B.J., Miller R.H., Pepinsky R.B.;
RT   "Death receptor 6 negatively regulates oligodendrocyte survival, maturation
RT   and myelination.";
RL   Nat. Med. 17:816-821(2011).
RN   [9]
RP   FUNCTION.
RX   PubMed=22761420; DOI=10.1074/jbc.m112.362038;
RA   Zeng L., Li T., Xu D.C., Liu J., Mao G., Cui M.Z., Fu X., Xu X.;
RT   "Death receptor 6 induces apoptosis not through type I or type II pathways,
RT   but via a unique mitochondria-dependent pathway by interacting with Bax
RT   protein.";
RL   J. Biol. Chem. 287:29125-29133(2012).
RN   [10]
RP   INDUCTION, TISSUE SPECIFICITY, AND INTERACTION WITH NGFR.
RX   PubMed=23559013; DOI=10.1038/cddis.2013.110;
RA   Hu Y., Lee X., Shao Z., Apicco D., Huang G., Gong B.J., Pepinsky R.B.,
RA   Mi S.;
RT   "A DR6/p75(NTR) complex is responsible for beta-amyloid-induced cortical
RT   neuron death.";
RL   Cell Death Dis. 4:E579-E579(2013).
RN   [11]
RP   INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX   PubMed=28743875; DOI=10.1038/s41598-017-06740-9;
RA   Luong T.T.D., Tran G.V.Q., Shin D.J., Lim Y.S., Hwang S.B.;
RT   "Hepatitis C Virus Exploits Death Receptor 6-mediated Signaling Pathway to
RT   Facilitate Viral Propagation.";
RL   Sci. Rep. 7:6445-6445(2017).
RN   [12]
RP   FUNCTION, SUBCELLULAR LOCATION, OXIDATION, AND INTERACTION WITH CASP8.
RX   PubMed=34012073; DOI=10.1038/s41422-021-00506-9;
RA   Zhang J.Y., Zhou B., Sun R.Y., Ai Y.L., Cheng K., Li F.N., Wang B.R.,
RA   Liu F.J., Jiang Z.H., Wang W.J., Zhou D., Chen H.Z., Wu Q.;
RT   "The metabolite alpha-KG induces GSDMC-dependent pyroptosis through death
RT   receptor 6-activated caspase-8.";
RL   Cell Res. 31:980-997(2021).
RN   [13]
RP   STRUCTURE BY NMR OF 562-655.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the carboxyl-terminal CARD-like domain in human
RT   TNFR-related death receptor-6.";
RL   Submitted (DEC-2006) to the PDB data bank.
RN   [14]
RP   X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 42-218, AND DISULFIDE BOND.
RX   PubMed=21463639; DOI=10.1016/j.jmb.2011.03.048;
RA   Kuester M., Kemmerzehl S., Dahms S.O., Roeser D., Than M.E.;
RT   "The crystal structure of death receptor 6 (DR6): a potential receptor of
RT   the amyloid precursor protein (APP).";
RL   J. Mol. Biol. 409:189-201(2011).
RN   [15]
RP   X-RAY CRYSTALLOGRAPHY (2.09 ANGSTROMS) OF 42-349, DISULFIDE BOND, AND
RP   GLYCOSYLATION.
RX   PubMed=22525750; DOI=10.1107/s0907444912004490;
RA   Ru H., Zhao L., Ding W., Jiao L., Shaw N., Liang W., Zhang L., Hung L.W.,
RA   Matsugaki N., Wakatsuki S., Liu Z.J.;
RT   "S-SAD phasing study of death receptor 6 and its solution conformation
RT   revealed by SAXS.";
RL   Acta Crystallogr. D 68:521-530(2012).
CC   -!- FUNCTION: Promotes apoptosis, possibly via a pathway that involves the
CC       activation of NF-kappa-B. Can also promote apoptosis mediated by BAX
CC       and by the release of cytochrome c from the mitochondria into the
CC       cytoplasm. Trophic-factor deprivation triggers the cleavage of surface
CC       APP by beta-secretase to release sAPP-beta which is further cleaved to
CC       release an N-terminal fragment of APP (N-APP). Negatively regulates
CC       oligodendrocyte survival, maturation and myelination. Plays a role in
CC       signaling cascades triggered by stimulation of T-cell receptors, in the
CC       adaptive immune response and in the regulation of T-cell
CC       differentiation and proliferation. Negatively regulates T-cell
CC       responses and the release of cytokines such as IL4, IL5, IL10, IL13 and
CC       IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and
CC       IgM in response to antigens. May inhibit the activation of JNK in
CC       response to T-cell stimulation. Also acts as a regulator of pyroptosis:
CC       recruits CASP8 in response to reactive oxygen species (ROS) and
CC       subsequent oxidation, leading to activation of GSDMC (PubMed:34012073).
CC       {ECO:0000269|PubMed:21725297, ECO:0000269|PubMed:22761420,
CC       ECO:0000269|PubMed:34012073, ECO:0000269|PubMed:9714541}.
CC   -!- SUBUNIT: Associates with TRADD (PubMed:9714541). Interacts with NGFR
CC       (PubMed:23559013). Interacts with CASP8 (PubMed:34012073).
CC       {ECO:0000269|PubMed:23559013, ECO:0000269|PubMed:34012073,
CC       ECO:0000269|PubMed:9714541}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with hepatitis C virus (HCV)
CC       non-structural protein 5A; this interaction allows the modulation by
CC       the virus of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-
CC       dependent manner. {ECO:0000269|PubMed:28743875}.
CC   -!- INTERACTION:
CC       O75509; P05067: APP; NbExp=2; IntAct=EBI-2313231, EBI-77613;
CC       O75509; P08138: NGFR; NbExp=4; IntAct=EBI-2313231, EBI-1387782;
CC       O75509; Q6UXB8: PI16; NbExp=3; IntAct=EBI-2313231, EBI-12810028;
CC       O75509; O43765: SGTA; NbExp=3; IntAct=EBI-2313231, EBI-347996;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19654028};
CC       Single-pass type I membrane protein {ECO:0000269|PubMed:19654028}.
CC       Note=Endocytosed following oxidation in response to reactive oxygen
CC       species (ROS). {ECO:0000269|PubMed:34012073}.
CC   -!- TISSUE SPECIFICITY: Detected in fetal spinal cord and in brain neurons,
CC       with higher levels in brain from Alzheimer disease patients (at protein
CC       level). Highly expressed in heart, brain, placenta, pancreas, lymph
CC       node, thymus and prostate. Detected at lower levels in lung, skeletal
CC       muscle, kidney, testis, uterus, small intestine, colon, spleen, bone
CC       marrow and fetal liver. Very low levels were found in adult liver and
CC       peripheral blood leukocytes. {ECO:0000269|PubMed:21725297,
CC       ECO:0000269|PubMed:23559013, ECO:0000269|PubMed:9714541}.
CC   -!- INDUCTION: Up-regulated by TNF. {ECO:0000269|PubMed:19654028,
CC       ECO:0000269|PubMed:23559013}.
CC   -!- PTM: Oxidized in response to reactive oxygen species (ROS), leading to
CC       endocytosis. {ECO:0000269|PubMed:34012073}.
CC   -!- CAUTION: It is uncertain whether Met-1 or Met-25 is the initiator.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH10241.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AF068868; AAC34583.1; -; mRNA.
DR   EMBL; AY358304; AAQ88671.1; -; mRNA.
DR   EMBL; AK315560; BAG37936.1; -; mRNA.
DR   EMBL; BT007420; AAP36088.1; -; mRNA.
DR   EMBL; AL096801; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC010241; AAH10241.1; ALT_INIT; mRNA.
DR   EMBL; BC017730; AAH17730.1; -; mRNA.
DR   EMBL; BC021572; AAH21572.1; -; mRNA.
DR   CCDS; CCDS4921.1; -.
DR   RefSeq; NP_055267.1; NM_014452.5.
DR   PDB; 2DBH; NMR; -; A=567-655.
DR   PDB; 3QO4; X-ray; 2.20 A; A=42-218.
DR   PDB; 3U3P; X-ray; 2.09 A; A=42-348.
DR   PDB; 3U3Q; X-ray; 2.70 A; A=42-348.
DR   PDB; 3U3S; X-ray; 2.70 A; A=42-348.
DR   PDB; 3U3T; X-ray; 3.21 A; A=42-348.
DR   PDB; 3U3V; X-ray; 2.96 A; A=42-348.
DR   PDBsum; 2DBH; -.
DR   PDBsum; 3QO4; -.
DR   PDBsum; 3U3P; -.
DR   PDBsum; 3U3Q; -.
DR   PDBsum; 3U3S; -.
DR   PDBsum; 3U3T; -.
DR   PDBsum; 3U3V; -.
DR   AlphaFoldDB; O75509; -.
DR   SMR; O75509; -.
DR   BioGRID; 118090; 34.
DR   CORUM; O75509; -.
DR   DIP; DIP-53299N; -.
DR   FunCoup; O75509; 896.
DR   IntAct; O75509; 21.
DR   MINT; O75509; -.
DR   STRING; 9606.ENSP00000296861; -.
DR   GlyConnect; 1981; 6 N-Linked glycans (5 sites).
DR   GlyCosmos; O75509; 9 sites, 7 glycans.
DR   GlyGen; O75509; 12 sites, 8 N-linked glycans (5 sites), 2 O-linked glycans (4 sites).
DR   iPTMnet; O75509; -.
DR   PhosphoSitePlus; O75509; -.
DR   SwissPalm; O75509; -.
DR   BioMuta; TNFRSF21; -.
DR   jPOST; O75509; -.
DR   MassIVE; O75509; -.
DR   PaxDb; 9606-ENSP00000296861; -.
DR   PeptideAtlas; O75509; -.
DR   ProteomicsDB; 50058; -.
DR   Antibodypedia; 1463; 654 antibodies from 39 providers.
DR   DNASU; 27242; -.
DR   Ensembl; ENST00000296861.2; ENSP00000296861.2; ENSG00000146072.7.
DR   GeneID; 27242; -.
DR   KEGG; hsa:27242; -.
DR   MANE-Select; ENST00000296861.2; ENSP00000296861.2; NM_014452.5; NP_055267.1.
DR   UCSC; uc003oyv.5; human.
DR   AGR; HGNC:13469; -.
DR   ClinPGx; PA37775; -.
DR   CTD; 27242; -.
DR   DisGeNET; 27242; -.
DR   GeneCards; TNFRSF21; -.
DR   HGNC; HGNC:13469; TNFRSF21.
DR   HPA; ENSG00000146072; Tissue enhanced (brain, urinary bladder).
DR   MalaCards; TNFRSF21; -.
DR   MIM; 605732; gene.
DR   OpenTargets; ENSG00000146072; -.
DR   VEuPathDB; HostDB:ENSG00000146072; -.
DR   eggNOG; ENOG502QVMX; Eukaryota.
DR   GeneTree; ENSGT00940000156212; -.
DR   HOGENOM; CLU_027496_0_0_1; -.
DR   InParanoid; O75509; -.
DR   OMA; QVGTQWI; -.
DR   OrthoDB; 8933063at2759; -.
DR   PAN-GO; O75509; 8 GO annotations based on evolutionary models.
DR   PhylomeDB; O75509; -.
DR   PathwayCommons; O75509; -.
DR   Reactome; R-HSA-1989781; PPARA activates gene expression.
DR   SignaLink; O75509; -.
DR   SIGNOR; O75509; -.
DR   Agora; ENSG00000146072; -.
DR   BioGRID-ORCS; 27242; 13 hits in 1157 CRISPR screens.
DR   ChiTaRS; TNFRSF21; human.
DR   EvolutionaryTrace; O75509; -.
DR   GeneWiki; TNFRSF21; -.
DR   GenomeRNAi; 27242; -.
DR   Pharos; O75509; Tbio.
DR   PRO; PR:O75509; -.
DR   Proteomes; UP000005640; Chromosome 6.
DR   RNAct; O75509; protein.
DR   Bgee; ENSG00000146072; Expressed in islet of Langerhans and 197 other cell types or tissues.
DR   ExpressionAtlas; O75509; baseline and differential.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0002250; P:adaptive immune response; ISS:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR   GO; GO:0007413; P:axonal fasciculation; IEA:Ensembl.
DR   GO; GO:0001783; P:B cell apoptotic process; ISS:UniProtKB.
DR   GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
DR   GO; GO:0006959; P:humoral immune response; ISS:UniProtKB.
DR   GO; GO:0042552; P:myelination; ISS:UniProtKB.
DR   GO; GO:0030889; P:negative regulation of B cell proliferation; ISS:UniProtKB.
DR   GO; GO:0032693; P:negative regulation of interleukin-10 production; ISS:UniProtKB.
DR   GO; GO:0032696; P:negative regulation of interleukin-13 production; ISS:UniProtKB.
DR   GO; GO:0032714; P:negative regulation of interleukin-5 production; ISS:UniProtKB.
DR   GO; GO:0031642; P:negative regulation of myelination; IMP:UniProtKB.
DR   GO; GO:0042130; P:negative regulation of T cell proliferation; ISS:UniProtKB.
DR   GO; GO:0051402; P:neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0097252; P:oligodendrocyte apoptotic process; ISS:UniProtKB.
DR   GO; GO:0048713; P:regulation of oligodendrocyte differentiation; ISS:UniProtKB.
DR   GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB.
DR   CDD; cd08778; Death_TNFRSF21; 1.
DR   CDD; cd10583; TNFRSF21; 1.
DR   FunFam; 1.10.533.10:FF:000005; Tumor necrosis factor receptor superfamily member 21; 1.
DR   FunFam; 2.10.50.10:FF:000010; Tumor necrosis factor receptor superfamily member 21; 1.
DR   FunFam; 2.10.50.10:FF:000011; Tumor necrosis factor receptor superfamily member 21; 1.
DR   FunFam; 1.10.533.10:FF:000009; tumor necrosis factor receptor superfamily member 21; 1.
DR   Gene3D; 1.10.533.10; Death Domain, Fas; 2.
DR   Gene3D; 2.10.50.10; Tumor Necrosis Factor Receptor, subunit A, domain 2; 2.
DR   InterPro; IPR011029; DEATH-like_dom_sf.
DR   InterPro; IPR000488; Death_dom.
DR   InterPro; IPR001368; TNFR/NGFR_Cys_rich_reg.
DR   InterPro; IPR022330; TNFR_21.
DR   InterPro; IPR034037; TNFRSF21_death.
DR   InterPro; IPR034034; TNFRSF21_N.
DR   PANTHER; PTHR46921; TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY MEMBER 21; 1.
DR   PANTHER; PTHR46921:SF1; TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY MEMBER 21; 1.
DR   Pfam; PF00531; Death; 1.
DR   Pfam; PF00020; TNFR_c6; 2.
DR   PRINTS; PR01971; TNFACTORR21.
DR   SMART; SM00005; DEATH; 1.
DR   SMART; SM01411; Ephrin_rec_like; 2.
DR   SMART; SM00208; TNFR; 4.
DR   SUPFAM; SSF47986; DEATH domain; 1.
DR   SUPFAM; SSF57586; TNF receptor-like; 2.
DR   PROSITE; PS50017; DEATH_DOMAIN; 1.
DR   PROSITE; PS00652; TNFR_NGFR_1; 1.
DR   PROSITE; PS50050; TNFR_NGFR_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Adaptive immunity; Apoptosis; Cell membrane; Disulfide bond;
KW   Glycoprotein; Host-virus interaction; Immunity; Lipoprotein; Membrane;
KW   Oxidation; Palmitate; Proteomics identification; Receptor;
KW   Reference proteome; Repeat; Signal; Transmembrane; Transmembrane helix.
FT   SIGNAL          1..41
FT                   /evidence="ECO:0000255"
FT   CHAIN           42..655
FT                   /note="Tumor necrosis factor receptor superfamily member
FT                   21"
FT                   /id="PRO_0000034602"
FT   TOPO_DOM        42..349
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        350..370
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        371..655
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REPEAT          50..88
FT                   /note="TNFR-Cys 1"
FT   REPEAT          90..131
FT                   /note="TNFR-Cys 2"
FT   REPEAT          133..167
FT                   /note="TNFR-Cys 3"
FT   REPEAT          170..211
FT                   /note="TNFR-Cys 4"
FT   DOMAIN          415..498
FT                   /note="Death"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00064"
FT   REGION          243..286
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          318..337
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        243..261
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        268..282
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   LIPID           368
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   CARBOHYD        82
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   CARBOHYD        141
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   CARBOHYD        252
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   CARBOHYD        257
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   CARBOHYD        278
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   CARBOHYD        289
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   DISULFID        67..80
FT   DISULFID        70..88
FT   DISULFID        91..106
FT   DISULFID        109..123
FT   DISULFID        113..131
FT   DISULFID        133..144
FT   DISULFID        150..168
FT   DISULFID        171..186
FT   DISULFID        192..211
FT   MUTAGEN         82
FT                   /note="N->Q: Abolishes one glycosylation site and reduces
FT                   total N-glycosylation; when associated with Q-252; Q-278
FT                   and Q-289."
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   MUTAGEN         141
FT                   /note="N->Q: Abolishes one glycosylation site and reduces
FT                   total N-glycosylation; when associated with Q-82; Q-252; Q-
FT                   278 and Q-289."
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   MUTAGEN         252
FT                   /note="N->Q: Abolishes one glycosylation site and reduces
FT                   total N-glycosylation; when associated with Q-278 and Q-
FT                   289."
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   MUTAGEN         257
FT                   /note="N->Q: Abolishes one glycosylation site and reduces
FT                   total N-glycosylation; when associated with Q-82; Q-141; Q-
FT                   252; Q-278 and Q-289."
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   MUTAGEN         278
FT                   /note="N->Q: Abolishes one glycosylation site and reduces
FT                   total N-glycosylation. Abolishes one glycosylation site and
FT                   reduces total N-glycosylation; when associated with Q-82;
FT                   Q-141; Q-252; Q-257 and Q-289."
