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   AATC_HUMAN              Reviewed;         413 AA.
AC   P17174; B2R6R7; B7Z7E9; Q5VW80;
DT   01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   28-JAN-2026, entry version 228.
DE   RecName: Full=Aspartate aminotransferase, cytoplasmic {ECO:0000305};
DE            Short=cAspAT;
DE            EC=2.6.1.1 {ECO:0000269|PubMed:21900944};
DE            EC=2.6.1.3 {ECO:0000250|UniProtKB:P13221};
DE   AltName: Full=Cysteine aminotransferase, cytoplasmic;
DE   AltName: Full=Cysteine transaminase, cytoplasmic;
DE            Short=cCAT;
DE   AltName: Full=Glutamate oxaloacetate transaminase 1;
DE   AltName: Full=Transaminase A;
GN   Name=GOT1 {ECO:0000312|HGNC:HGNC:4432};
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=Liver;
RX   PubMed=1974457; DOI=10.1021/bi00474a011;
RA   Bousquet-Lemercier B., Pol S., Pave-Preux M., Hanoune J., Barouki R.;
RT   "Properties of human liver cytosolic aspartate aminotransferase mRNAs
RT   generated by alternative polyadenylation site selection.";
RL   Biochemistry 29:5293-5299(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Wang C.Y., Huang Y.Q., Shi J.D., Marron M.P., Ruan Q.G., Hawkins-Lee B.,
RA   Ochoa B., She J.X.;
RT   "Genomic structure and mutation analysis of GOT1 in the urofacial (Ochoa)
RT   syndrome gene critical region on chromosome 10.";
RL   Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RA   Yu W., Sarginson J., Gibbs R.A.;
RL   Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 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   [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 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   PROTEIN SEQUENCE OF 2-413.
RC   TISSUE=Liver;
RX   PubMed=2241899; DOI=10.1042/bj2700651;
RA   Doyle J.M., Schinina M.E., Bossa F., Doonan S.;
RT   "The amino acid sequence of cytosolic aspartate aminotransferase from human
RT   liver.";
RL   Biochem. J. 270:651-657(1990).
RN   [9]
RP   FUNCTION.
RX   PubMed=16039064; DOI=10.1016/j.neulet.2005.06.030;
RA   D'Aniello A., Fisher G., Migliaccio N., Cammisa G., D'Aniello E.,
RA   Spinelli P.;
RT   "Amino acids and transaminases activity in ventricular CSF and in brain of
RT   normal and Alzheimer patients.";
RL   Neurosci. Lett. 388:49-53(2005).
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   INVOLVEMENT IN ASTQTL1, VARIANT ASN-389 DEL, FUNCTION, CATALYTIC ACTIVITY,
RP   CHARACTERIZATION OF VARIANT ASN-389 DEL, AND POLYMORPHISM.
RX   PubMed=21900944; DOI=10.1038/jhg.2011.105;
RA   Shen H., Damcott C., Shuldiner S.R., Chai S., Yang R., Hu H., Gibson Q.,
RA   Ryan K.A., Mitchell B.D., Gong D.W.;
RT   "Genome-wide association study identifies genetic variants in GOT1
RT   determining serum aspartate aminotransferase levels.";
RL   J. Hum. Genet. 56:801-805(2011).
RN   [12]
RP   FETAL BLOOD LEVELS.
RX   PubMed=22633534; DOI=10.1016/j.earlhumdev.2012.05.001;
RA   Zlotnik A., Tsesis S., Gruenbaum B.F., Ohayon S., Gruenbaum S.E., Boyko M.,
RA   Sheiner E., Brotfain E., Shapira Y., Teichberg V.I.;
RT   "Relationship between glutamate, GOT and GPT levels in maternal and fetal
RT   blood: a potential mechanism for fetal neuroprotection.";
RL   Early Hum. Dev. 88:773-778(2012).
RN   [13]
RP   CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION
RP   BY MASS 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   [14]
RP   IDENTIFICATION BY 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   [15]
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   [16]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=27827456; DOI=10.1038/srep36749;
RA   Irino Y., Toh R., Nagao M., Mori T., Honjo T., Shinohara M., Tsuda S.,
RA   Nakajima H., Satomi-Kobayashi S., Shinke T., Tanaka H., Ishida T.,
RA   Miyata O., Hirata K.I.;
RT   "2-Aminobutyric acid modulates glutathione homeostasis in the myocardium.";
RL   Sci. Rep. 6:36749-36749(2016).