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   MUTAGEN         289
FT                   /note="N->Q: Abolishes one glycosylation site and reduces
FT                   total N-glycosylation; when associated with Q-278."
FT                   /evidence="ECO:0000269|PubMed:19654028"
FT   MUTAGEN         368
FT                   /note="C->V: Abolishes palmitoylation."
FT   STRAND          53..57
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   TURN            59..61
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          64..68
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          74..78
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          82..84
FT                   /evidence="ECO:0007829|PDB:3U3T"
FT   STRAND          87..90
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          99..101
FT                   /evidence="ECO:0007829|PDB:3U3V"
FT   STRAND          118..121
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          130..132
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          137..140
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          143..146
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          154..158
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          162..164
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          167..170
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          181..183
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   HELIX           193..195
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          198..201
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          205..207
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          210..212
FT                   /evidence="ECO:0007829|PDB:3U3P"
FT   STRAND          571..573
FT                   /evidence="ECO:0007829|PDB:2DBH"
FT   HELIX           579..591
FT                   /evidence="ECO:0007829|PDB:2DBH"
FT   HELIX           598..606
FT                   /evidence="ECO:0007829|PDB:2DBH"
FT   HELIX           609..616
FT                   /evidence="ECO:0007829|PDB:2DBH"
FT   HELIX           621..635
FT                   /evidence="ECO:0007829|PDB:2DBH"
FT   HELIX           637..650
FT                   /evidence="ECO:0007829|PDB:2DBH"
FT   HELIX           652..654
FT                   /evidence="ECO:0007829|PDB:2DBH"
SQ   SEQUENCE   655 AA;  71845 MW;  48939391C4852A33 CRC64;
     MGTSPSSSTA LASCSRIARR ATATMIAGSL LLLGFLSTTT AQPEQKASNL IGTYRHVDRA
     TGQVLTCDKC PAGTYVSEHC TNTSLRVCSS CPVGTFTRHE NGIEKCHDCS QPCPWPMIEK
     LPCAALTDRE CTCPPGMFQS NATCAPHTVC PVGWGVRKKG TETEDVRCKQ CARGTFSDVP
     SSVMKCKAYT DCLSQNLVVI KPGTKETDNV CGTLPSFSSS TSPSPGTAIF PRPEHMETHE
     VPSSTYVPKG MNSTESNSSA SVRPKVLSSI QEGTVPDNTS SARGKEDVNK TLPNLQVVNH
     QQGPHHRHIL KLLPSMEATG GEKSSTPIKG PKRGHPRQNL HKHFDINEHL PWMIVLFLLL
     VLVVIVVCSI RKSSRTLKKG PRQDPSAIVE KAGLKKSMTP TQNREKWIYY CNGHGIDILK
     LVAAQVGSQW KDIYQFLCNA SEREVAAFSN GYTADHERAY AALQHWTIRG PEASLAQLIS
     ALRQHRRNDV VEKIRGLMED TTQLETDKLA LPMSPSPLSP SPIPSPNAKL ENSALLTVEP
     SPQDKNKGFF VDESEPLLRC DSTSSGSSAL SRNGSFITKE KKDTVLRQVR LDPCDLQPIF
     DDMLHFLNPE ELRVIEEIPQ AEDKLDRLFE IIGVKSQEAS QTLLDSVYSH LPDLL
//
ID   TREM2_HUMAN             Reviewed;         230 AA.
AC   Q9NZC2; Q8N5H8; Q8WYN6;
DT   19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-2000, sequence version 1.
DT   28-JAN-2026, entry version 185.
DE   RecName: Full=Triggering receptor expressed on myeloid cells 2;
DE            Short=TREM-2;
DE   AltName: Full=Triggering receptor expressed on monocytes 2;
DE   Flags: Precursor;
GN   Name=TREM2 {ECO:0000312|HGNC:HGNC:17761};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RX   PubMed=10799849; DOI=10.4049/jimmunol.164.10.4991;
RA   Bouchon A., Dietrich J., Colonna M.;
RT   "Inflammatory responses can be triggered by TREM-1, a novel receptor
RT   expressed on neutrophils and monocytes.";
RL   J. Immunol. 164:4991-4995(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA   Begum N.A., Tsukasa S.;
RT   "Identification of a novel variant of triggering receptor, TREM-2V, by mRNA
RT   differential display.";
RL   Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   FUNCTION, AND INTERACTION WITH TYROBP.
RX   PubMed=11602640; DOI=10.1084/jem.194.8.1111;
RA   Bouchon A., Hernandez-Munain C., Cella M., Colonna M.;
RT   "A DAP12-mediated pathway regulates expression of CC chemokine receptor 7
RT   and maturation of human dendritic cells.";
RL   J. Exp. Med. 194:1111-1122(2001).
RN   [5]
RP   TISSUE SPECIFICITY, INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2
RP   44-TRP--THR-230 DEL; 78-TRP--THR-230 DEL; GLY-134 AND ASN-186.
RX   PubMed=12080485; DOI=10.1086/342259;
RA   Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J.,
RA   Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A.,
RA   Tranebjaerg L., Konttinen Y., Peltonen L.;
RT   "Mutations in two genes encoding different subunits of a receptor signaling
RT   complex result in an identical disease phenotype.";
RL   Am. J. Hum. Genet. 71:656-662(2002).
RN   [6]
RP   ERRATUM OF PUBMED:12080485.
RA   Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J.,
RA   Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A.,
RA   Tranebjaerg L., Konttinen Y., Peltonen L.;
RL   Am. J. Hum. Genet. 72:225-225(2003).
RN   [7]
RP   FUNCTION, INVOLVEMENT IN PLOSL2, VARIANT PLOSL2 14-GLU--THR-230 DEL, AND
RP   CHARACTERIZATION OF VARIANT PLOSL2 14-GLU--THR-230 DEL.
RX   PubMed=12925681; DOI=10.1084/jem.20030027;
RA   Paloneva J., Mandelin J., Kiialainen A., Bohling T., Prudlo J., Hakola P.,
RA   Haltia M., Konttinen Y.T., Peltonen L.;
RT   "DAP12/TREM2 deficiency results in impaired osteoclast differentiation and
RT   osteoporotic features.";
RL   J. Exp. Med. 198:669-675(2003).
RN   [8]
RP   INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2 33-GLN--THR-230 DEL AND GLY-126.
RX   PubMed=15883308; DOI=10.1212/01.wnl.0000160304.00003.ca;
RA   Kluenemann H.H., Ridha B.H., Magy L., Wherrett J.R., Hemelsoet D.M.,
RA   Keen R.W., De Bleecker J.L., Rossor M.N., Marienhagen J., Klein H.E.,
RA   Peltonen L., Paloneva J.;
RT   "The genetic causes of basal ganglia calcification, dementia, and bone
RT   cysts: DAP12 and TREM2.";
RL   Neurology 64:1502-1507(2005).
RN   [9]
RP   FUNCTION.
RX   PubMed=18957693; DOI=10.1126/scisignal.1159665;
RA   Helming L., Tomasello E., Kyriakides T.R., Martinez F.O., Takai T.,
RA   Gordon S., Vivier E.;
RT   "Essential role of DAP12 signaling in macrophage programming into a fusion-
RT   competent state.";
RL   Sci. Signal. 1:RA11-RA11(2008).
RN   [10]
RP   INTERACTION WITH TYROBP.
RX   PubMed=25957402; DOI=10.1074/jbc.m115.645986;
RA   Zhong L., Chen X.F., Zhang Z.L., Wang Z., Shi X.Z., Xu K., Zhang Y.W.,
RA   Xu H., Bu G.;
RT   "DAP12 stabilizes the C-terminal fragment of the triggering receptor
RT   expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-
RT   inflammatory response.";
RL   J. Biol. Chem. 290:15866-15877(2015).
RN   [11]
RP   SUBCELLULAR LOCATION, AND PROTEOLYTIC PROCESSING.
RX   PubMed=24078628; DOI=10.1074/jbc.m113.517540;
RA   Wunderlich P., Glebov K., Kemmerling N., Tien N.T., Neumann H., Walter J.;
RT   "Sequential proteolytic processing of the triggering receptor expressed on
RT   myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-
RT   dependent intramembranous cleavage.";
RL   J. Biol. Chem. 288:33027-33036(2013).
RN   [12]
RP   FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, CHARACTERIZATION OF
RP   VARIANTS CYS-38; HIS-47 AND MET-66, AND MUTAGENESIS OF CYS-36 AND CYS-60.
RX   PubMed=24990881; DOI=10.1126/scitranslmed.3009093;
RA   Kleinberger G., Yamanishi Y., Suarez-Calvet M., Czirr E., Lohmann E.,
RA   Cuyvers E., Struyfs H., Pettkus N., Wenninger-Weinzierl A., Mazaheri F.,
RA   Tahirovic S., Lleo A., Alcolea D., Fortea J., Willem M., Lammich S.,
RA   Molinuevo J.L., Sanchez-Valle R., Antonell A., Ramirez A., Heneka M.T.,
RA   Sleegers K., van der Zee J., Martin J.J., Engelborghs S.,
RA   Demirtas-Tatlidede A., Zetterberg H., Van Broeckhoven C., Gurvit H.,
RA   Wyss-Coray T., Hardy J., Colonna M., Haass C.;
RT   "TREM2 mutations implicated in neurodegeneration impair cell surface
RT   transport and phagocytosis.";
RL   Sci. Transl. Med. 6:243RA86-243RA86(2014).
RN   [13]
RP   SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT AD17 HIS-47,
RP   CHARACTERIZATION OF VARIANTS PHE-16; MET-27; VAL-28; PHE-31;
RP   33-GLN--THR-230; CYS-38; CYS-47; MET-66; ASN-87; SER-130; GLN-136; TRP-136;
RP   LYS-151; TYR-157; ARG-162; THR-196; GLN-215 AND ILE-223, AND VARIANT
RP   ASP-202 (ISOFORM 2).
RX   PubMed=27589997; DOI=10.1186/s40478-016-0367-7;
RA   Sirkis D.W., Bonham L.W., Aparicio R.E., Geier E.G., Ramos E.M., Wang Q.,
RA   Karydas A., Miller Z.A., Miller B.L., Coppola G., Yokoyama J.S.;
RT   "Rare TREM2 variants associated with Alzheimer's disease display reduced
RT   cell surface expression.";
RL   Acta Neuropathol. Commun. 4:98-98(2016).
RN   [14]
RP   VARIANTS TYR-157 AND THR-192, AND VARIANTS CYS-183 AND CYS-200 (ISOFORM 2).
RX   PubMed=27067662; DOI=10.1016/j.neurobiolaging.2016.02.023;
RA   Jiang T., Tan L., Chen Q., Tan M.S., Zhou J.S., Zhu X.C., Lu H., Wang H.F.,
RA   Zhang Y.D., Yu J.T.;
RT   "A rare coding variant in TREM2 increases risk for Alzheimer's disease in
RT   Han Chinese.";
RL   Neurobiol. Aging 42:E1-E3(2016).
RN   [15]
RP   FUNCTION, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47;
RP   HIS-62; MET-66 AND ASN-87, AND MUTAGENESIS OF LYS-48.
RX   PubMed=27477018; DOI=10.1016/j.neuron.2016.06.015;
RA   Yeh F.L., Wang Y., Tom I., Gonzalez L.C., Sheng M.;
RT   "TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby
RT   Facilitates Uptake of Amyloid-Beta by Microglia.";
RL   Neuron 91:328-340(2016).
RN   [16]
RP   TISSUE SPECIFICITY, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62.
RX   PubMed=28802038; DOI=10.1016/j.cell.2017.07.023;
RA   Ulland T.K., Song W.M., Huang S.C., Ulrich J.D., Sergushichev A.,
RA   Beatty W.L., Loboda A.A., Zhou Y., Cairns N.J., Kambal A., Loginicheva E.,
RA   Gilfillan S., Cella M., Virgin H.W., Unanue E.R., Wang Y., Artyomov M.N.,
RA   Holtzman D.M., Colonna M.;
RT   "TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.";
RL   Cell 170:649-663(2017).
RN   [17]
RP   SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND CHARACTERIZATION OF
RP   VARIANT TYR-157.
RX   PubMed=28855300; DOI=10.15252/emmm.201707672;
RA   Schlepckow K., Kleinberger G., Fukumori A., Feederle R.,
RA   Lichtenthaler S.F., Steiner H., Haass C.;
RT   "An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and
RT   affects shedding and phagocytic function.";
RL   EMBO Mol. Med. 9:1356-1365(2017).
RN   [18]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PROTEOLYTIC PROCESSING, AND
RP   CHARACTERIZATION OF VARIANT TYR-157.
RX   PubMed=28855301; DOI=10.15252/emmm.201707673;
RA   Thornton P., Sevalle J., Deery M.J., Fraser G., Zhou Y., Staahl S.,
RA   Franssen E.H., Dodd R.B., Qamar S., Gomez Perez-Nievas B., Nicol L.S.,
RA   Eketjaell S., Revell J., Jones C., Billinton A., St George-Hyslop P.H.,
RA   Chessell I., Crowther D.C.;
RT   "TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the
RT   Alzheimer's disease-associated H157Y variant.";
RL   EMBO Mol. Med. 9:1366-1378(2017).
RN   [19]
RP   SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS CYS-38 AND MET-66, AND
RP   CHARACTERIZATION OF VARIANTS PLOSL2 GLY-126; GLY-134 AND ASN-186.
RX   PubMed=28768830; DOI=10.1091/mbc.e17-06-0423;
RA   Sirkis D.W., Aparicio R.E., Schekman R.;
RT   "Neurodegeneration-associated mutant TREM2 proteins abortively cycle
RT   between the ER and ER-Golgi intermediate compartment.";
RL   Mol. Biol. Cell 28:2723-2733(2017).
RN   [20]
RP   SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND CHARACTERIZATION OF
RP   VARIANT HIS-47.
RX   PubMed=28923481; DOI=10.1016/j.neulet.2017.09.034;
RA   Feuerbach D., Schindler P., Barske C., Joller S., Beng-Louka E.,
RA   Worringer K.A., Kommineni S., Kaykas A., Ho D.J., Ye C., Welzenbach K.,
RA   Elain G., Klein L., Brzak I., Mir A.K., Farady C.J., Aichholz R., Popp S.,
RA   George N., Neumann U.;
RT   "ADAM17 is the main sheddase for the generation of human triggering
RT   receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2
RT   after Histidine 157.";
RL   Neurosci. Lett. 660:109-114(2017).
RN   [21]
RP   CHARACTERIZATION OF VARIANT HIS-47.
RX   PubMed=30442540; DOI=10.1016/j.jalz.2018.09.006;
RA   Claes C., Van Den Daele J., Boon R., Schouteden S., Colombo A.,
RA   Monasor L.S., Fiers M., Ordovas L., Nami F., Bohrmann B., Tahirovic S.,
RA   De Strooper B., Verfaillie C.M.;
RT   "Human stem cell-derived monocytes and microglia-like cells reveal impaired
RT   amyloid plaque clearance upon heterozygous or homozygous loss of TREM2.";
RL   Alzheimers Dement. 15:453-464(2018).
RN   [22]
RP   FUNCTION, AND TISSUE SPECIFICITY.
RX   PubMed=29752066; DOI=10.1016/j.immuni.2018.04.016;
RA   Filipello F., Morini R., Corradini I., Zerbi V., Canzi A., Michalski B.,
RA   Erreni M., Markicevic M., Starvaggi-Cucuzza C., Otero K., Piccio L.,
RA   Cignarella F., Perrucci F., Tamborini M., Genua M., Rajendran L., Menna E.,
RA   Vetrano S., Fahnestock M., Paolicelli R.C., Matteoli M.;
RT   "The Microglial Innate Immune Receptor TREM2 Is Required for Synapse
RT   Elimination and Normal Brain Connectivity.";
RL   Immunity 48:979-991(2018).
RN   [23]
RP   FUNCTION, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62.
RX   PubMed=29518356; DOI=10.1016/j.neuron.2018.01.031;
RA   Zhao Y., Wu X., Li X., Jiang L.L., Gui X., Liu Y., Sun Y., Zhu B.,
RA   Pina-Crespo J.C., Zhang M., Zhang N., Chen X., Bu G., An Z., Huang T.Y.,
RA   Xu H.;
RT   "TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function.";
RL   Neuron 97:1023-1031(2018).
RN   [24] {ECO:0007744|PDB:5ELI}
RP   X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 19-133, DISULFIDE BONDS, SUBUNIT,
RP   SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-68; ARG-76 AND ARG-77,
RP   GLYCOSYLATION AT ASN-79, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47;
RP   HIS-62; MET-66; ASN-87 AND LYS-96, AND CHARACTERIZATION OF VARIANT PLOSL2
RP   GLY-126.
RX   PubMed=27995897; DOI=10.7554/elife.20391;
RA   Kober D.L., Alexander-Brett J.M., Karch C.M., Cruchaga C., Colonna M.,
RA   Holtzman M.J., Brett T.J.;
RT   "Neurodegenerative disease mutations in TREM2 reveal a functional surface
RT   and distinct loss-of-function mechanisms.";
RL   Elife 5:E20391-E20391(2016).
RN   [25] {ECO:0007744|PDB:6B8O}
RP   X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 19-174 IN COMPLEX WITH
RP   PHOSPHATIDYLSERINE, PHOSPHOLIPID-BINDING, DISULFIDE BONDS, FUNCTION,
RP   SUBUNIT, GLYCOSYLATION AT ASN-20 AND ASN-79, CHARACTERIZATION OF VARIANT
RP   HIS-47, AND MUTAGENESIS OF ASN-20.
RX   PubMed=29794134; DOI=10.1074/jbc.ra118.002352;
RA   Sudom A., Talreja S., Danao J., Bragg E., Kegel R., Min X., Richardson J.,
RA   Zhang Z., Sharkov N., Marcora E., Thibault S., Bradley J., Wood S.,
RA   Lim A.C., Chen H., Wang S., Foltz I.N., Sambashivan S., Wang Z.;
RT   "Molecular basis for the loss-of-function effects of the Alzheimer's
RT   disease-associated R47H variant of the immune receptor TREM2.";
RL   J. Biol. Chem. 293:12634-12646(2018).