RN   [17]
RP   X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 14-412 IN COMPLEX WITH PYRIDOXAL
RP   PHOSPHATE AND TARTARIC ACID, SUBUNIT, AND PYRIDOXAL PHOSPHATE AT LYS-259.
RG   Structural genomics consortium (SGC);
RT   "Crystal structure of human glutamate oxaloacetate transaminase 1 (GOT1).";
RL   Submitted (AUG-2009) to the PDB data bank.
CC   -!- FUNCTION: Biosynthesis of L-glutamate from L-aspartate or L-cysteine
CC       (PubMed:21900944). Important regulator of levels of glutamate, the
CC       major excitatory neurotransmitter of the vertebrate central nervous
CC       system. Acts as a scavenger of glutamate in brain neuroprotection. The
CC       aspartate aminotransferase activity is involved in hepatic glucose
CC       synthesis during development and in adipocyte glyceroneogenesis. Using
CC       L-cysteine as substrate, regulates levels of mercaptopyruvate, an
CC       important source of hydrogen sulfide. Mercaptopyruvate is converted
CC       into H(2)S via the action of 3-mercaptopyruvate sulfurtransferase
CC       (3MST). Hydrogen sulfide is an important synaptic modulator and
CC       neuroprotectant in the brain. In addition, catalyzes (2S)-2-
CC       aminobutanoate, a by-product in the cysteine biosynthesis pathway
CC       (PubMed:27827456). {ECO:0000269|PubMed:16039064,
CC       ECO:0000269|PubMed:21900944, ECO:0000269|PubMed:27827456}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-aspartate + 2-oxoglutarate = oxaloacetate + L-glutamate;
CC         Xref=Rhea:RHEA:21824, ChEBI:CHEBI:16452, ChEBI:CHEBI:16810,
CC         ChEBI:CHEBI:29985, ChEBI:CHEBI:29991; EC=2.6.1.1;
CC         Evidence={ECO:0000269|PubMed:21900944};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21825;
CC         Evidence={ECO:0000250|UniProtKB:P13221};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-cysteine + 2-oxoglutarate = 2-oxo-3-sulfanylpropanoate + L-
CC         glutamate; Xref=Rhea:RHEA:17441, ChEBI:CHEBI:16810,
CC         ChEBI:CHEBI:29985, ChEBI:CHEBI:35235, ChEBI:CHEBI:57678; EC=2.6.1.3;
CC         Evidence={ECO:0000250|UniProtKB:P13221};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17442;
CC         Evidence={ECO:0000250|UniProtKB:P13221};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(2S)-2-aminobutanoate + 2-oxoglutarate = 2-oxobutanoate + L-
CC         glutamate; Xref=Rhea:RHEA:70223, ChEBI:CHEBI:16763,
CC         ChEBI:CHEBI:16810, ChEBI:CHEBI:29985, ChEBI:CHEBI:74359;
CC         Evidence={ECO:0000269|PubMed:27827456};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70225;
CC         Evidence={ECO:0000269|PubMed:27827456};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3-sulfino-L-alanine + 2-oxoglutarate = 3-sulfinopyruvate + L-
CC         glutamate; Xref=Rhea:RHEA:70295, ChEBI:CHEBI:16810,
CC         ChEBI:CHEBI:29985, ChEBI:CHEBI:61085, ChEBI:CHEBI:140699;
CC         Evidence={ECO:0000250|UniProtKB:P13221};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:70297;
CC         Evidence={ECO:0000250|UniProtKB:P13221};
CC   -!- COFACTOR:
CC       Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
CC   -!- SUBUNIT: Homodimer. {ECO:0000269|Ref.17}.
CC   -!- INTERACTION:
CC       P17174; P15056: BRAF; NbExp=5; IntAct=EBI-727329, EBI-365980;
CC       P17174; P00533: EGFR; NbExp=3; IntAct=EBI-727329, EBI-297353;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:1974457}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P17174-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P17174-2; Sequence=VSP_055799;
CC   -!- POLYMORPHISM: Genetic variations in GOT1 are associated with low serum
CC       aspartate aminotransferase and define the aspartate aminotransferase
CC       serum level quantitative trait locus 1 (ASTQTL1) [MIM:614419].
CC       {ECO:0000269|PubMed:21900944}.