RN   [26]
RP   INVOLVEMENT IN PLOSL2, AND VARIANT PLOSL2 33-GLN--THR-230 DEL.
RX   PubMed=12754369; DOI=10.1136/jnnp.74.6.825-a;
RA   Soragna D., Papi L., Ratti M.T., Sestini R., Tupler R., Montalbetti L.;
RT   "An Italian family affected by Nasu-Hakola disease with a novel genetic
RT   mutation in the TREM2 gene.";
RL   J. Neurol. Neurosurg. Psych. 74:825-826(2003).
RN   [27]
RP   INVOLVEMENT IN PLOSL2, AND VARIANT PLOSL2 33-GLN--THR-230 DEL.
RX   PubMed=23399524; DOI=10.1016/j.jns.2013.01.021;
RA   Bock V., Botturi A., Gaviani P., Lamperti E., Maccagnano C., Piccio L.,
RA   Silvani A., Salmaggi A.;
RT   "Polycystic Lipomembranous Osteodysplasia with Sclerosing
RT   Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of
RT   the literature.";
RL   J. Neurol. Sci. 326:115-119(2013).
RN   [28]
RP   CHARACTERIZATION OF VARIANT PLOSL2 33-GLN--THR-230 DEL, CHARACTERIZATION OF
RP   VARIANTS CYS-38; HIS-47 AND MET-66, AND SUBCELLULAR LOCATION.
RX   PubMed=25615530; DOI=10.1111/tra.12264;
RA   Park J.S., Ji I.J., An H.J., Kang M.J., Kang S.W., Kim D.H., Yoon S.Y.;
RT   "Disease-associated mutations of TREM2 alter the processing of N-linked
RT   oligosaccharides in the Golgi apparatus.";
RL   Traffic 16:510-518(2015).
RN   [29]
RP   VARIANT PLOSL2 33-GLN--THR-230 DEL.
RX   PubMed=29142083; DOI=10.1212/wnl.0000000000004747;
RA   Ghezzi L., Carandini T., Arighi A., Fenoglio C., Arcaro M., De Riz M.,
RA   Pietroboni A.M., Fumagalli G.G., Basilico P., Calvi A., Scarioni M.,
RA   Colombi A., Serpente M., Marotta G., Benti R., Scarpini E., Galimberti D.;
RT   "Evidence of CNS beta-amyloid deposition in Nasu-Hakola disease due to the
RT   TREM2 Q33X mutation.";
RL   Neurology 89:2503-2505(2017).
RN   [30]
RP   INVOLVEMENT IN AD17, AND VARIANT AD17 HIS-47.
RX   PubMed=23150908; DOI=10.1056/nejmoa1211103;
RA   Jonsson T., Stefansson H., Steinberg S., Jonsdottir I., Jonsson P.V.,
RA   Snaedal J., Bjornsson S., Huttenlocher J., Levey A.I., Lah J.J.,
RA   Rujescu D., Hampel H., Giegling I., Andreassen O.A., Engedal K.,
RA   Ulstein I., Djurovic S., Ibrahim-Verbaas C., Hofman A., Ikram M.A.,
RA   van Duijn C.M., Thorsteinsdottir U., Kong A., Stefansson K.;
RT   "Variant of TREM2 associated with the risk of Alzheimer's disease.";
RL   N. Engl. J. Med. 368:107-116(2013).
RN   [31]
RP   INVOLVEMENT IN AD17, VARIANTS AD17 HIS-47 AND HIS-62, VARIANTS
RP   33-GLN--THR-230 DEL; HIS-52; MET-66; ASN-87; LYS-96; TRP-136; GLN-136;
RP   LYS-151; TYR-157; PRO-211; GLN-215 AND ILE-223, AND VARIANTS
RP   191-TRP--THR-230 DEL AND ASP-202 (ISOFORM 2).
RX   PubMed=24899047; DOI=10.1093/hmg/ddu277;
RA   Jin S.C., Benitez B.A., Karch C.M., Cooper B., Skorupa T., Carrell D.,
RA   Norton J.B., Hsu S., Harari O., Cai Y., Bertelsen S., Goate A.M.,
RA   Cruchaga C.;
RT   "Coding variants in TREM2 increase risk for Alzheimer's disease.";
RL   Hum. Mol. Genet. 23:5838-5846(2014).
RN   [32]
RP   INVOLVEMENT IN AD17, AND VARIANTS AD17 HIS-47 AND HIS-62.
RX   PubMed=38899702; DOI=10.1056/nejmc2314334;
RA   Stefansson H., Walters G.B., Sveinbjornsson G., Tragante V., Einarsson G.,
RA   Helgason H., Sigurdsson A., Beyter D., Snaebjarnarson A.S.,
RA   Ivarsdottir E.V., Thorleifsson G., Halldorsson B.V., Norddahl G.,
RA   Styrkarsdottir U., Sturluson A., Holm H., Helgason A., Moore K.,
RA   Eggertsson H.P., Oddsson A.H., Jonsdottir G.A., Gunnarsson A.F.,
RA   Bjornsdottir G., Gisladottir R.S., Thorgeirsson T.E., Skuladottir A.,
RA   Gudbjartsson D.F., Sulem P., Jonsson P., Thordardottir S., Snaedal J.,
RA   Eyjolfsdottir H., Creese B., Ballard C., Corbett A.,
RA   Vasconcelos Da Silva M., Aarsland D., Andreassen O.A., Selbaek G.,
RA   Djurovic S., Stordal E., Fladby T., Haavik J., Igland J., Giil L.M.,
RA   Eriksson S., Hallmans G., Loevheim H., Lopatko Lindman K., Trupp M.,
RA   Forsgren L., Werge T., Banasik K., Brunak S., Ullum H., Frikke-Schmidt R.,
RA   Ostrowski S.R., Didriksen M., Soerensen E., Simonsen A.H., Nielsen J.E.,
RA   Waldemar G., Pedersen O.B., Erikstrup C., Knowlton K.U., Nadauld L.D.,
RA   Stefansson K.;
RT   "Homozygosity for R47H in TREM2 and the Risk of Alzheimer's Disease.";
RL   N. Engl. J. Med. 390:2217-2219(2024).
CC   -!- FUNCTION: Forms a receptor signaling complex with TYROBP which mediates
CC       signaling and cell activation following ligand binding
CC       (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a
CC       cleavage product of the amyloid-beta precursor protein APP, and
CC       mediates its uptake and degradation by microglia (PubMed:27477018,
CC       PubMed:29518356). Binding to amyloid-beta 42 mediates microglial
CC       activation, proliferation, migration, apoptosis and expression of pro-
CC       inflammatory cytokines, such as IL6R and CCL3, and the anti-
CC       inflammatory cytokine ARG1 (By similarity). Acts as a receptor for
CC       lipoprotein particles such as LDL, VLDL, and HDL and for
CC       apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4,
CC       and CLU and enhances their uptake in microglia (PubMed:27477018). Binds
CC       phospholipids (preferably anionic lipids) such as phosphatidylserine,
CC       phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin
CC       (PubMed:29794134). Regulates microglial proliferation by acting as an
CC       upstream regulator of the Wnt/beta-catenin signaling cascade (By
CC       similarity). Required for microglial phagocytosis of apoptotic neurons
CC       (PubMed:24990881). Also required for microglial activation and
CC       phagocytosis of myelin debris after neuronal injury and of neuronal
CC       synapses during synapse elimination in the developing brain (By
CC       similarity). Regulates microglial chemotaxis and process outgrowth, and
CC       also the microglial response to oxidative stress and lipopolysaccharide
CC       (By similarity). It suppresses PI3K and NF-kappa-B signaling in
CC       response to lipopolysaccharide; thus promoting phagocytosis,
CC       suppressing pro-inflammatory cytokine and nitric oxide production,
CC       inhibiting apoptosis and increasing expression of IL10 and TGFB (By
CC       similarity). During oxidative stress, it promotes anti-apoptotic NF-
CC       kappa-B signaling and ERK signaling (By similarity). Plays a role in
CC       microglial MTOR activation and metabolism (By similarity). Regulates
CC       age-related changes in microglial numbers (PubMed:29752066). Triggers
CC       activation of the immune responses in macrophages and dendritic cells
CC       (PubMed:10799849). Mediates cytokine-induced formation of
CC       multinucleated giant cells which are formed by the fusion of
CC       macrophages (By similarity). In dendritic cells, receptor of SEMA6D
CC       with PLEXNA1 as coreceptor and mediates up-regulation of chemokine
CC       receptor CCR7 and dendritic cell maturation and survival
CC       (PubMed:11602640). Involved in the positive regulation of osteoclast
CC       differentiation (PubMed:12925681). {ECO:0000250|UniProtKB:Q99NH8,
CC       ECO:0000269|PubMed:10799849, ECO:0000269|PubMed:11602640,
CC       ECO:0000269|PubMed:12925681, ECO:0000269|PubMed:24990881,
CC       ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:29518356,
CC       ECO:0000269|PubMed:29752066, ECO:0000269|PubMed:29794134}.
CC   -!- SUBUNIT: Monomer (PubMed:27995897). After ectodomain shedding, the
CC       extracellular domain oligomerizes, which is enhanced and stabilized by
CC       binding of phosphatidylserine (PubMed:29794134). Interacts with
CC       TYROBP/DAP12 (PubMed:11602640, PubMed:25957402). Interaction with
CC       TYROBP is required for stabilization of the TREM2 C-terminal fragment
CC       (TREM2-CTF) which is produced by proteolytic processing
CC       (PubMed:25957402). Interacts with PLXNA1 (via TIG domains); the
CC       interaction mediates SEMA6D binding and signaling through TYROBP (By
CC       similarity). {ECO:0000250|UniProtKB:Q99NH8,
CC       ECO:0000269|PubMed:11602640, ECO:0000269|PubMed:25957402,
CC       ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:29794134}.
CC   -!- INTERACTION:
CC       Q9NZC2; P02649: APOE; NbExp=4; IntAct=EBI-14036387, EBI-1222467;
CC       Q9NZC2; PRO_0000000092 [P05067]: APP; NbExp=4; IntAct=EBI-14036387, EBI-821758;
CC       Q9NZC2; P49768: PSEN1; NbExp=5; IntAct=EBI-14036387, EBI-297277;
CC       Q9NZC2; O43914: TYROBP; NbExp=4; IntAct=EBI-14036387, EBI-2214794;
CC   -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane
CC       {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881,
CC       ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27589997,
CC       ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830,
CC       ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301,
CC       ECO:0000269|PubMed:28923481}; Single-pass type I membrane protein
CC       {ECO:0000255}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted {ECO:0000305}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q9NZC2-1; Sequence=Displayed;
CC       Name=2; Synonyms=TREM-2V;
CC         IsoId=Q9NZC2-2; Sequence=VSP_010792;
CC       Name=3;
CC         IsoId=Q9NZC2-3; Sequence=VSP_010793;
CC   -!- TISSUE SPECIFICITY: Expressed in the brain, specifically in microglia
CC       and in the fusiform gyrus (at protein level) (PubMed:27477018,
CC       PubMed:28802038, PubMed:28855300, PubMed:29752066). Expressed on
CC       macrophages and dendritic cells but not on granulocytes or monocytes
CC       (PubMed:10799849, PubMed:28855301). In the CNS strongest expression
CC       seen in the basal ganglia, corpus callosum, medulla oblongata and
CC       spinal cord (PubMed:12080485). {ECO:0000269|PubMed:10799849,
CC       ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:27477018,
CC       ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:28855300,
CC       ECO:0000269|PubMed:28855301, ECO:0000269|PubMed:29752066}.
CC   -!- PTM: Undergoes ectodomain shedding through proteolytic cleavage by
CC       ADAM10 and ADAM17 to produce a transmembrane segment, the TREM2 C-
CC       terminal fragment (TREM2-CTF), which is subsequently cleaved by gamma-
CC       secretase. {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881,
CC       ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301,
CC       ECO:0000269|PubMed:28923481}.
CC   -!- DISEASE: Polycystic lipomembranous osteodysplasia with sclerosing
CC       leukoencephalopathy 2 (PLOSL2) [MIM:618193]: An autosomal recessive
CC       disease characterized by presenile frontal dementia with
CC       leukoencephalopathy and basal ganglia calcification. In most cases the
CC       disorder first manifests in early adulthood as pain and swelling in
CC       ankles and feet, followed by bone fractures. Neurologic symptoms
CC       manifest in the fourth decade of life as a frontal lobe syndrome with
CC       loss of judgment, euphoria, and disinhibition. Progressive decline in
CC       other cognitive domains begins to develop at about the same time. The
CC       disorder culminates in a profound dementia and death by age 50 years.
CC       {ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:12754369,
CC       ECO:0000269|PubMed:12925681, ECO:0000269|PubMed:15883308,
CC       ECO:0000269|PubMed:23399524, ECO:0000269|PubMed:25615530,
CC       ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830,
CC       ECO:0000269|PubMed:28923481, ECO:0000269|PubMed:29142083}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Alzheimer disease 17 (AD17) [MIM:615080]: A late-onset form of
CC       Alzheimer disease. Alzheimer disease is a neurodegenerative disorder
CC       characterized by progressive dementia, loss of cognitive abilities, and
CC       deposition of fibrillar amyloid proteins as intraneuronal
CC       neurofibrillary tangles, extracellular amyloid plaques and vascular
CC       amyloid deposits. The major constituents of these plaques are
CC       neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that
CC       are produced by the proteolysis of the transmembrane APP protein. The
CC       cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products,
CC       such as C31, are also implicated in neuronal death.
CC       {ECO:0000269|PubMed:23150908, ECO:0000269|PubMed:24899047,
CC       ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:38899702}. Note=Disease
CC       susceptibility is associated with variants affecting the gene
CC       represented in this entry.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAB78736.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AF213457; AAF69824.1; -; mRNA.
DR   EMBL; AB062787; BAB78736.1; ALT_INIT; mRNA.
DR   EMBL; BC032362; AAH32362.1; -; mRNA.
DR   CCDS; CCDS4852.1; -. [Q9NZC2-1]
DR   CCDS; CCDS64422.1; -. [Q9NZC2-2]
DR   RefSeq; NP_001258750.1; NM_001271821.2. [Q9NZC2-2]
DR   RefSeq; NP_061838.1; NM_018965.4. [Q9NZC2-1]
DR   PDB; 5ELI; X-ray; 3.10 A; A/B=19-133.
DR   PDB; 5UD7; X-ray; 2.20 A; A/B/C/D/E/F=19-174.
DR   PDB; 5UD8; X-ray; 1.80 A; A/B=19-130.
DR   PDB; 6B8O; X-ray; 2.20 A; A/B/C/D/E/F=19-174.
DR   PDB; 6XDS; X-ray; 1.47 A; A=18-135.
DR   PDB; 6Y6C; X-ray; 2.26 A; A/B=19-174.
DR   PDB; 6YMQ; X-ray; 3.07 A; D000/G/H/I/J/K=19-131.
DR   PDB; 6YYE; X-ray; 3.36 A; A/B=19-131.
DR   PDB; 6Z0G; NMR; -; A=161-206.
DR   PDB; 6Z0H; NMR; -; A=161-206.
DR   PDB; 6Z0I; NMR; -; A=161-206.
DR   PDB; 8T51; X-ray; 1.90 A; E/F=148-166.
DR   PDB; 8T59; X-ray; 2.00 A; E/F=148-166.
DR   PDB; 9PWN; X-ray; 1.80 A; A=131-148.
DR   PDB; 9PX5; X-ray; 3.70 A; A=18-135.
DR   PDBsum; 5ELI; -.
DR   PDBsum; 5UD7; -.
DR   PDBsum; 5UD8; -.
DR   PDBsum; 6B8O; -.
DR   PDBsum; 6XDS; -.
DR   PDBsum; 6Y6C; -.
DR   PDBsum; 6YMQ; -.
DR   PDBsum; 6YYE; -.
DR   PDBsum; 6Z0G; -.
DR   PDBsum; 6Z0H; -.
DR   PDBsum; 6Z0I; -.
DR   PDBsum; 8T51; -.
DR   PDBsum; 8T59; -.
DR   PDBsum; 9PWN; -.
DR   PDBsum; 9PX5; -.
DR   AlphaFoldDB; Q9NZC2; -.
DR   SMR; Q9NZC2; -.
DR   BioGRID; 119925; 25.
DR   FunCoup; Q9NZC2; 306.
DR   IntAct; Q9NZC2; 9.
DR   STRING; 9606.ENSP00000362205; -.
DR   TCDB; 8.A.218.1.1; the triggering receptor expressed on myeloid cells 2 (trem2) family.
DR   GlyCosmos; Q9NZC2; 2 sites, No reported glycans.
DR   GlyGen; Q9NZC2; 2 sites.
DR   iPTMnet; Q9NZC2; -.
DR   PhosphoSitePlus; Q9NZC2; -.
DR   BioMuta; TREM2; -.
DR   DMDM; 50401689; -.
DR   MassIVE; Q9NZC2; -.
DR   PaxDb; 9606-ENSP00000362205; -.
DR   PeptideAtlas; Q9NZC2; -.
DR   ProteomicsDB; 83358; -. [Q9NZC2-1]
DR   ProteomicsDB; 83359; -. [Q9NZC2-2]
DR   ProteomicsDB; 83360; -. [Q9NZC2-3]
DR   ABCD; Q9NZC2; 4 sequenced antibodies.
DR   Antibodypedia; 2280; 739 antibodies from 39 providers.
DR   DNASU; 54209; -.
DR   Ensembl; ENST00000338469.3; ENSP00000342651.4; ENSG00000095970.18. [Q9NZC2-2]
DR   Ensembl; ENST00000373113.8; ENSP00000362205.3; ENSG00000095970.18. [Q9NZC2-1]
DR   Ensembl; ENST00000373122.8; ENSP00000362214.4; ENSG00000095970.18. [Q9NZC2-3]
DR   GeneID; 54209; -.