CC   -!- MISCELLANEOUS: In eukaryotes there are cytoplasmic, mitochondrial and
CC       chloroplastic isozymes.
CC   -!- MISCELLANEOUS: Aspartate aminotransferase activity found to be
CC       increased in cerebral spinal fluid (CSF) of patients with Alzheimer
CC       disease (PubMed:16039064). Fetal serum levels of the enzyme in the
CC       umbilical artery and vein are found to be significantly higher than
CC       maternal serum levels (PubMed:22633534). {ECO:0000305|PubMed:16039064,
CC       ECO:0000305|PubMed:22633534}.
CC   -!- SIMILARITY: Belongs to the class-I pyridoxal-phosphate-dependent
CC       aminotransferase family. {ECO:0000305}.
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DR   EMBL; M37400; AAA35563.1; -; mRNA.
DR   EMBL; AF080467; AAC32851.1; -; Genomic_DNA.
DR   EMBL; AF080459; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF080460; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF080461; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF080462; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF080463; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF080464; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF080465; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF080466; AAC32851.1; JOINED; Genomic_DNA.
DR   EMBL; AF052153; AAC28622.1; -; mRNA.
DR   EMBL; AK301916; BAH13585.1; -; mRNA.
DR   EMBL; AK312684; BAG35564.1; -; mRNA.
DR   EMBL; AL391684; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471066; EAW49869.1; -; Genomic_DNA.
DR   EMBL; BC000498; AAH00498.1; -; mRNA.
DR   CCDS; CCDS7479.1; -. [P17174-1]
DR   PIR; S13035; S13035.
DR   PIR; S29027; S29027.
DR   RefSeq; NP_002070.1; NM_002079.3. [P17174-1]
DR   PDB; 3II0; X-ray; 2.05 A; A/B/C/D=14-412.
DR   PDB; 3WZF; X-ray; 2.99 A; A=2-413.
DR   PDB; 6DNA; X-ray; 3.00 A; A/B/C/D/E/F=6-410.
DR   PDB; 6DNB; X-ray; 1.70 A; A=3-413.
DR   PDB; 6DND; X-ray; 2.10 A; A/B=3-413.
DR   PDB; 6LIG; X-ray; 2.62 A; A/B=3-413.
DR   PDB; 8Z0E; X-ray; 1.82 A; A/B=1-413.
DR   PDBsum; 3II0; -.
DR   PDBsum; 3WZF; -.
DR   PDBsum; 6DNA; -.
DR   PDBsum; 6DNB; -.
DR   PDBsum; 6DND; -.
DR   PDBsum; 6LIG; -.
DR   PDBsum; 8Z0E; -.
DR   AlphaFoldDB; P17174; -.
DR   SMR; P17174; -.
DR   BioGRID; 109067; 274.
DR   FunCoup; P17174; 2117.
DR   IntAct; P17174; 194.
DR   MINT; P17174; -.
DR   STRING; 9606.ENSP00000359539; -.
DR   BindingDB; P17174; -.
DR   ChEMBL; CHEMBL2189139; -.
DR   DrugBank; DB00210; Adapalene.
DR   DrugBank; DB00128; Aspartic acid.
DR   DrugBank; DB09130; Copper.
DR   DrugBank; DB00151; Cysteine.
DR   DrugBank; DB00142; Glutamic acid.
DR   DrugBank; DB04299; Maleic acid.
DR   DrugBank; DB00114; Pyridoxal phosphate.
DR   DrugCentral; P17174; -.
DR   GlyGen; P17174; 2 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; P17174; -.
DR   PhosphoSitePlus; P17174; -.
DR   SwissPalm; P17174; -.
DR   BioMuta; GOT1; -.
DR   DMDM; 5902703; -.
DR   REPRODUCTION-2DPAGE; IPI00219029; -.
DR   jPOST; P17174; -.
DR   MassIVE; P17174; -.
DR   PaxDb; 9606-ENSP00000359539; -.
DR   PeptideAtlas; P17174; -.
DR   PRIDE; P17174; -.
DR   ProteomicsDB; 53459; -. [P17174-1]
DR   ProteomicsDB; 6862; -.
DR   Pumba; P17174; -.
DR   Antibodypedia; 31077; 571 antibodies from 38 providers.
DR   DNASU; 2805; -.
DR   Ensembl; ENST00000370508.7; ENSP00000359539.5; ENSG00000120053.13. [P17174-1]
DR   GeneID; 2805; -.