DR   KEGG; hsa:54209; -.
DR   MANE-Select; ENST00000373113.8; ENSP00000362205.3; NM_018965.4; NP_061838.1.
DR   UCSC; uc003opy.4; human. [Q9NZC2-1]
DR   AGR; HGNC:17761; -.
DR   ClinPGx; PA38468; -.
DR   CTD; 54209; -.
DR   DisGeNET; 54209; -.
DR   GeneCards; TREM2; -.
DR   GeneReviews; TREM2; -.
DR   HGNC; HGNC:17761; TREM2.
DR   HPA; ENSG00000095970; Tissue enhanced (brain, choroid plexus).
DR   MalaCards; TREM2; -.
DR   MIM; 605086; gene.
DR   MIM; 615080; phenotype.
DR   MIM; 618193; phenotype.
DR   NIAGADS; ENSG00000095970; -.
DR   OpenTargets; ENSG00000095970; -.
DR   Orphanet; 803; Amyotrophic lateral sclerosis.
DR   Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR   Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR   Orphanet; 2770; Nasu-Hakola disease.
DR   Orphanet; 100070; Progressive non-fluent aphasia.
DR   Orphanet; 100069; Semantic dementia.
DR   VEuPathDB; HostDB:ENSG00000095970; -.
DR   eggNOG; ENOG502S4HV; Eukaryota.
DR   GeneTree; ENSGT00470000042297; -.
DR   HOGENOM; CLU_076120_0_0_1; -.
DR   InParanoid; Q9NZC2; -.
DR   OMA; CAPSFRH; -.
DR   OrthoDB; 9805957at2759; -.
DR   PAN-GO; Q9NZC2; 8 GO annotations based on evolutionary models.
DR   PhylomeDB; Q9NZC2; -.
DR   PathwayCommons; Q9NZC2; -.
DR   Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR   Reactome; R-HSA-2172127; DAP12 interactions.
DR   Reactome; R-HSA-2424491; DAP12 signaling.
DR   Reactome; R-HSA-416700; Other semaphorin interactions.
DR   SignaLink; Q9NZC2; -.
DR   Agora; ENSG00000095970; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 54209; 13 hits in 1137 CRISPR screens.
DR   ChiTaRS; TREM2; human.
DR   GeneWiki; TREM2; -.
DR   GenomeRNAi; 54209; -.
DR   Pharos; Q9NZC2; Tbio.
DR   PRO; PR:Q9NZC2; -.
DR   Proteomes; UP000005640; Chromosome 6.
DR   RNAct; Q9NZC2; protein.
DR   Bgee; ENSG00000095970; Expressed in C1 segment of cervical spinal cord and 133 other cell types or tissues.
DR   ExpressionAtlas; Q9NZC2; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IDA:BHF-UCL.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0044853; C:plasma membrane raft; IDA:ARUK-UCL.
DR   GO; GO:0002116; C:semaphorin receptor complex; ISS:UniProt.
DR   GO; GO:0001540; F:amyloid-beta binding; IPI:ARUK-UCL.
DR   GO; GO:0034186; F:apolipoprotein A-I binding; IPI:ARUK-UCL.
DR   GO; GO:0034185; F:apolipoprotein binding; IPI:ARUK-UCL.
DR   GO; GO:0008013; F:beta-catenin binding; IPI:ARUK-UCL.
DR   GO; GO:0008035; F:high-density lipoprotein particle binding; IDA:ARUK-UCL.
DR   GO; GO:0019209; F:kinase activator activity; IMP:ARUK-UCL.
DR   GO; GO:0008289; F:lipid binding; TAS:ARUK-UCL.
DR   GO; GO:0001530; F:lipopolysaccharide binding; IEA:Ensembl.
DR   GO; GO:0071813; F:lipoprotein particle binding; IDA:ARUK-UCL.
DR   GO; GO:0070891; F:lipoteichoic acid binding; IEA:Ensembl.
DR   GO; GO:0030169; F:low-density lipoprotein particle binding; IDA:ARUK-UCL.
DR   GO; GO:0042834; F:peptidoglycan binding; IEA:Ensembl.
DR   GO; GO:0008429; F:phosphatidylethanolamine binding; IDA:ARUK-UCL.
DR   GO; GO:0001786; F:phosphatidylserine binding; IDA:ARUK-UCL.
DR   GO; GO:0005543; F:phospholipid binding; IDA:UniProtKB.
DR   GO; GO:1990782; F:protein tyrosine kinase binding; ISS:ARUK-UCL.
DR   GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL.
DR   GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL.
DR   GO; GO:0017154; F:semaphorin receptor activity; IEA:Ensembl.
DR   GO; GO:0030215; F:semaphorin receptor binding; IEA:Ensembl.
DR   GO; GO:0038023; F:signaling receptor activity; IMP:ARUK-UCL.
DR   GO; GO:0120146; F:sulfatide binding; IDA:ARUK-UCL.
DR   GO; GO:0004888; F:transmembrane signaling receptor activity; IDA:UniProt.
DR   GO; GO:0034189; F:very-low-density lipoprotein particle binding; IDA:ARUK-UCL.
DR   GO; GO:0097242; P:amyloid-beta clearance; IDA:UniProt.
DR   GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IMP:ARUK-UCL.
DR   GO; GO:0043277; P:apoptotic cell clearance; ISS:UniProtKB.
DR   GO; GO:0048143; P:astrocyte activation; ISS:ARUK-UCL.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProt.
DR   GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR   GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR   GO; GO:0071396; P:cellular response to lipid; IMP:ARUK-UCL.
DR   GO; GO:0071402; P:cellular response to lipoprotein particle stimulus; IDA:UniProt.
DR   GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl.
DR   GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IDA:ARUK-UCL.
DR   GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl.
DR   GO; GO:0150062; P:complement-mediated synapse pruning; ISS:ARUK-UCL.
DR   GO; GO:0038160; P:CXCL12-activated CXCR4 signaling pathway; IMP:ARUK-UCL.
DR   GO; GO:0050829; P:defense response to Gram-negative bacterium; ISS:ARUK-UCL.
DR   GO; GO:0097028; P:dendritic cell differentiation; IDA:BHF-UCL.
DR   GO; GO:0097062; P:dendritic spine maintenance; ISS:ARUK-UCL.
DR   GO; GO:0032497; P:detection of lipopolysaccharide; IEA:Ensembl.
DR   GO; GO:0070392; P:detection of lipoteichoic acid; IEA:Ensembl.
DR   GO; GO:0032499; P:detection of peptidoglycan; IEA:Ensembl.
DR   GO; GO:1905805; P:excitatory synapse pruning; ISS:ARUK-UCL.
DR   GO; GO:0006959; P:humoral immune response; TAS:ProtInc.
DR   GO; GO:0098657; P:import into cell; ISS:ARUK-UCL.
DR   GO; GO:0055088; P:lipid homeostasis; ISS:ARUK-UCL.
DR   GO; GO:0007613; P:memory; IDA:ARUK-UCL.
DR   GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL.
DR   GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:ARUK-UCL.
DR   GO; GO:0061518; P:microglial cell proliferation; ISS:ARUK-UCL.
DR   GO; GO:1905907; P:negative regulation of amyloid fibril formation; ISS:ARUK-UCL.
DR   GO; GO:0061889; P:negative regulation of astrocyte activation; ISS:ARUK-UCL.
DR   GO; GO:1904093; P:negative regulation of autophagic cell death; ISS:ARUK-UCL.
DR   GO; GO:0010507; P:negative regulation of autophagy; ISS:ARUK-UCL.
DR   GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; ISS:ARUK-UCL.
DR   GO; GO:0050866; P:negative regulation of cell activation; ISS:ARUK-UCL.
DR   GO; GO:0010887; P:negative regulation of cholesterol storage; ISS:ARUK-UCL.
DR   GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL.
DR   GO; GO:0070345; P:negative regulation of fat cell proliferation; ISS:ARUK-UCL.
DR   GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISS:ARUK-UCL.
DR   GO; GO:0002862; P:negative regulation of inflammatory response to antigenic stimulus; ISS:ARUK-UCL.
DR   GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Ensembl.
DR   GO; GO:1902227; P:negative regulation of macrophage colony-stimulating factor signaling pathway; IMP:ARUK-UCL.
DR   GO; GO:0150079; P:negative regulation of neuroinflammatory response; IMP:ARUK-UCL.
DR   GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IMP:ARUK-UCL.
DR   GO; GO:1903753; P:negative regulation of p38MAPK cascade; ISS:ARUK-UCL.
DR   GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:ARUK-UCL.
DR   GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0010891; P:negative regulation of triglyceride storage; ISS:ARUK-UCL.
DR   GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl.
DR   GO; GO:0030316; P:osteoclast differentiation; IMP:UniProtKB.
DR   GO; GO:0006911; P:phagocytosis, engulfment; IEA:Ensembl.
DR   GO; GO:0006910; P:phagocytosis, recognition; IMP:ARUK-UCL.
DR   GO; GO:1900223; P:positive regulation of amyloid-beta clearance; IMP:ARUK-UCL.
DR   GO; GO:0002588; P:positive regulation of antigen processing and presentation of peptide antigen via MHC class II; IDA:BHF-UCL.
DR   GO; GO:2001171; P:positive regulation of ATP biosynthetic process; ISS:ARUK-UCL.
DR   GO; GO:1903082; P:positive regulation of C-C chemokine receptor CCR7 signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IDA:BHF-UCL.
DR   GO; GO:1905291; P:positive regulation of CAMKK-AMPK signaling cascade; ISS:ARUK-UCL.
DR   GO; GO:2000350; P:positive regulation of CD40 signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0050921; P:positive regulation of chemotaxis; ISS:ARUK-UCL.
DR   GO; GO:0010875; P:positive regulation of cholesterol efflux; ISS:ARUK-UCL.
DR   GO; GO:0045960; P:positive regulation of complement activation, classical pathway; ISS:ARUK-UCL.
DR   GO; GO:1901076; P:positive regulation of engulfment of apoptotic cell; IMP:UniProtKB.
DR   GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL.
DR   GO; GO:1904951; P:positive regulation of establishment of protein localization; ISS:ARUK-UCL.
DR   GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:0010983; P:positive regulation of high-density lipoprotein particle clearance; ISS:ARUK-UCL.
DR   GO; GO:0032733; P:positive regulation of interleukin-10 production; IEA:Ensembl.
DR   GO; GO:1902533; P:positive regulation of intracellular signal transduction; IDA:ARUK-UCL.
DR   GO; GO:1905581; P:positive regulation of low-density lipoprotein particle clearance; ISS:ARUK-UCL.
DR   GO; GO:0034241; P:positive regulation of macrophage fusion; ISS:UniProtKB.
DR   GO; GO:1903980; P:positive regulation of microglial cell activation; IMP:UniProtKB.
DR   GO; GO:1904141; P:positive regulation of microglial cell migration; IMP:ARUK-UCL.
DR   GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IEA:Ensembl.
DR   GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR   GO; GO:0050766; P:positive regulation of phagocytosis; IMP:ARUK-UCL.
DR   GO; GO:0060100; P:positive regulation of phagocytosis, engulfment; IMP:UniProtKB.
DR   GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:ARUK-UCL.
DR   GO; GO:0043268; P:positive regulation of potassium ion transport; ISS:ARUK-UCL.
DR   GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; ISS:ARUK-UCL.
DR   GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IDA:BHF-UCL.
DR   GO; GO:0050714; P:positive regulation of protein secretion; IMP:UniProtKB.
DR   GO; GO:1905808; P:positive regulation of synapse pruning; IMP:ARUK-UCL.
DR   GO; GO:0032008; P:positive regulation of TOR signaling; ISS:ARUK-UCL.
DR   GO; GO:0070269; P:pyroptotic inflammatory response; ISS:ARUK-UCL.
DR   GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL.
DR   GO; GO:0010468; P:regulation of gene expression; ISS:ARUK-UCL.
DR   GO; GO:0110089; P:regulation of hippocampal neuron apoptotic process; ISS:ARUK-UCL.
DR   GO; GO:0045088; P:regulation of innate immune response; ISS:ARUK-UCL.
DR   GO; GO:0032675; P:regulation of interleukin-6 production; ISS:ARUK-UCL.
DR   GO; GO:0019216; P:regulation of lipid metabolic process; IMP:ARUK-UCL.
DR   GO; GO:0071640; P:regulation of macrophage inflammatory protein 1 alpha production; ISS:ARUK-UCL.
DR   GO; GO:1903376; P:regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0120035; P:regulation of plasma membrane bounded cell projection organization; IGI:ARUK-UCL.
DR   GO; GO:0060075; P:regulation of resting membrane potential; ISS:ARUK-UCL.
DR   GO; GO:0034151; P:regulation of toll-like receptor 6 signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0032006; P:regulation of TOR signaling; ISS:ARUK-UCL.
DR   GO; GO:0045728; P:respiratory burst after phagocytosis; ISS:ARUK-UCL.
DR   GO; GO:0048678; P:response to axon injury; IMP:ARUK-UCL.
DR   GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR   GO; GO:0035176; P:social behavior; IMP:ARUK-UCL.
DR   GO; GO:0002291; P:T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; IEA:Ensembl.
DR   DisProt; DP04132; -.
DR   FunFam; 2.60.40.10:FF:001076; Triggering receptor expressed on myeloid cells 2; 1.
DR   Gene3D; 2.60.40.10; Immunoglobulins; 1.
DR   InterPro; IPR036179; Ig-like_dom_sf.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR013106; Ig_V-set.
DR   InterPro; IPR052314; Immune_rcpt_domain.
DR   PANTHER; PTHR16423:SF11; IG-LIKE DOMAIN-CONTAINING PROTEIN; 1.
DR   PANTHER; PTHR16423; TREM-LIKE TRANSCRIPT PROTEIN; 1.
DR   Pfam; PF07686; V-set; 1.
DR   SUPFAM; SSF48726; Immunoglobulin; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis;
KW   Cell membrane; Disease variant; Disulfide bond; Glycoprotein;
KW   Immunoglobulin domain; Lipid-binding; Membrane; Neurodegeneration;
KW   Proteomics identification; Receptor; Reference proteome; Secreted; Signal;
KW   Transmembrane; Transmembrane helix.
FT   SIGNAL          1..18
FT                   /evidence="ECO:0000255"
FT   CHAIN           19..230
FT                   /note="Triggering receptor expressed on myeloid cells 2"
FT                   /id="PRO_0000014987"
FT   TOPO_DOM        19..174
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        175..195
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        196..230
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          29..112
FT                   /note="Ig-like V-type"
FT   BINDING         67
FT                   /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT                   /ligand_id="ChEBI:CHEBI:57262"
FT                   /evidence="ECO:0000269|PubMed:29794134,
FT                   ECO:0007744|PDB:6B8O"
FT   BINDING         68
FT                   /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT                   /ligand_id="ChEBI:CHEBI:57262"
FT                   /evidence="ECO:0000269|PubMed:29794134,
FT                   ECO:0007744|PDB:6B8O"
FT   BINDING         77
FT                   /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT                   /ligand_id="ChEBI:CHEBI:57262"
FT                   /evidence="ECO:0000269|PubMed:29794134,
FT                   ECO:0007744|PDB:6B8O"
FT   BINDING         88
FT                   /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT                   /ligand_id="ChEBI:CHEBI:57262"
FT                   /evidence="ECO:0000269|PubMed:29794134,
FT                   ECO:0007744|PDB:6B8O"
FT   SITE            157..158
FT                   /note="Cleavage of ectodomain"
FT                   /evidence="ECO:0000269|PubMed:28855300,
FT                   ECO:0000269|PubMed:28855301, ECO:0000269|PubMed:28923481"
FT   CARBOHYD        20
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:29794134,
FT                   ECO:0007744|PDB:6B8O"
FT   CARBOHYD        79
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:27995897,
FT                   ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI,
FT                   ECO:0007744|PDB:6B8O"
FT   DISULFID        36..110
FT                   /evidence="ECO:0000269|PubMed:27995897,
FT                   ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI,
FT                   ECO:0007744|PDB:5UD7, ECO:0007744|PDB:5UD8,
FT                   ECO:0007744|PDB:6B8O"
FT   DISULFID        51..60
FT                   /evidence="ECO:0000269|PubMed:27995897,
FT                   ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI,
FT                   ECO:0007744|PDB:5UD8, ECO:0007744|PDB:6B8O"
FT   VAR_SEQ         162..230
FT                   /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC
FT                   GHDPGYQLQTLPGLRDT -> AERHVKEDDGRKSPGEVPPGTSPACILATWPPGLLVLL
FT                   WQETTLPEHCFSWTLEAGTG (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_010792"
FT   VAR_SEQ         162..230
FT                   /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC
FT                   GHDPGYQLQTLPGLRDT -> PSQGSHLPSCLSKEPLGRRNPLPTHFHPSPPGLHLSHQ
FT                   DSSSQRPLGCSLAWTEARDTSTQ (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_010793"
FT   VARIANT         14..230
FT                   /note="Missing (in PLOSL2; results in decreased osteoclast
FT                   differentiation; no TREM2 transcripts can be detected in
FT                   patient cells homozygous for the variant)"
FT                   /evidence="ECO:0000269|PubMed:12925681"
FT                   /id="VAR_081676"
FT   VARIANT         16
FT                   /note="S -> F (in dbSNP:rs777808487)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_090043"
FT   VARIANT         27
FT                   /note="V -> M (no effect on cell membrane localization;
FT                   dbSNP:rs768745050)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081812"
FT   VARIANT         28
FT                   /note="A -> V (increases cell membrane localization;
FT                   dbSNP:rs2234252)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081813"
FT   VARIANT         31
FT                   /note="S -> F (decreases cell membrane localization;
FT                   dbSNP:rs746216516)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081814"
FT   VARIANT         33..230
FT                   /note="Missing (in PLOSL2; complete loss of protein
FT                   expression)"
FT                   /evidence="ECO:0000269|PubMed:12754369,
FT                   ECO:0000269|PubMed:15883308, ECO:0000269|PubMed:23399524,
FT                   ECO:0000269|PubMed:24899047, ECO:0000269|PubMed:25615530,
FT                   ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:29142083"
FT                   /id="VAR_081677"
FT   VARIANT         38
FT                   /note="Y -> C (results in defective protein maturation and
FT                   trafficking; loss of proteolytic cleavage by ADAM10 and
FT                   ectodomain shedding; increases protein aggregation;
FT                   decreases cell membrane localization; decreased
FT                   phagocytosis; loss of LDL, CLU and APOE binding; greatly
FT                   decreases LDL and CLU uptake into cells;
FT                   dbSNP:rs797044603)"
FT                   /evidence="ECO:0000269|PubMed:24990881,
FT                   ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018,
FT                   ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897,
FT                   ECO:0000269|PubMed:28768830"
FT                   /id="VAR_081815"
FT   VARIANT         44..230
FT                   /note="Missing (in PLOSL2)"
FT                   /evidence="ECO:0000269|PubMed:12080485"
FT                   /id="VAR_081678"
FT   VARIANT         47
FT                   /note="R -> C (decreased cell surface expression;
FT                   dbSNP:rs753325601)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081816"
FT   VARIANT         47
FT                   /note="R -> H (likely risk factor for AD17; no effect on
FT                   cell membrane localization; no effect on autophagy in
FT                   microglia; no effect on phagocytosis, including amyloid
FT                   plaque clearance by microglia; reduces ectodomain shedding
FT                   caused by proteolytic cleavage by ADAM10, while also
FT                   reducing the oligomerization of the extracellular domain
FT                   after shedding; decreases binding to and uptake of LDL and
FT                   CLU into cells; decreases binding to APOE, phospholipids
FT                   and oligomeric APP cleavage product beta-amyloid peptide
FT                   42; dbSNP:rs75932628)"
FT                   /evidence="ECO:0000269|PubMed:23150908,
FT                   ECO:0000269|PubMed:24899047, ECO:0000269|PubMed:24990881,
FT                   ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018,
FT                   ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897,
FT                   ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:28923481,
FT                   ECO:0000269|PubMed:29518356, ECO:0000269|PubMed:29794134,
FT                   ECO:0000269|PubMed:30442540, ECO:0000269|PubMed:38899702"
FT                   /id="VAR_081817"
FT   VARIANT         52
FT                   /note="R -> H (in dbSNP:rs374851046)"
FT                   /evidence="ECO:0000269|PubMed:24899047"
FT                   /id="VAR_090044"
FT   VARIANT         62
FT                   /note="R -> H (likely risk factor for AD17; does not affect
FT                   protein structure; no effect on cell membrane localization;
FT                   increases autophagy in microglia; decreases LDL, CLU and
FT                   APOE binding; decreases LDL uptake into cells; no effect on
FT                   CLU uptake into cells; decreases the uptake of APP-LDL
FT                   complex in macrophages; decreases binding to oligomeric APP
FT                   cleavage product beta-amyloid peptide 42;
FT                   dbSNP:rs143332484)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27995897,
FT                   ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:29518356,
FT                   ECO:0000269|PubMed:38899702"
FT                   /id="VAR_081818"
FT   VARIANT         66
FT                   /note="T -> M (results in defective protein maturation and
FT                   trafficking; loss of proteolytic cleavage by ADAM10 and
FT                   ectodomain shedding; increases protein aggregation;
FT                   decreases cell membrane localization; decreases
FT                   phagocytosis; loss of LDL, CLU and APOE binding; greatly
FT                   decreases LDL and CLU uptake into cells;
FT                   dbSNP:rs201258663)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:24990881, ECO:0000269|PubMed:25615530,
FT                   ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27589997,
FT                   ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830"
FT                   /id="VAR_081819"
FT   VARIANT         78..230
FT                   /note="Missing (in PLOSL2)"
FT                   /evidence="ECO:0000269|PubMed:12080485"
FT                   /id="VAR_081679"
FT   VARIANT         87
FT                   /note="D -> N (decreases LDL, CLU and APOE binding;
FT                   decreases LDL and CLU uptake into cells; no effect on cell
FT                   membrane localization; dbSNP:rs142232675)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27589997,
FT                   ECO:0000269|PubMed:27995897"
FT                   /id="VAR_081820"
FT   VARIANT         96
FT                   /note="T -> K (does not change protein structure; changes
FT                   protein stability; increases binding to THP-1 cells;
FT                   dbSNP:rs2234253)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27995897"
FT                   /id="VAR_061329"
FT   VARIANT         96
FT                   /note="T -> R (in dbSNP:rs2234253)"
FT                   /id="VAR_061330"
FT   VARIANT         126
FT                   /note="V -> G (in PLOSL2; results in defective protein
FT                   maturation; increases protein aggregation; decreases cell
FT                   membrane localization; dbSNP:rs121908402)"
FT                   /evidence="ECO:0000269|PubMed:15883308,
FT                   ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830"
FT                   /id="VAR_081680"
FT   VARIANT         130
FT                   /note="A -> S (no effect on protein expression and
FT                   maturation; dbSNP:rs759576705)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081821"
FT   VARIANT         134
FT                   /note="D -> G (in PLOSL2; uncertain significance; decreased
FT                   protein level; dbSNP:rs28939079)"
FT                   /evidence="ECO:0000269|PubMed:12080485,
FT                   ECO:0000269|PubMed:28768830"
FT                   /id="VAR_019334"
FT   VARIANT         136
FT                   /note="R -> Q (slightly decreases cell membrane
FT                   localization; dbSNP:rs149622783)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081822"
FT   VARIANT         136
FT                   /note="R -> W (decreases cell membrane localization;
FT                   dbSNP:rs772641807)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081823"
FT   VARIANT         151
FT                   /note="E -> K (decreases cell membrane localization;
FT                   dbSNP:rs79011726)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081824"
FT   VARIANT         157
FT                   /note="H -> Y (accelerates ectodomain shedding but does not
FT                   alter the cleavage site; decreases cell membrane
FT                   localization; decreases phagocytosis; dbSNP:rs2234255)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27067662, ECO:0000269|PubMed:27589997,
FT                   ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301"
FT                   /id="VAR_033625"
FT   VARIANT         162
FT                   /note="S -> R (no effect on protein expression and
FT                   maturation; dbSNP:rs371702633)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081825"
FT   VARIANT         186
FT                   /note="K -> N (in PLOSL2; uncertain significance; increased
FT                   localization at the cell membrane; dbSNP:rs28937876)"
FT                   /evidence="ECO:0000269|PubMed:12080485,
FT                   ECO:0000269|PubMed:28768830"
FT                   /id="VAR_019335"
FT   VARIANT         192
FT                   /note="A -> T (in dbSNP:rs150277350)"
FT                   /evidence="ECO:0000269|PubMed:27067662"
FT                   /id="VAR_077696"
FT   VARIANT         196
FT                   /note="A -> T (in dbSNP:rs1345120258)"
FT                   /evidence="ECO:0000269|PubMed:27589997"
FT                   /id="VAR_090045"
FT   VARIANT         211
FT                   /note="L -> P (in dbSNP:rs2234256)"
FT                   /evidence="ECO:0000269|PubMed:24899047"
FT                   /id="VAR_033626"
FT   VARIANT         215
FT                   /note="H -> Q (in dbSNP:rs1161481912)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27589997"
FT                   /id="VAR_090046"
FT   VARIANT         223
FT                   /note="T -> I (affects protein maturation;
FT                   dbSNP:rs138355759)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27589997"
FT                   /id="VAR_081826"
FT   MUTAGEN         20
FT                   /note="N->D: Loss of glycosylation."
FT                   /evidence="ECO:0000269|PubMed:29794134"
FT   MUTAGEN         36
FT                   /note="C->A: Loss of proteolytic cleavage by ADAM10 and
FT                   ectodomain shedding. Decreases protein maturation and cell
FT                   membrane localization."
FT                   /evidence="ECO:0000269|PubMed:24990881"
FT   MUTAGEN         48
FT                   /note="K->M: Loss of LDL, CLU and APOE binding."
FT                   /evidence="ECO:0000269|PubMed:27477018"
FT   MUTAGEN         60
FT                   /note="C->A: Loss of proteolytic cleavage by ADAM10 and
FT                   ectodomain shedding. Decreases protein maturation and cell
FT                   membrane localization."
FT                   /evidence="ECO:0000269|PubMed:24990881"
FT   MUTAGEN         68
FT                   /note="N->K: No effect on cell membrane localization."
FT                   /evidence="ECO:0000269|PubMed:27995897"
FT   MUTAGEN         76
FT                   /note="R->D: Decreases binding to THP-1 cells."
FT                   /evidence="ECO:0000269|PubMed:27995897"
FT   MUTAGEN         77
FT                   /note="R->D: Decreases binding to THP-1 cells."
FT                   /evidence="ECO:0000269|PubMed:27995897"
FT   STRAND          19..27
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   STRAND          32..37
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   TURN            40..45
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   STRAND          48..53
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   TURN            55..57
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   STRAND          60..65
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   HELIX           70..72
FT                   /evidence="ECO:0007829|PDB:6B8O"
FT   STRAND          74..77
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   STRAND          80..87
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   TURN            88..91
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   STRAND          92..99
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   HELIX           102..104
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   STRAND          106..114
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   STRAND          117..129
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   HELIX           132..135
FT                   /evidence="ECO:0007829|PDB:6XDS"
FT   TURN            154..157
FT                   /evidence="ECO:0007829|PDB:8T51"
FT   HELIX           159..162
FT                   /evidence="ECO:0007829|PDB:8T51"
FT   HELIX           163..165
FT                   /evidence="ECO:0007829|PDB:6Z0G"
FT   HELIX           172..189
FT                   /evidence="ECO:0007829|PDB:6Z0G"
FT   HELIX           191..198
FT                   /evidence="ECO:0007829|PDB:6Z0G"
FT   VARIANT         Q9NZC2-2:183
FT                   /note="S -> C (in dbSNP:rs200820365)"
FT                   /evidence="ECO:0000269|PubMed:27067662"
FT                   /id="VAR_082839"
FT   VARIANT         Q9NZC2-2:191..219
FT                   /note="Missing"
FT                   /evidence="ECO:0000269|PubMed:24899047"
FT                   /id="VAR_090047"
FT   VARIANT         Q9NZC2-2:200
FT                   /note="W -> C (in dbSNP:rs1391283629)"
FT                   /evidence="ECO:0000269|PubMed:27067662"
FT                   /id="VAR_082840"
FT   VARIANT         Q9NZC2-2:202
FT                   /note="E -> D (in dbSNP:rs530314472)"
FT                   /evidence="ECO:0000269|PubMed:24899047,
FT                   ECO:0000269|PubMed:27589997"
FT                   /id="VAR_090048"
SQ   SEQUENCE   230 AA;  25447 MW;  C894AA210F708AF7 CRC64;
     MEPLRLLILL FVTELSGAHN TTVFQGVAGQ SLQVSCPYDS MKHWGRRKAW CRQLGEKGPC
     QRVVSTHNLW LLSFLRRWNG STAITDDTLG GTLTITLRNL QPHDAGLYQC QSLHGSEADT
     LRKVLVEVLA DPLDHRDAGD LWFPGESESF EDAHVEHSIS RSLLEGEIPF PPTSILLLLA
     CIFLIKILAA SALWAAAWHG QKPGTHPPSE LDCGHDPGYQ LQTLPGLRDT
//
ID   TYOBP_HUMAN             Reviewed;         113 AA.
AC   O43914; A8K2X0; F5H389; Q6FGA5; Q9UMT3;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-1998, sequence version 1.
DT   28-JAN-2026, entry version 194.
DE   RecName: Full=TYRO protein tyrosine kinase-binding protein {ECO:0000312|HGNC:HGNC:12449};
DE   AltName: Full=DNAX-activation protein 12 {ECO:0000303|PubMed:9490415};
DE   AltName: Full=Killer-activating receptor-associated protein;
DE            Short=KAR-associated protein;
DE   Flags: Precursor;
GN   Name=TYROBP {ECO:0000312|HGNC:HGNC:12449};
GN   Synonyms=DAP12 {ECO:0000303|PubMed:9490415},
GN   KARAP {ECO:0000250|UniProtKB:O54885};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), FUNCTION, AND
RP   PHOSPHORYLATION.
RX   PubMed=9490415; DOI=10.1038/35642;
RA   Lanier L.L., Corliss B.C., Wu J., Leong C., Phillips J.H.;
RT   "Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved
RT   in activating NK cells.";
RL   Nature 391:703-707(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC   TISSUE=Lymphoid tissue;
RA   Cantoni C., Biassoni R.;
RT   "Killer activating receptor associated protein isoform b.";
RL   Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA   Begum N.A., Seya T.;
RT   "Dendritic cells express two types of immunoreceptor DAP12 transcripts.";
RL   Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Umbilical cord blood;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC   TISSUE=Macrophage;
RX   PubMed=16344560; DOI=10.1101/gr.4039406;
RA   Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T., Yamashita R.,
RA   Yamamoto J., Sekine M., Tsuritani K., Wakaguri H., Ishii S., Sugiyama T.,
RA   Saito K., Isono Y., Irie R., Kushida N., Yoneyama T., Otsuka R., Kanda K.,
RA   Yokoi T., Kondo H., Wagatsuma M., Murakawa K., Ishida S., Ishibashi T.,
RA   Takahashi-Fujii A., Tanase T., Nagai K., Kikuchi H., Nakai K., Isogai T.,
RA   Sugano S.;
RT   "Diversification of transcriptional modulation: large-scale identification
RT   and characterization of putative alternative promoters of human genes.";
RL   Genome Res. 16:55-65(2006).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA   Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA   Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA   Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA   Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA   Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA   Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA   Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA   Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA   McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA   Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA   Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA   She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA   Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA   Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [10]
RP   FUNCTION, INTERACTION WITH KLRD1, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP   ASP-50.
RX   PubMed=9655483; DOI=10.1016/s1074-7613(00)80574-9;
RA   Lanier L.L., Corliss B., Wu J., Phillips J.H.;
RT   "Association of DAP12 with activating CD94/NKG2C NK cell receptors.";
RL   Immunity 8:693-701(1998).
RN   [11]
RP   FUNCTION, AND INTERACTION WITH CLECSF5.
RX   PubMed=10449773; DOI=10.1073/pnas.96.17.9792;
RA   Bakker A.B.H., Baker E., Sutherland G.R., Phillips J.H., Lanier L.L.;
RT   "Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor
RT   involved in the activation of myeloid cells.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:9792-9796(1999).
RN   [12]
RP   FUNCTION, AND INTERACTION WITH SIRPB1.
RX   PubMed=10604985; DOI=10.4049/jimmunol.164.1.9;
RA   Dietrich J., Cella M., Seiffert M., Buehring H.-J., Colonna M.;
RT   "Signal-regulatory protein beta 1 is a DAP12-associated activating receptor
RT   expressed in myeloid cells.";
RL   J. Immunol. 164:9-12(2000).
RN   [13]
RP   INVOLVEMENT IN PLOSL1.
RX   PubMed=10888890; DOI=10.1038/77153;
RA   Paloneva J., Kestilae M., Wu J., Salminen A., Boehling T., Ruotsalainen V.,
RA   Hakola P., Bakker A.B.H., Phillips J.H., Pekkarinen P., Lanier L.L.,
RA   Timonen T., Peltonen L.;
RT   "Loss-of-function mutations in TYROBP (DAP12) result in a presenile
RT   dementia with bone cysts.";
RL   Nat. Genet. 25:357-361(2000).
RN   [14]
RP   FUNCTION, AND INTERACTION WITH TREM1.
RX   PubMed=10799849; DOI=10.4049/jimmunol.164.10.4991;
RA   Bouchon A., Dietrich J., Colonna M.;
RT   "Inflammatory responses can be triggered by TREM-1, a novel receptor
RT   expressed on neutrophils and monocytes.";
RL   J. Immunol. 164:4991-4995(2000).
RN   [15]
RP   FUNCTION, AND INTERACTION WITH TREM2.
RX   PubMed=11602640; DOI=10.1084/jem.194.8.1111;
RA   Bouchon A., Hernandez-Munain C., Cella M., Colonna M.;
RT   "A DAP12-mediated pathway regulates expression of CC chemokine receptor 7
RT   and maturation of human dendritic cells.";
RL   J. Exp. Med. 194:1111-1122(2001).
RN   [16]
RP   INVOLVEMENT IN PLOSL1.
RX   PubMed=12370476; DOI=10.1212/wnl.59.7.1105;
RA   Kondo T., Takahashi K., Kohara N., Takahashi Y., Hayashi S., Takahashi H.,
RA   Matsuo H., Yamazaki M., Inoue K., Miyamoto K., Yamamura T.;
RT   "Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease):
RT   three genetic forms.";
RL   Neurology 59:1105-1107(2002).
RN   [17]
RP   TISSUE SPECIFICITY.
RX   PubMed=11922939; DOI=10.1016/s0161-5890(02)00004-4;
RA   Gingras M.-C., Lapillonne H., Margolin J.F.;
RT   "TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of
RT   myeloid development.";
RL   Mol. Immunol. 38:817-824(2002).
RN   [18]
RP   FUNCTION, AND INTERACTION WITH CD300E.
RX   PubMed=15557162; DOI=10.4049/jimmunol.173.11.6703;
RA   Aguilar H., Alvarez-Errico D., Garcia-Montero A.C., Orfao A., Sayos J.,
RA   Lopez-Botet M.;
RT   "Molecular characterization of a novel immune receptor restricted to the
RT   monocytic lineage.";
RL   J. Immunol. 173:6703-6711(2004).
RN   [19]
RP   INTERACTION WITH KLRD1.