DR   KEGG; hsa:2805; -.
DR   MANE-Select; ENST00000370508.7; ENSP00000359539.5; NM_002079.3; NP_002070.1.
DR   UCSC; uc001kpr.4; human. [P17174-1]
DR   AGR; HGNC:4432; -.
DR   ClinPGx; PA28817; -.
DR   CTD; 2805; -.
DR   DisGeNET; 2805; -.
DR   GeneCards; GOT1; -.
DR   HGNC; HGNC:4432; GOT1.
DR   HPA; ENSG00000120053; Tissue enhanced (heart muscle, skeletal muscle, tongue).
DR   MalaCards; GOT1; -.
DR   MIM; 138180; gene.
DR   MIM; 614419; phenotype.
DR   OpenTargets; ENSG00000120053; -.
DR   VEuPathDB; HostDB:ENSG00000120053; -.
DR   eggNOG; KOG1412; Eukaryota.
DR   GeneTree; ENSGT00950000183082; -.
DR   HOGENOM; CLU_032440_1_2_1; -.
DR   InParanoid; P17174; -.
DR   OMA; GTWTHIT; -.
DR   OrthoDB; 6752799at2759; -.
DR   PAN-GO; P17174; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P17174; -.
DR   BioCyc; MetaCyc:HS04361-MONOMER; -.
DR   BRENDA; 2.6.1.1; 2681.
DR   BRENDA; 2.6.1.64; 2681.
DR   PathwayCommons; P17174; -.
DR   Reactome; R-HSA-1237112; Methionine salvage pathway.
DR   Reactome; R-HSA-8963693; Aspartate and asparagine metabolism.
DR   Reactome; R-HSA-9856872; Malate-aspartate shuttle.
DR   SABIO-RK; P17174; -.
DR   SignaLink; P17174; -.
DR   SIGNOR; P17174; -.
DR   Agora; ENSG00000120053; -.
DR   BioGRID-ORCS; 2805; 25 hits in 1159 CRISPR screens.
DR   ChiTaRS; GOT1; human.
DR   EvolutionaryTrace; P17174; -.
DR   GeneWiki; GOT1; -.
DR   GenomeRNAi; 2805; -.
DR   Pharos; P17174; Tbio.
DR   PRO; PR:P17174; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; P17174; protein.
DR   Bgee; ENSG00000120053; Expressed in heart right ventricle and 205 other cell types or tissues.
DR   ExpressionAtlas; P17174; baseline and differential.
DR   GO; GO:0043679; C:axon terminus; IEA:Ensembl.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR   GO; GO:0120554; F:2-aminobutanoate transaminase activity; IDA:FlyBase.
DR   GO; GO:0031406; F:carboxylic acid binding; IEA:Ensembl.
DR   GO; GO:0004069; F:L-aspartate:2-oxoglutarate aminotransferase activity; IDA:UniProtKB.
DR   GO; GO:0047801; F:L-cysteine transaminase activity; ISS:UniProtKB.
DR   GO; GO:0004609; F:phosphatidylserine decarboxylase activity; IEA:Ensembl.
DR   GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR   GO; GO:0006103; P:2-oxoglutarate metabolic process; ISS:UniProtKB.
DR   GO; GO:0006532; P:aspartate biosynthetic process; IBA:GO_Central.
DR   GO; GO:0006531; P:aspartate metabolic process; ISS:UniProtKB.
DR   GO; GO:0032869; P:cellular response to insulin stimulus; IEP:UniProtKB.
DR   GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR   GO; GO:0055089; P:fatty acid homeostasis; IEA:Ensembl.
DR   GO; GO:0006094; P:gluconeogenesis; IEA:Ensembl.
DR   GO; GO:0006536; P:glutamate metabolic process; ISS:UniProtKB.
DR   GO; GO:0006114; P:glycerol biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0006533; P:L-aspartate catabolic process; IDA:UniProtKB.
DR   GO; GO:0097054; P:L-glutamate biosynthetic process; IEA:Ensembl.
DR   GO; GO:0019550; P:L-glutamate catabolic process to aspartate; IEA:Ensembl.
DR   GO; GO:0043490; P:malate-aspartate shuttle; IMP:FlyBase.
DR   GO; GO:0032966; P:negative regulation of collagen biosynthetic process; IEA:Ensembl.
DR   GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; IEA:Ensembl.
DR   GO; GO:0051902; P:negative regulation of mitochondrial depolarization; IEA:Ensembl.