RX   PubMed=15940674; DOI=10.1002/eji.200425843;
RA   Guma M., Busch L.K., Salazar-Fontana L.I., Bellosillo B., Morte C.,
RA   Garcia P., Lopez-Botet M.;
RT   "The CD94/NKG2C killer lectin-like receptor constitutes an alternative
RT   activation pathway for a subset of CD8+ T cells.";
RL   Eur. J. Immunol. 35:2071-2080(2005).
RN   [20]
RP   INTERACTION WITH SIGLEC14.
RX   PubMed=17012248; DOI=10.1096/fj.06-5800com;
RA   Angata T., Hayakawa T., Yamanaka M., Varki A., Nakamura M.;
RT   "Discovery of Siglec-14, a novel sialic acid receptor undergoing concerted
RT   evolution with Siglec-5 in primates.";
RL   FASEB J. 20:1964-1973(2006).
RN   [21]
RP   FUNCTION, AND INTERACTION WITH CD300LB.
RX   PubMed=16920917; DOI=10.4049/jimmunol.177.5.2819;
RA   Martinez-Barriocanal A., Sayos J.;
RT   "Molecular and functional characterization of CD300b, a new activating
RT   immunoglobulin receptor able to transduce signals through two different
RT   pathways.";
RL   J. Immunol. 177:2819-2830(2006).
RN   [22]
RP   FUNCTION, AND INTERACTION WITH CD300LB.
RX   PubMed=17928527; DOI=10.1182/blood-2007-04-085787;
RA   Yamanishi Y., Kitaura J., Izawa K., Matsuoka T., Oki T., Lu Y., Shibata F.,
RA   Yamazaki S., Kumagai H., Nakajima H., Maeda-Yamamoto M., Tybulewicz V.L.J.,
RA   Takai T., Kitamura T.;
RT   "Analysis of mouse LMIR5/CLM-7 as an activating receptor: differential
RT   regulation of LMIR5/CLM-7 in mouse versus human cells.";
RL   Blood 111:688-698(2008).
RN   [23]
RP   INTERACTION WITH KIR2DS5.
RX   PubMed=18624290; DOI=10.1002/eji.200838434;
RA   Della Chiesa M., Romeo E., Falco M., Balsamo M., Augugliaro R., Moretta L.,
RA   Bottino C., Moretta A., Vitale M.;
RT   "Evidence that the KIR2DS5 gene codes for a surface receptor triggering
RT   natural killer cell function.";
RL   Eur. J. Immunol. 38:2284-2289(2008).
RN   [24]
RP   FUNCTION.
RX   PubMed=18957693; DOI=10.1126/scisignal.1159665;
RA   Helming L., Tomasello E., Kyriakides T.R., Martinez F.O., Takai T.,
RA   Gordon S., Vivier E.;
RT   "Essential role of DAP12 signaling in macrophage programming into a fusion-
RT   competent state.";
RL   Sci. Signal. 1:RA11-RA11(2008).
RN   [25]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [26]
RP   FUNCTION.
RX   PubMed=21727189; DOI=10.1084/jem.20101623;
RA   Nakano-Yokomizo T., Tahara-Hanaoka S., Nakahashi-Oda C., Nabekura T.,
RA   Tchao N.K., Kadosaki M., Totsuka N., Kurita N., Nakamagoe K., Tamaoka A.,
RA   Takai T., Yasui T., Kikutani H., Honda S., Shibuya K., Lanier L.L.,
RA   Shibuya A.;
RT   "The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven
RT   adaptive immune responses.";
RL   J. Exp. Med. 208:1661-1671(2011).
RN   [27]
RP   FUNCTION, INTERACTION WITH KIR2DS1, AND MUTAGENESIS OF ASP-50.
RX   PubMed=23715743; DOI=10.1189/jlb.0213093;
RA   Mulrooney T.J., Posch P.E., Hurley C.K.;
RT   "DAP12 impacts trafficking and surface stability of killer immunoglobulin-
RT   like receptors on natural killer cells.";
RL   J. Leukoc. Biol. 94:301-313(2013).
RN   [28]
RP   FUNCTION, INTERACTION WITH TREM2, AND MUTAGENESIS OF ASP-50.
RX   PubMed=25957402; DOI=10.1074/jbc.m115.645986;
RA   Zhong L., Chen X.F., Zhang Z.L., Wang Z., Shi X.Z., Xu K., Zhang Y.W.,
RA   Xu H., Bu G.;
RT   "DAP12 stabilizes the C-terminal fragment of the triggering receptor
RT   expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-
RT   inflammatory response.";
RL   J. Biol. Chem. 290:15866-15877(2015).
RN   [29]
RP   FUNCTION, AND INTERACTION WITH CD300H.
RX   PubMed=26221034; DOI=10.1074/jbc.m115.643361;
RA   Niizuma K., Tahara-Hanaoka S., Noguchi E., Shibuya A.;
RT   "Identification and Characterization of CD300H, a New Member of the Human
RT   CD300 Immunoreceptor Family.";
RL   J. Biol. Chem. 290:22298-22308(2015).
RN   [30]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [31]
RP   INTERACTION WITH SIGLEC1.
RX   PubMed=26358190; DOI=10.1038/cr.2015.108;
RA   Zheng Q., Hou J., Zhou Y., Yang Y., Xie B., Cao X.;
RT   "Siglec1 suppresses antiviral innate immune response by inducing TBK1
RT   degradation via the ubiquitin ligase TRIM27.";
RL   Cell Res. 25:1121-1136(2015).
RN   [32]
RP   STRUCTURE BY NMR OF 35-67 IN COMPLEX WITH KLRC2, SUBUNIT, DISULFIDE BOND,
RP   MUTAGENESIS OF THR-54, AND INTERACTION WITH KLRC2 AND KIR2DS3.
RX   PubMed=20890284; DOI=10.1038/ni.1943;
RA   Call M.E., Wucherpfennig K.W., Chou J.J.;
RT   "The structural basis for intramembrane assembly of an activating
RT   immunoreceptor complex.";
RL   Nat. Immunol. 11:1023-1029(2010).
RN   [33] {ECO:0007744|PDB:4WO1, ECO:0007744|PDB:4WOL}
RP   X-RAY CRYSTALLOGRAPHY (1.77 ANGSTROMS) OF 35-67, SUBUNIT, TRANSMEMBRANE
RP   DOMAIN, METAL-BINDING, DISULFIDE BOND, AND MUTAGENESIS OF GLY-41; GLY-45;
RP   GLY-49; ASP-50 AND THR-54.
RX   PubMed=25981043; DOI=10.1016/j.celrep.2015.04.045;
RA   Knoblich K., Park S., Lutfi M., van 't Hag L., Conn C.E., Seabrook S.A.,
RA   Newman J., Czabotar P.E., Im W., Call M.E., Call M.J.;
RT   "Transmembrane complexes of DAP12 crystallized in lipid membranes provide
RT   insights into control of oligomerization in immunoreceptor assembly.";
RL   Cell Rep. 11:1184-1192(2015).
RN   [34]
RP   VARIANTS GLU-2; CYS-23; ALA-47;
RP   PRO-ALA-ASP-GLY-ARG-LEU-VAL-LEU-GLY-ASP-ARG-ASP-GLY-ARG-50 INS; LEU-55;
RP   TRP-80; VAL-84 AND LEU-89.
RX   PubMed=27658901; DOI=10.1016/j.neurobiolaging.2016.07.028;
RA   Pottier C., Ravenscroft T.A., Brown P.H., Finch N.A., Baker M., Parsons M.,
RA   Asmann Y.W., Ren Y., Christopher E., Levitch D., van Blitterswijk M.,
RA   Cruchaga C., Campion D., Nicolas G., Richard A.C., Guerreiro R., Bras J.T.,
RA   Zuchner S., Gonzalez M.A., Bu G., Younkin S., Knopman D.S., Josephs K.A.,
RA   Parisi J.E., Petersen R.C., Ertekin-Taner N., Graff-Radford N.R.,
RA   Boeve B.F., Dickson D.W., Rademakers R.;
RT   "TYROBP genetic variants in early-onset Alzheimer's disease.";
RL   Neurobiol. Aging 48:222.E9-222.E15(2016).
RN   [35]
RP   VARIANT LEU-55.
RX   PubMed=28716534; DOI=10.1016/j.neurobiolaging.2017.06.019;
RA   Darwent L., Carmona S., Lohmann E., Guven G., Kun-Rodrigues C., Bilgic B.,
RA   Hanagasi H., Gurvit H., Erginel-Unaltuna N., Pak M., Hardy J.,
RA   Singleton A., Bras J., Guerreiro R.;
RT   "Mutations in TYROBP are not a common cause of dementia in a Turkish
RT   cohort.";
RL   Neurobiol. Aging 58:240.E1-240.E3(2017).
CC   -!- FUNCTION: Adapter protein which non-covalently associates with
CC       activating receptors found on the surface of a variety of immune cells
CC       to mediate signaling and cell activation following ligand binding by
CC       the receptors (PubMed:10604985, PubMed:9490415, PubMed:9655483). TYROBP
CC       is tyrosine-phosphorylated in the ITAM domain following ligand binding
CC       by the associated receptors which leads to activation of additional
CC       tyrosine kinases and subsequent cell activation (PubMed:9490415). Also
CC       has an inhibitory role in some cells (PubMed:21727189). Non-covalently
CC       associates with activating receptors of the CD300 family to mediate
CC       cell activation (PubMed:15557162, PubMed:16920917, PubMed:17928527,
CC       PubMed:26221034). Also mediates cell activation through association
CC       with activating receptors of the CD200R family (By similarity).
CC       Required for neutrophil activation mediated by integrin (By
CC       similarity). Required for the activation of myeloid cells mediated by
CC       the CLEC5A/MDL1 receptor (PubMed:10449773). Associates with natural
CC       killer (NK) cell receptors such as KIR2DS2 and the KLRD1/KLRC2
CC       heterodimer to mediate NK cell activation (PubMed:23715743,
CC       PubMed:9490415, PubMed:9655483). Also enhances trafficking and cell
CC       surface expression of NK cell receptors KIR2DS1, KIR2DS2 and KIR2DS4
CC       and ensures their stability at the cell surface (PubMed:23715743).
CC       Associates with SIRPB1 to mediate activation of myeloid cells such as
CC       monocytes and dendritic cells (PubMed:10604985). Associates with TREM1
CC       to mediate activation of neutrophils and monocytes (PubMed:10799849).
CC       Associates with TREM2 on monocyte-derived dendritic cells to mediate
CC       up-regulation of chemokine receptor CCR7 and dendritic cell maturation
CC       and survival (PubMed:11602640). Association with TREM2 mediates
CC       cytokine-induced formation of multinucleated giant cells which are
CC       formed by the fusion of macrophages (PubMed:18957693). Stabilizes the
CC       TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain
CC       shedding which suppresses the release of pro-inflammatory cytokines
CC       (PubMed:25957402). In microglia, required with TREM2 for phagocytosis
CC       of apoptotic neurons (By similarity). Required with ITGAM/CD11B in
CC       microglia to control production of microglial superoxide ions which
CC       promote the neuronal apoptosis that occurs during brain development (By
CC       similarity). Promotes pro-inflammatory responses in microglia following
CC       nerve injury which accelerates degeneration of injured neurons (By
CC       similarity). Positively regulates the expression of the IRAK3/IRAK-M
CC       kinase and IL10 production by liver dendritic cells and inhibits their
CC       T cell allostimulatory ability (By similarity). Negatively regulates B
CC       cell proliferation (PubMed:21727189). Required for CSF1-mediated
CC       osteoclast cytoskeletal organization (By similarity). Positively
CC       regulates multinucleation during osteoclast development (By
CC       similarity). {ECO:0000250|UniProtKB:O54885,
CC       ECO:0000269|PubMed:10449773, ECO:0000269|PubMed:10604985,
CC       ECO:0000269|PubMed:10799849, ECO:0000269|PubMed:11602640,
CC       ECO:0000269|PubMed:15557162, ECO:0000269|PubMed:16920917,
CC       ECO:0000269|PubMed:17928527, ECO:0000269|PubMed:18957693,
CC       ECO:0000269|PubMed:21727189, ECO:0000269|PubMed:23715743,
CC       ECO:0000269|PubMed:25957402, ECO:0000269|PubMed:26221034,
CC       ECO:0000269|PubMed:9490415, ECO:0000269|PubMed:9655483}.
CC   -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:20890284). Homotrimer;
CC       disulfide-linked (PubMed:25981043). Homotetramer; disulfide-linked
CC       (PubMed:25981043). Homotrimers and homotetramers form when low levels
CC       of partner receptors are available and are competitive with assembly
CC       with interacting receptors (PubMed:25981043). They may represent
CC       alternative oligomerization states or may be intermediates in the
CC       receptor assembly process (PubMed:25981043). Binding of a metal cation
CC       aids in homooligomerization through coordination of the metal ion by
CC       the subunits of the oligomer (PubMed:25981043). Interacts with TREM1
CC       (PubMed:10799849). Interacts with TREM2 (PubMed:11602640,
CC       PubMed:25957402). Interacts with SIRPB1 (PubMed:10604985). Interacts
CC       with CLECSF5 (PubMed:10449773). Interacts with SIGLEC14
CC       (PubMed:17012248). Interacts with CD300LB and CD300E (PubMed:15557162,
CC       PubMed:16920917, PubMed:17928527). Interacts with CD300C2 (By
CC       similarity). Interacts (via ITAM domain) with SYK (via SH2 domains);
CC       activates SYK mediating neutrophil and macrophage integrin-mediated
CC       activation (By similarity). Interacts with KLRC2, KIR2DS3 and KIR2DS5
CC       (PubMed:18624290, PubMed:20890284). Interacts with CD300H
CC       (PubMed:26221034). Interacts with KIR2DS1 (PubMed:23715743). Interacts
CC       with KLRD1 (PubMed:15940674, PubMed:9655483). Interacts with SIGLEC1
CC       (PubMed:26358190). {ECO:0000250|UniProtKB:O54885,
CC       ECO:0000269|PubMed:10449773, ECO:0000269|PubMed:10604985,
CC       ECO:0000269|PubMed:10799849, ECO:0000269|PubMed:11602640,
CC       ECO:0000269|PubMed:15557162, ECO:0000269|PubMed:16920917,
CC       ECO:0000269|PubMed:17012248, ECO:0000269|PubMed:17928527,
CC       ECO:0000269|PubMed:18624290, ECO:0000269|PubMed:20890284,
CC       ECO:0000269|PubMed:23715743, ECO:0000269|PubMed:25957402,
CC       ECO:0000269|PubMed:25981043, ECO:0000269|PubMed:26221034,
CC       ECO:0000269|PubMed:26358190, ECO:0000269|PubMed:9655483}.
CC   -!- INTERACTION:
CC       O43914; Q14953: KIR2DS5; NbExp=3; IntAct=EBI-2214794, EBI-16823921;
CC       O43914; O95944: NCR2; NbExp=2; IntAct=EBI-2214794, EBI-14058375;
CC       O43914; O00241: SIRPB1; NbExp=4; IntAct=EBI-2214794, EBI-2615458;
CC       O43914; Q969S0: SLC35B4; NbExp=3; IntAct=EBI-2214794, EBI-10281213;
CC       O43914; Q8N2M4: TMEM86A; NbExp=3; IntAct=EBI-2214794, EBI-12015604;
CC       O43914; Q9NZC2: TREM2; NbExp=4; IntAct=EBI-2214794, EBI-14036387;
CC       O43914; O43914: TYROBP; NbExp=2; IntAct=EBI-2214794, EBI-2214794;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9655483};
CC       Single-pass type I membrane protein {ECO:0000255}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=KARAP-a;
CC         IsoId=O43914-1; Sequence=Displayed;
CC       Name=2; Synonyms=KARAP-b;
CC         IsoId=O43914-2; Sequence=VSP_012909;
CC       Name=3;
CC         IsoId=O43914-3; Sequence=VSP_046066;
CC   -!- TISSUE SPECIFICITY: Expressed at low levels in the early development of
CC       the hematopoietic system and in the promonocytic stage and at high
CC       levels in mature monocytes. Expressed in hematological cells and
CC       tissues such as peripheral blood leukocytes and spleen. Also found in
CC       bone marrow, lymph nodes, placenta, lung and liver. Expressed at lower
CC       levels in different parts of the brain especially in the basal ganglia
CC       and corpus callosum. {ECO:0000269|PubMed:11922939}.
CC   -!- PTM: Following ligand binding by associated receptors, tyrosine
CC       phosphorylated in the ITAM domain which leads to activation of
CC       additional tyrosine kinases and subsequent cell activation.
CC       {ECO:0000269|PubMed:9490415}.
CC   -!- DISEASE: Polycystic lipomembranous osteodysplasia with sclerosing
CC       leukoencephalopathy 1 (PLOSL1) [MIM:221770]: A recessively inherited
CC       disease characterized by presenile dementia along with large-scale
CC       destruction of cancellous bones. Initial symptoms, starting in the
CC       twenties, are pain and swelling resulting from cysts in the wrists and
CC       ankles. Extremity bone fractures could occur with minor trauma. At
CC       around 30 years of age, patients gradually develop neuropsychiatric
CC       symptoms, including epileptic seizures, agnosia, apraxia, speech
CC       disorder, memory disturbance, euphoria, and loss of social inhibitions.
CC       The disorder usually leads to death in the fifth decade of life.
CC       {ECO:0000269|PubMed:10888890, ECO:0000269|PubMed:12370476}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the TYROBP family. {ECO:0000305}.
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DR   EMBL; AF019562; AAD09436.1; -; mRNA.
DR   EMBL; AF019563; AAD09437.1; -; Genomic_DNA.
DR   EMBL; AJ010098; CAB52288.1; -; mRNA.
DR   EMBL; AY074782; AAL74017.1; -; mRNA.
DR   EMBL; BT009851; AAP88853.1; -; mRNA.
DR   EMBL; AK290385; BAF83074.1; -; mRNA.
DR   EMBL; CR450342; CAG29338.1; -; mRNA.
DR   EMBL; CR542202; CAG46999.1; -; mRNA.