DR   GO; GO:0007219; P:Notch signaling pathway; IEA:Ensembl.
DR   GO; GO:0006107; P:oxaloacetate metabolic process; IEA:Ensembl.
DR   GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR   GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl.
DR   GO; GO:0009743; P:response to carbohydrate; IEA:Ensembl.
DR   GO; GO:0051384; P:response to glucocorticoid; IEP:UniProtKB.
DR   GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl.
DR   GO; GO:1990267; P:response to transition metal nanoparticle; IEA:Ensembl.
DR   GO; GO:0060290; P:transdifferentiation; IEA:Ensembl.
DR   CDD; cd00609; AAT_like; 1.
DR   FunFam; 3.40.640.10:FF:000044; Aspartate aminotransferase; 1.
DR   FunFam; 3.90.1150.10:FF:000001; Aspartate aminotransferase; 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; IPR000796; Asp_trans.
DR   InterPro; IPR004838; NHTrfase_class1_PyrdxlP-BS.
DR   InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR   InterPro; IPR015421; PyrdxlP-dep_Trfase_major.
DR   InterPro; IPR015422; PyrdxlP-dep_Trfase_small.
DR   NCBIfam; NF006719; PRK09257.1; 1.
DR   PANTHER; PTHR11879; ASPARTATE AMINOTRANSFERASE; 1.
DR   PANTHER; PTHR11879:SF3; ASPARTATE AMINOTRANSFERASE, CYTOPLASMIC; 1.
DR   Pfam; PF00155; Aminotran_1_2; 1.
DR   PRINTS; PR00799; TRANSAMINASE.
DR   SUPFAM; SSF53383; PLP-dependent transferases; 1.
DR   PROSITE; PS00105; AA_TRANSFER_CLASS_1; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Amino-acid biosynthesis;
KW   Aminotransferase; Cytoplasm; Direct protein sequencing; Phosphoprotein;
KW   Proteomics identification; Pyridoxal phosphate; Reference proteome;
KW   Transferase.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:2241899,
FT                   ECO:0007744|PubMed:22223895"
FT   CHAIN           2..413
FT                   /note="Aspartate aminotransferase, cytoplasmic"
FT                   /id="PRO_0000123879"
FT   BINDING         39
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT   BINDING         141
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT   BINDING         195
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT   BINDING         387
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT   MOD_RES         149
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P13221"
FT   MOD_RES         259
FT                   /note="N6-(pyridoxal phosphate)lysine"
FT                   /evidence="ECO:0000250"
FT   VAR_SEQ         1..39
FT                   /note="MAPPSVFAEVPQAQPVLVFKLTADFREDPDPRKVNLGVG -> MQVWSPWKG
FT                   AMCPRPHKP (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_055799"
FT   VARIANT         389
FT                   /note="Missing (results in markedly diminished enzymatic
FT                   activity; dbSNP:rs749913156)"
FT                   /evidence="ECO:0000269|PubMed:21900944"
FT                   /id="VAR_067256"
FT   CONFLICT        215
FT                   /note="H -> R (in Ref. 8; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   TURN            6..9
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           17..27
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          29..31
FT                   /evidence="ECO:0007829|PDB:6DNA"
FT   HELIX           52..63
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           78..89
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           94..97
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          101..107
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           108..123
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          124..128
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          134..139
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           142..151
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          156..160
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   TURN            164..167
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           171..179
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          186..190
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   TURN            195..197
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           203..216
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          219..225
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   TURN            227..231
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           234..237
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           239..246
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          251..256
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   TURN            258..260
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           264..266
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          268..274
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           278..294
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          296..298
FT                   /evidence="ECO:0007829|PDB:6LIG"
FT   HELIX           302..311
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           314..344
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           353..356
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   STRAND          359..363
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           368..376
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   TURN            384..386
FT                   /evidence="ECO:0007829|PDB:3WZF"
FT   STRAND          387..389
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           390..392
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   TURN            395..397
FT                   /evidence="ECO:0007829|PDB:6DNB"
FT   HELIX           398..411
FT                   /evidence="ECO:0007829|PDB:6DNB"
SQ   SEQUENCE   413 AA;  46248 MW;  69FE68BF0C045219 CRC64;
     MAPPSVFAEV PQAQPVLVFK LTADFREDPD PRKVNLGVGA YRTDDCHPWV LPVVKKVEQK
     IANDNSLNHE YLPILGLAEF RSCASRLALG DDSPALKEKR VGGVQSLGGT GALRIGADFL
     ARWYNGTNNK NTPVYVSSPT WENHNAVFSA AGFKDIRSYR YWDAEKRGLD LQGFLNDLEN
     APEFSIVVLH ACAHNPTGID PTPEQWKQIA SVMKHRFLFP FFDSAYQGFA SGNLERDAWA
     IRYFVSEGFE FFCAQSFSKN FGLYNERVGN LTVVGKEPES ILQVLSQMEK IVRITWSNPP
     AQGARIVAST LSNPELFEEW TGNVKTMADR ILTMRSELRA RLEALKTPGT WNHITDQIGM
     FSFTGLNPKQ VEYLVNEKHI YLLPSGRINV SGLTTKNLDY VATSIHEAVT KIQ
//
ID   CASP4_HUMAN             Reviewed;         377 AA.