DR   EMBL; BP295666; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AD000833; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AD000864; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC011175; AAH11175.1; -; mRNA.
DR   CCDS; CCDS12482.1; -. [O43914-1]
DR   CCDS; CCDS46058.1; -. [O43914-2]
DR   CCDS; CCDS54255.1; -. [O43914-3]
DR   RefSeq; NP_001166985.1; NM_001173514.2. [O43914-3]
DR   RefSeq; NP_003323.1; NM_003332.4. [O43914-1]
DR   RefSeq; NP_937758.1; NM_198125.3. [O43914-2]
DR   PDB; 2L34; NMR; -; A/B=35-67.
DR   PDB; 2L35; NMR; -; A=35-67, B=35-66.
DR   PDB; 4WO1; X-ray; 2.14 A; A/B/C/D=35-67.
DR   PDB; 4WOL; X-ray; 1.77 A; A/B/C=35-67.
DR   PDB; 7Q5W; X-ray; 2.20 A; GGG/HHH/III/JJJ/KKK/LLL=88-107.
DR   PDBsum; 2L34; -.
DR   PDBsum; 2L35; -.
DR   PDBsum; 4WO1; -.
DR   PDBsum; 4WOL; -.
DR   PDBsum; 7Q5W; -.
DR   AlphaFoldDB; O43914; -.
DR   SASBDB; O43914; -.
DR   SMR; O43914; -.
DR   BioGRID; 113155; 89.
DR   CORUM; O43914; -.
DR   FunCoup; O43914; 301.
DR   IntAct; O43914; 100.
DR   STRING; 9606.ENSP00000262629; -.
DR   TCDB; 8.A.128.1.1; the signaling adaptor protein karap/dap12/tyrobp (sap) family.
DR   iPTMnet; O43914; -.
DR   PhosphoSitePlus; O43914; -.
DR   BioMuta; TYROBP; -.
DR   MassIVE; O43914; -.
DR   PaxDb; 9606-ENSP00000262629; -.
DR   PeptideAtlas; O43914; -.
DR   ProteomicsDB; 26198; -.
DR   ProteomicsDB; 49229; -. [O43914-1]
DR   ProteomicsDB; 49230; -. [O43914-2]
DR   Antibodypedia; 4010; 291 antibodies from 39 providers.
DR   DNASU; 7305; -.
DR   Ensembl; ENST00000262629.9; ENSP00000262629.3; ENSG00000011600.13. [O43914-1]
DR   Ensembl; ENST00000544690.6; ENSP00000445332.1; ENSG00000011600.13. [O43914-3]
DR   Ensembl; ENST00000589517.1; ENSP00000468447.1; ENSG00000011600.13. [O43914-2]
DR   GeneID; 7305; -.
DR   KEGG; hsa:7305; -.
DR   MANE-Select; ENST00000262629.9; ENSP00000262629.3; NM_003332.4; NP_003323.1.
DR   UCSC; uc002ocm.4; human. [O43914-1]
DR   AGR; HGNC:12449; -.
DR   ClinPGx; PA37100; -.
DR   CTD; 7305; -.
DR   DisGeNET; 7305; -.
DR   GeneCards; TYROBP; -.
DR   GeneReviews; TYROBP; -.
DR   HGNC; HGNC:12449; TYROBP.
DR   HPA; ENSG00000011600; Tissue enhanced (bone marrow, lymphoid tissue).
DR   MalaCards; TYROBP; -.
DR   MIM; 221770; phenotype.
DR   MIM; 604142; gene.
DR   OpenTargets; ENSG00000011600; -.
DR   Orphanet; 2770; Nasu-Hakola disease.
DR   VEuPathDB; HostDB:ENSG00000011600; -.
DR   eggNOG; ENOG502SCVI; Eukaryota.
DR   GeneTree; ENSGT00390000016786; -.
DR   HOGENOM; CLU_141718_0_0_1; -.
DR   InParanoid; O43914; -.
DR   OMA; QRQPYYK; -.
DR   OrthoDB; 9901873at2759; -.
DR   PAN-GO; O43914; 9 GO annotations based on evolutionary models.
DR   PhylomeDB; O43914; -.
DR   PathwayCommons; O43914; -.
DR   Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR   Reactome; R-HSA-2172127; DAP12 interactions.
DR   Reactome; R-HSA-2424491; DAP12 signaling.
DR   Reactome; R-HSA-391160; Signal regulatory protein family interactions.
DR   Reactome; R-HSA-416700; Other semaphorin interactions.
DR   Reactome; R-HSA-6798695; Neutrophil degranulation.
DR   SignaLink; O43914; -.
DR   SIGNOR; O43914; -.
DR   Agora; ENSG00000011600; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 7305; 18 hits in 1151 CRISPR screens.
DR   ChiTaRS; TYROBP; human.
DR   EvolutionaryTrace; O43914; -.
DR   GeneWiki; TYROBP; -.
DR   GenomeRNAi; 7305; -.
DR   Pharos; O43914; Tbio.
DR   PRO; PR:O43914; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; O43914; protein.
DR   Bgee; ENSG00000011600; Expressed in monocyte and 186 other cell types or tissues.
DR   ExpressionAtlas; O43914; baseline and differential.
DR   GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; TAS:ARUK-UCL.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0030667; C:secretory granule membrane; TAS:Reactome.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0060090; F:molecular adaptor activity; IDA:UniProt.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProt.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB.
DR   GO; GO:0030036; P:actin cytoskeleton organization; ISS:UniProtKB.
DR   GO; GO:0097242; P:amyloid-beta clearance; IDA:UniProt.
DR   GO; GO:0043277; P:apoptotic cell clearance; ISS:UniProtKB.
DR   GO; GO:0006968; P:cellular defense response; TAS:ProtInc.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProt.
DR   GO; GO:0030900; P:forebrain development; ISS:ARUK-UCL.
DR   GO; GO:0007229; P:integrin-mediated signaling pathway; IEA:Ensembl.
DR   GO; GO:0035556; P:intracellular signal transduction; TAS:ProtInc.
DR   GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:UniProtKB.
DR   GO; GO:0002274; P:myeloid leukocyte activation; IDA:UniProtKB.
DR   GO; GO:0002228; P:natural killer cell mediated immunity; IDA:UniProt.
DR   GO; GO:0030889; P:negative regulation of B cell proliferation; IMP:UniProtKB.
DR   GO; GO:0032693; P:negative regulation of interleukin-10 production; ISS:ARUK-UCL.
DR   GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; ISS:ARUK-UCL.
DR   GO; GO:0032911; P:negative regulation of transforming growth factor beta1 production; ISS:ARUK-UCL.
DR   GO; GO:0032480; P:negative regulation of type I interferon production; IDA:UniProt.
DR   GO; GO:0002283; P:neutrophil activation involved in immune response; IBA:GO_Central.
DR   GO; GO:0030316; P:osteoclast differentiation; IMP:MGI.
DR   GO; GO:0010628; P:positive regulation of gene expression; ISS:ARUK-UCL.
DR   GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISS:ARUK-UCL.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:ARUK-UCL.
DR   GO; GO:0034241; P:positive regulation of macrophage fusion; IMP:UniProtKB.
DR   GO; GO:1904151; P:positive regulation of microglial cell mediated cytotoxicity; ISS:UniProtKB.
DR   GO; GO:0032816; P:positive regulation of natural killer cell activation; IBA:GO_Central.
DR   GO; GO:2001206; P:positive regulation of osteoclast development; ISS:UniProtKB.
DR   GO; GO:2000010; P:positive regulation of protein localization to cell surface; IMP:UniProtKB.
DR   GO; GO:1902685; P:positive regulation of receptor localization to synapse; ISS:ARUK-UCL.
DR   GO; GO:0032930; P:positive regulation of superoxide anion generation; ISS:ARUK-UCL.
DR   GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:ARUK-UCL.
DR   GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR   GO; GO:0048678; P:response to axon injury; ISS:ARUK-UCL.
DR   GO; GO:0071526; P:semaphorin-plexin signaling pathway; ISS:UniProtKB.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0002222; P:stimulatory killer cell immunoglobulin-like receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0002291; P:T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; ISS:UniProtKB.
DR   FunFam; 1.10.287.770:FF:000004; TYRO protein tyrosine kinase-binding protein; 1.
DR   Gene3D; 1.10.287.770; YojJ-like; 1.
DR   InterPro; IPR026200; Tyrobp.
DR   PANTHER; PTHR17554; TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; 1.
DR   PANTHER; PTHR17554:SF2; TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Calcium; Cell membrane; Disulfide bond;
KW   Immunity; Membrane; Metal-binding; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Signal; Transmembrane;
KW   Transmembrane helix.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000255"
FT   CHAIN           22..113
FT                   /note="TYRO protein tyrosine kinase-binding protein"
FT                   /id="PRO_0000022603"
FT   TOPO_DOM        22..40
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000305|PubMed:25981043"
FT   TRANSMEM        41..61
FT                   /note="Helical"
FT                   /evidence="ECO:0000269|PubMed:25981043"
FT   TOPO_DOM        62..113
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305|PubMed:25981043"
FT   DOMAIN          80..108
FT                   /note="ITAM"
FT   REGION          75..113
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        87..113
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         50
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_note="ligand shared between two neighboring
FT                   subunits in homooligomer"
FT                   /evidence="ECO:0000269|PubMed:25981043"
FT   SITE            54
FT                   /note="Important for interaction with transmembrane
FT                   receptors"
FT                   /evidence="ECO:0000269|PubMed:20890284"
FT   MOD_RES         91
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:O54885"
FT   MOD_RES         102
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:O54885"
FT   DISULFID        35
FT                   /note="Interchain"
FT                   /evidence="ECO:0000269|PubMed:20890284,
FT                   ECO:0000269|PubMed:25981043, ECO:0007744|PDB:2L34,
FT                   ECO:0007744|PDB:2L35, ECO:0007744|PDB:4WOL"
FT   VAR_SEQ         20..30
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:16344560"
FT                   /id="VSP_046066"
FT   VAR_SEQ         77
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.2,
FT                   ECO:0000303|Ref.3"
FT                   /id="VSP_012909"
FT   VARIANT         2
FT                   /note="G -> E (found in patients with early-onset Alzheimer
FT                   disease; uncertain significance; associated in cis with L-
FT                   55 in some patients; dbSNP:rs200649978)"
FT                   /evidence="ECO:0000269|PubMed:27658901"
FT                   /id="VAR_081398"
FT   VARIANT         23
FT                   /note="R -> C (found in patients with early-onset Alzheimer
FT                   disease; uncertain significance; dbSNP:rs769635655)"
FT                   /evidence="ECO:0000269|PubMed:27658901"
FT                   /id="VAR_081399"
FT   VARIANT         47
FT                   /note="V -> A (found in patients with early-onset Alzheimer
FT                   disease; uncertain significance; dbSNP:rs372140827)"
FT                   /evidence="ECO:0000269|PubMed:27658901"
FT                   /id="VAR_081400"
FT   VARIANT         50
FT                   /note="D -> DPADGRLVLGDRDGR (found in patients with early-
FT                   onset Alzheimer disease; uncertain significance; causes
FT                   reduced expression; also leads to reduced expression of
FT                   TREM2)"
FT                   /evidence="ECO:0000269|PubMed:27658901"
FT                   /id="VAR_081401"
FT   VARIANT         55
FT                   /note="V -> L (found in patients with early-onset Alzheimer
FT                   disease; uncertain significance; associated in cis with E-2
FT                   in some patients; dbSNP:rs77782321)"
FT                   /evidence="ECO:0000269|PubMed:27658901,
FT                   ECO:0000269|PubMed:28716534"
FT                   /id="VAR_081402"
FT   VARIANT         80
FT                   /note="R -> W (found in patients with early-onset Alzheimer
FT                   disease; uncertain significance; dbSNP:rs140188939)"
FT                   /evidence="ECO:0000269|PubMed:27658901"
FT                   /id="VAR_081403"
FT   VARIANT         84
FT                   /note="I -> V (found in patients with early-onset Alzheimer
FT                   disease; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:27658901"
FT                   /id="VAR_081404"
FT   VARIANT         89
FT                   /note="S -> L (found in patients with early-onset Alzheimer
FT                   disease; uncertain significance; dbSNP:rs557854792)"
FT                   /evidence="ECO:0000269|PubMed:27658901"
FT                   /id="VAR_081405"
FT   VARIANT         111
FT                   /note="Y -> H (in dbSNP:rs14714)"
FT                   /id="VAR_011985"
FT   MUTAGEN         41
FT                   /note="G->L: Does not significantly alter the formation of
FT                   homotrimers or homotetramers; when associated with L-45 and
FT                   L-49."
FT                   /evidence="ECO:0000269|PubMed:25981043"
FT   MUTAGEN         45
FT                   /note="G->L: Does not significantly alter the formation of
FT                   homotrimers or homotetramers; when associated with L-41 and
FT                   L-49."
FT                   /evidence="ECO:0000269|PubMed:25981043"
FT   MUTAGEN         49
FT                   /note="G->L: Does not significantly alter the formation of
FT                   homotrimers or homotetramers; when associated with L-41 and
FT                   L-45."
FT                   /evidence="ECO:0000269|PubMed:25981043"
FT   MUTAGEN         50
FT                   /note="D->A: Reduced cell surface expression of KIR2DS1.
FT                   Severely impairs formation of homotrimers and
FT                   homotetramers. Abolishes interaction with TREM2 and
FT                   stabilization of TREM2-CTF. Impairs the expression of
FT                   KLRD1-KLRC2 on the cell surface."
FT                   /evidence="ECO:0000269|PubMed:23715743,
FT                   ECO:0000269|PubMed:25957402, ECO:0000269|PubMed:25981043,
FT                   ECO:0000269|PubMed:9655483"
FT   MUTAGEN         50
FT                   /note="D->E,Q: Severely impairs formation of homotrimers
FT                   and homotetramers."
FT                   /evidence="ECO:0000269|PubMed:25981043"
FT   MUTAGEN         50
FT                   /note="D->N: Reduces formation of homotrimers and
FT                   homotetramers."
FT                   /evidence="ECO:0000269|PubMed:25981043"
FT   MUTAGEN         54
FT                   /note="T->A: Reduced interaction with KLRC2 and KIR2DS3.
FT                   Reduces homotrimer formation and increases homotetramer
FT                   formation."
FT                   /evidence="ECO:0000269|PubMed:20890284,
FT                   ECO:0000269|PubMed:25981043"
FT   HELIX           40..65
FT                   /evidence="ECO:0007829|PDB:4WOL"
SQ   SEQUENCE   113 AA;  12179 MW;  267CB1C1756F89F0 CRC64;
     MGGLEPCSRL LLLPLLLAVS GLRPVQAQAQ SDCSCSTVSP GVLAGIVMGD LVLTVLIALA
     VYFLGRLVPR GRGAAEAATR KQRITETESP YQELQGQRSD VYSDLNTQRP YYK
//
ID   UNC5C_HUMAN             Reviewed;         931 AA.
AC   O95185; Q8IUT0;
DT   11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT   05-MAY-2009, sequence version 2.
DT   28-JAN-2026, entry version 191.
DE   RecName: Full=Netrin receptor UNC5C;
DE   AltName: Full=Protein unc-5 homolog 3;
DE   AltName: Full=Protein unc-5 homolog C;
DE   Flags: Precursor;
GN   Name=UNC5C; Synonyms=UNC5H3;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP   THR-721.
RC   TISSUE=Brain;
RX   PubMed=9782087; DOI=10.1006/geno.1998.5425;
RA   Ackerman S.L., Knowles B.B.;
RT   "Cloning and mapping of the UNC5C gene to human chromosome 4q21-q23.";
RL   Genomics 52:205-208(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   DOWN-REGULATION IN CANCER.
RX   PubMed=12655055; DOI=10.1073/pnas.0738063100;
RA   Thiebault K., Mazelin L., Pays L., Llambi F., Joly M.-O., Scoazec J.-Y.,
RA   Saurin J.-C., Romeo G., Mehlen P.;
RT   "The netrin-1 receptors UNC5H are putative tumor suppressors controlling
RT   cell death commitment.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:4173-4178(2003).
RN   [5]
RP   INTERACTION WITH DSCAM.
RX   PubMed=22685302; DOI=10.1074/jbc.m112.340174;
RA   Purohit A.A., Li W., Qu C., Dwyer T., Shao Q., Guan K.L., Liu G.;
RT   "Down syndrome cell adhesion molecule (DSCAM) associates with
RT   uncoordinated-5C (UNC5C) in netrin-1-mediated growth cone collapse.";
RL   J. Biol. Chem. 287:27126-27138(2012).
RN   [6]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INVOLVEMENT IN AD, VARIANT AD
RP   MET-835, AND CHARACTERIZATION OF VARIANT AD MET-835.
RX   PubMed=25419706; DOI=10.1038/nm.3736;
RG   Alzheimer's Disease Genetics Consortium;
RA   Wetzel-Smith M.K., Hunkapiller J., Bhangale T.R., Srinivasan K.,
RA   Maloney J.A., Atwal J.K., Sa S.M., Yaylaoglu M.B., Foreman O., Ortmann W.,
RA   Rathore N., Hansen D.V., Tessier-Lavigne M., Mayeux R., Pericak-Vance M.,
RA   Haines J., Farrer L.A., Schellenberg G.D., Goate A., Behrens T.W.,
RA   Cruchaga C., Watts R.J., Graham R.R.;
RT   "A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and
RT   increases neuronal cell death.";
RL   Nat. Med. 20:1452-1457(2014).
RN   [7]
RP   INTERACTION WITH DAPK1, AND CHARACTERIZATION OF VARIANT AD MET-835.
RX   PubMed=27068745; DOI=10.1074/jbc.m115.698092;
RA   Hashimoto Y., Toyama Y., Kusakari S., Nawa M., Matsuoka M.;
RT   "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor
RT   Uncoordinated-5C-induced Signaling That Merges with Amyloid beta Precursor
RT   Protein Signaling.";
RL   J. Biol. Chem. 291:12282-12293(2016).
RN   [8]
RP   FUNCTION, AND INTERACTION WITH TUBB3.
RX   PubMed=28483977; DOI=10.1523/jneurosci.2617-16.2017;
RA   Shao Q., Yang T., Huang H., Alarmanazi F., Liu G.;
RT   "Uncoupling of UNC5C with Polymerized TUBB3 in Microtubules Mediates
RT   Netrin-1 Repulsion.";
RL   J. Neurosci. 37:5620-5633(2017).
CC   -!- FUNCTION: Receptor for netrin required for axon guidance (By
CC       similarity). Mediates axon repulsion of neuronal growth cones in the
CC       developing nervous system upon ligand binding (By similarity).
CC       NTN1/Netrin-1 binding might cause dissociation of UNC5C from
CC       polymerized TUBB3 in microtubules and thereby lead to increased
CC       microtubule dynamics and axon repulsion (PubMed:28483977). Axon
CC       repulsion in growth cones may also be caused by its association with
CC       DCC that may trigger signaling for repulsion (By similarity). Might
CC       also collaborate with DSCAM in NTN1-mediated axon repulsion
CC       independently of DCC (By similarity). Also involved in corticospinal
CC       tract axon guidance independently of DCC (By similarity). Involved in
CC       dorsal root ganglion axon projection towards the spinal cord
CC       (PubMed:28483977). It also acts as a dependence receptor required for
CC       apoptosis induction when not associated with netrin ligand (By
CC       similarity). {ECO:0000250|UniProtKB:O08747,
CC       ECO:0000250|UniProtKB:Q761X5, ECO:0000269|PubMed:28483977}.
CC   -!- SUBUNIT: Interacts with DCC (via cytoplasmic domain) (By similarity).
CC       Interacts (tyrosine phosphorylated form) with PTPN11 (By similarity).
CC       Interacts (via extracellular domain) with FLRT3 (via extracellular
CC       domain) (By similarity). Interacts (via Ig-like C2-type domain) with
CC       DSCAM (via extracellular domain) (PubMed:22685302). Interacts (via
CC       death domain) with DAPK1 (PubMed:27068745). Interacts (via cytoplasmic
CC       domain) with TUBB3; this interaction is decreased by NTN1/Netrin-1
CC       (PubMed:28483977). {ECO:0000250|UniProtKB:O08747,
CC       ECO:0000269|PubMed:22685302, ECO:0000269|PubMed:27068745,
CC       ECO:0000269|PubMed:28483977}.
CC   -!- INTERACTION:
CC       O95185; Q13509: TUBB3; NbExp=2; IntAct=EBI-11343380, EBI-350989;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:25419706};
CC       Single-pass type I membrane protein {ECO:0000255}. Cell surface
CC       {ECO:0000269|PubMed:25419706}. Synapse, synaptosome
CC       {ECO:0000250|UniProtKB:Q761X5}. Cell projection, axon
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, dendrite
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, growth cone
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, lamellipodium
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, filopodium
CC       {ECO:0000250|UniProtKB:O08747}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=O95185-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O95185-2; Sequence=VSP_011700, VSP_011701;
CC   -!- TISSUE SPECIFICITY: Mainly expressed in brain (PubMed:9782087).
CC       Expressed in temporal lobe cortical neurons and in neurons of the
CC       hippocampal pyramidal layer (PubMed:25419706). Also expressed in kidney
CC       (PubMed:9782087). Not expressed in developing or adult lung
CC       (PubMed:9782087). {ECO:0000269|PubMed:25419706,
CC       ECO:0000269|PubMed:9782087}.
CC   -!- PTM: Proteolytically cleaved by caspases during apoptosis. The cleavage
CC       does not take place when the receptor is associated with netrin ligand.
CC       Its cleavage by caspases is required to induce apoptosis.
CC       {ECO:0000250|UniProtKB:Q761X5}.
CC   -!- PTM: Phosphorylated on different cytoplasmic tyrosine residues.
CC       Phosphorylation of Tyr-568 leads to an interaction with PTPN11
CC       phosphatase, suggesting that its activity is regulated by
CC       phosphorylation/dephosphorylation. Tyrosine phosphorylation is netrin-
CC       dependent. {ECO:0000250|UniProtKB:O08747}.
CC   -!- DISEASE: Alzheimer disease (AD) [MIM:104300]: Alzheimer disease is a
CC       neurodegenerative disorder characterized by progressive dementia, loss
CC       of cognitive abilities, and deposition of fibrillar amyloid proteins as
CC       intraneuronal neurofibrillary tangles, extracellular amyloid plaques
CC       and vascular amyloid deposits. The major constituents of these plaques
CC       are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42,
CC       that are produced by the proteolysis of the transmembrane APP protein.
CC       The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved
CC       products, such as C31, are also implicated in neuronal death.
CC       {ECO:0000269|PubMed:25419706, ECO:0000269|PubMed:27068745}.
CC       Note=Disease susceptibility may be associated with variants affecting
CC       the gene represented in this entry.
CC   -!- MISCELLANEOUS: Down-regulated in multiple cancers including colorectal,
CC       breast, ovary, uterus, stomach, lung, or kidney cancers.
CC       {ECO:0000269|PubMed:12655055}.
CC   -!- SIMILARITY: Belongs to the unc-5 family. {ECO:0000305}.
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DR   EMBL; AF055634; AAC67491.1; -; mRNA.
DR   EMBL; AC098584; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC105395; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC106881; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC041156; AAH41156.1; -; mRNA.
DR   CCDS; CCDS3643.1; -. [O95185-1]
DR   RefSeq; NP_003719.3; NM_003728.3. [O95185-1]
DR   AlphaFoldDB; O95185; -.
DR   SMR; O95185; -.
DR   BioGRID; 114186; 38.
DR   DIP; DIP-46276N; -.
DR   FunCoup; O95185; 326.
DR   IntAct; O95185; 9.
DR   MINT; O95185; -.
DR   STRING; 9606.ENSP00000406022; -.
DR   GlyCosmos; O95185; 2 sites, No reported glycans.
DR   GlyGen; O95185; 3 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; O95185; -.
DR   PhosphoSitePlus; O95185; -.
DR   BioMuta; UNC5C; -.
DR   jPOST; O95185; -.
DR   MassIVE; O95185; -.
DR   PaxDb; 9606-ENSP00000406022; -.
DR   PeptideAtlas; O95185; -.
DR   ProteomicsDB; 50694; -. [O95185-1]
DR   ProteomicsDB; 50695; -. [O95185-2]
DR   Pumba; O95185; -.
DR   Antibodypedia; 2665; 258 antibodies from 33 providers.
DR   DNASU; 8633; -.
DR   Ensembl; ENST00000453304.6; ENSP00000406022.1; ENSG00000182168.16. [O95185-1]
DR   Ensembl; ENST00000506749.5; ENSP00000426153.1; ENSG00000182168.16. [O95185-2]
DR   GeneID; 8633; -.
DR   KEGG; hsa:8633; -.
DR   MANE-Select; ENST00000453304.6; ENSP00000406022.1; NM_003728.4; NP_003719.3.
DR   UCSC; uc003hto.4; human. [O95185-1]
DR   AGR; HGNC:12569; -.
DR   ClinPGx; PA37206; -.
DR   CTD; 8633; -.
DR   DisGeNET; 8633; -.
DR   GeneCards; UNC5C; -.
DR   HGNC; HGNC:12569; UNC5C.
DR   HPA; ENSG00000182168; Tissue enhanced (thyroid).
DR   MalaCards; UNC5C; -.
DR   MIM; 104300; phenotype.
DR   MIM; 603610; gene.
DR   OpenTargets; ENSG00000182168; -.
DR   VEuPathDB; HostDB:ENSG00000182168; -.
DR   eggNOG; KOG1480; Eukaryota.
DR   GeneTree; ENSGT00950000182815; -.
DR   HOGENOM; CLU_014383_2_1_1; -.
DR   InParanoid; O95185; -.
DR   OMA; CECQAWS; -.
DR   OrthoDB; 5973910at2759; -.
DR   PAN-GO; O95185; 2 GO annotations based on evolutionary models.
DR   PhylomeDB; O95185; -.
DR   PathwayCommons; O95185; -.
DR   Reactome; R-HSA-418886; Netrin mediated repulsion signals.
DR   SignaLink; O95185; -.
DR   SIGNOR; O95185; -.
DR   Agora; ENSG00000182168; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 8633; 6 hits in 1142 CRISPR screens.
DR   ChiTaRS; UNC5C; human.
DR   GeneWiki; UNC5C; -.
DR   GenomeRNAi; 8633; -.
DR   Pharos; O95185; Tbio.
DR   PRO; PR:O95185; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; O95185; protein.
DR   Bgee; ENSG00000182168; Expressed in corpus callosum and 134 other cell types or tissues.
DR   ExpressionAtlas; O95185; baseline and differential.
DR   GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR   GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR   GO; GO:0030175; C:filopodium; ISS:UniProtKB.
DR   GO; GO:0030426; C:growth cone; ISS:UniProtKB.
DR   GO; GO:0030027; C:lamellipodium; ISS:UniProtKB.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR   GO; GO:0005042; F:netrin receptor activity; IBA:GO_Central.
DR   GO; GO:0005043; F:netrin receptor activity involved in chemorepulsion; ISS:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0015631; F:tubulin binding; IPI:UniProtKB.
DR   GO; GO:0033564; P:anterior/posterior axon guidance; IEA:Ensembl.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0007411; P:axon guidance; IBA:GO_Central.
DR   GO; GO:0007420; P:brain development; TAS:ProtInc.
DR   GO; GO:0061643; P:chemorepulsion of axon; ISS:UniProtKB.
DR   GO; GO:1990791; P:dorsal root ganglion development; IDA:UniProtKB.
DR   GO; GO:0035234; P:ectopic germ cell programmed cell death; IEA:Ensembl.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0051094; P:positive regulation of developmental process; IEA:Ensembl.
DR   GO; GO:2000243; P:positive regulation of reproductive process; IEA:Ensembl.
DR   GO; GO:2001222; P:regulation of neuron migration; IEA:Ensembl.
DR   CDD; cd08799; Death_UNC5C; 1.
DR   FunFam; 1.10.533.10:FF:000001; Unc-5 netrin receptor B; 1.
DR   FunFam; 2.20.100.10:FF:000002; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.20.100.10:FF:000008; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.60.220.30:FF:000003; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.60.40.10:FF:000037; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.60.40.10:FF:000039; Unc-5 netrin receptor C; 1.
DR   Gene3D; 2.60.220.30; -; 1.
DR   Gene3D; 1.10.533.10; Death Domain, Fas; 1.
DR   Gene3D; 2.60.40.10; Immunoglobulins; 2.
DR   Gene3D; 2.20.100.10; Thrombospondin type-1 (TSP1) repeat; 2.
DR   InterPro; IPR011029; DEATH-like_dom_sf.
DR   InterPro; IPR000488; Death_dom.
DR   InterPro; IPR042154; Death_UNC5C.
DR   InterPro; IPR007110; Ig-like_dom.
DR   InterPro; IPR036179; Ig-like_dom_sf.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR013098; Ig_I-set.
DR   InterPro; IPR003599; Ig_sub.
DR   InterPro; IPR003598; Ig_sub2.
DR   InterPro; IPR000884; TSP1_rpt.
DR   InterPro; IPR036383; TSP1_rpt_sf.
DR   InterPro; IPR037936; UNC5A-D.
DR   InterPro; IPR057755; UNC5A-D-like_N.
DR   InterPro; IPR033772; UPA.
DR   InterPro; IPR000906; ZU5_dom.
DR   PANTHER; PTHR12582; NETRIN RECEPTOR UNC5; 1.
DR   PANTHER; PTHR12582:SF7; NETRIN RECEPTOR UNC5C; 1.
DR   Pfam; PF00531; Death; 1.
DR   Pfam; PF07679; I-set; 1.
DR   Pfam; PF00090; TSP_1; 2.
DR   Pfam; PF25609; Unc5_NetrinR_N; 1.
DR   Pfam; PF17217; UPA; 1.
DR   Pfam; PF00791; ZU5; 1.
DR   PRINTS; PR01705; TSP1REPEAT.
DR   SMART; SM00005; DEATH; 1.
DR   SMART; SM00409; IG; 1.
DR   SMART; SM00408; IGc2; 1.
DR   SMART; SM00209; TSP1; 2.
DR   SMART; SM00218; ZU5; 1.
DR   SUPFAM; SSF47986; DEATH domain; 1.
DR   SUPFAM; SSF48726; Immunoglobulin; 2.
DR   SUPFAM; SSF82895; TSP-1 type 1 repeat; 2.
DR   PROSITE; PS50835; IG_LIKE; 1.
DR   PROSITE; PS50092; TSP1; 2.
DR   PROSITE; PS51145; ZU5; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Alzheimer disease; Amyloidosis; Apoptosis;
KW   Cell membrane; Cell projection; Developmental protein; Disulfide bond;
KW   Glycoprotein; Immunoglobulin domain; Membrane; Neurodegeneration;
KW   Phosphoprotein; Proteomics identification; Receptor; Reference proteome;
KW   Repeat; Signal; Synapse; Synaptosome; Transmembrane; Transmembrane helix.
FT   SIGNAL          1..40
FT                   /evidence="ECO:0000255"
FT   CHAIN           41..931
FT                   /note="Netrin receptor UNC5C"
FT                   /id="PRO_0000036075"
FT   TOPO_DOM        41..380
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        381..401
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        402..931
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          62..159
FT                   /note="Ig-like"
FT   DOMAIN          161..256
FT                   /note="Ig-like C2-type"
FT   DOMAIN          260..314
FT                   /note="TSP type-1 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DOMAIN          316..368
FT                   /note="TSP type-1 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DOMAIN          530..673
FT                   /note="ZU5"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00485"
FT   DOMAIN          850..929
FT                   /note="Death"
FT   REGION          402..931
FT                   /note="Required for netrin-mediated axon repulsion of
FT                   neuronal growth cones"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   REGION          694..712
FT                   /note="Interaction with DCC"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   SITE            415..416
FT                   /note="Cleavage; by caspase-3"
FT                   /evidence="ECO:0000250|UniProtKB:Q761X5"
FT   MOD_RES         502
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   MOD_RES         568
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   CARBOHYD        236
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        361
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        83..144
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        95..142
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        188..239
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        272..309
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DISULFID        276..313
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DISULFID        287..299
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DISULFID        328..362
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        332..367
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        340..352
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   VAR_SEQ         370
FT                   /note="T -> SFIYPISTEQRTQNEYGFSS (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_011700"
FT   VAR_SEQ         579..931
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_011701"
FT   VARIANT         37
FT                   /note="G -> V (in dbSNP:rs2306715)"
FT                   /id="VAR_019731"
FT   VARIANT         721
FT                   /note="M -> T (in dbSNP:rs2289043)"
FT                   /evidence="ECO:0000269|PubMed:9782087"
FT                   /id="VAR_019732"
FT   VARIANT         835
FT                   /note="T -> M (in AD; increased susceptibility to neuronal
FT                   cell death; dbSNP:rs137875858)"
FT                   /evidence="ECO:0000269|PubMed:25419706,
FT                   ECO:0000269|PubMed:27068745"
FT                   /id="VAR_081368"
FT   VARIANT         841
FT                   /note="A -> T (in dbSNP:rs34585936)"
FT                   /id="VAR_055327"
FT   CONFLICT        219
FT                   /note="T -> I (in Ref. 3; AAH41156)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        489
FT                   /note="T -> S (in Ref. 1; AAC67491)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        651
FT                   /note="Q -> K (in Ref. 1; AAC67491)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   931 AA;  103146 MW;  98A95995129532A7 CRC64;
     MRKGLRATAA RCGLGLGYLL QMLVLPALAL LSASGTGSAA QDDDFFHELP ETFPSDPPEP
     LPHFLIEPEE AYIVKNKPVN LYCKASPATQ IYFKCNSEWV HQKDHIVDER VDETSGLIVR
     EVSIEISRQQ VEELFGPEDY WCQCVAWSSA GTTKSRKAYV RIAYLRKTFE QEPLGKEVSL
     EQEVLLQCRP PEGIPVAEVE WLKNEDIIDP VEDRNFYITI DHNLIIKQAR LSDTANYTCV
     AKNIVAKRKS TTATVIVYVN GGWSTWTEWS VCNSRCGRGY QKRTRTCTNP APLNGGAFCE
     GQSVQKIACT TLCPVDGRWT PWSKWSTCGT ECTHWRRREC TAPAPKNGGK DCDGLVLQSK
     NCTDGLCMQT APDSDDVALY VGIVIAVIVC LAISVVVALF VYRKNHRDFE SDIIDSSALN
     GGFQPVNIKA ARQDLLAVPP DLTSAAAMYR GPVYALHDVS DKIPMTNSPI LDPLPNLKIK
     VYNTSGAVTP QDDLSEFTSK LSPQMTQSLL ENEALSLKNQ SLARQTDPSC TAFGSFNSLG
     GHLIVPNSGV SLLIPAGAIP QGRVYEMYVT VHRKETMRPP MDDSQTLLTP VVSCGPPGAL
     LTRPVVLTMH HCADPNTEDW KILLKNQAAQ GQWEDVVVVG EENFTTPCYI QLDAEACHIL
     TENLSTYALV GHSTTKAAAK RLKLAIFGPL CCSSLEYSIR VYCLDDTQDA LKEILHLERQ
     MGGQLLEEPK ALHFKGSTHN LRLSIHDIAH SLWKSKLLAK YQEIPFYHVW SGSQRNLHCT
     FTLERFSLNT VELVCKLCVR QVEGEGQIFQ LNCTVSEEPT GIDLPLLDPA NTITTVTGPS
     AFSIPLPIRQ KLCSSLDAPQ TRGHDWRMLA HKLNLDRYLN YFATKSSPTG VILDLWEAQN
     FPDGNLSMLA AVLEEMGRHE TVVSLAAEGQ Y
//