AC   P49662; A2NHL8; A2NHL9; A2NHM0; B3KPZ9; B4DJH5; B4E2D2; O95601; Q7KYX7;
AC   Q9UG96;
DT   01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1996, sequence version 1.
DT   28-JAN-2026, entry version 223.
DE   RecName: Full=Caspase-4 {ECO:0000303|PubMed:15123740};
DE            Short=CASP-4 {ECO:0000303|PubMed:15123740};
DE            EC=3.4.22.57 {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714, ECO:0000269|PubMed:7797510};
DE   AltName: Full=ICE and Ced-3 homolog 2 {ECO:0000303|PubMed:7797510};
DE            Short=ICH-2 {ECO:0000303|PubMed:7797510};
DE   AltName: Full=ICE(rel)-II {ECO:0000303|PubMed:7797592};
DE   AltName: Full=Mih1 {ECO:0000303|Ref.4};
DE   AltName: Full=Protease TX {ECO:0000303|PubMed:7743998};
DE   Contains:
DE     RecName: Full=Caspase-4 subunit p10;
DE   Contains:
DE     RecName: Full=Caspase-4 subunit p20;
DE   Flags: Precursor;
GN   Name=CASP4 {ECO:0000303|PubMed:15123740, ECO:0000312|HGNC:HGNC:1505};
GN   Synonyms=ICH2 {ECO:0000303|PubMed:7797510};
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, MUTAGENESIS OF CYS-258,
RP   3D-STRUCTURE MODELING, AUTOCATALYSIS, AND TISSUE SPECIFICITY.
RC   TISSUE=Placenta;
RX   PubMed=7743998; DOI=10.1002/j.1460-2075.1995.tb07183.x;
RA   Faucheu C., Diu A., Chan A.W.E., Blanchet A.-M., Miossec C., Herve F.,
RA   Collard-Dutilleul V., Gu Y., Aldape R.A., Lippke J.A., Rocher C.,
RA   Su M.S.-S., Livingston D.J., Hercend T., Lalanne J.-L.;
RT   "A novel human protease similar to the interleukin-1 beta converting enzyme
RT   induces apoptosis in transfected cells.";
RL   EMBO J. 14:1914-1922(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC   TISSUE=Monocytic leukemia;
RX   PubMed=7797592; DOI=10.1074/jbc.270.26.15870;
RA   Munday N.A., Vaillancourt J.P., Ali A., Casano F.J., Miller D.K.,
RA   Molineaux S.M., Yamin T.-T., Yu V.L., Nicholson D.W.;
RT   "Molecular cloning and pro-apoptotic activity of ICErelII and ICErelIII,
RT   members of the ICE/CED-3 family of cysteine proteases.";
RL   J. Biol. Chem. 270:15870-15876(1995).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP   TISSUE SPECIFICITY, AUTOCATALYTIC CLEAVAGE AT ASP-289, AND
RP   BIOPHYSICOCHEMICAL PROPERTIES.
RC   TISSUE=Thymus;
RX   PubMed=7797510; DOI=10.1074/jbc.270.25.15250;
RA   Kamens J., Paskind M., Hugunin M., Talanian R.V., Allen H., Banach D.,
RA   Bump N.J., Hackett M.C., Johnston C.G., Li P., Mankovich J.A.,
RA   Terranova M., Ghayur T.;
RT   "Identification and characterization of ICH-2, a novel member of the
RT   interleukin-1 beta-converting enzyme family of cysteine proteases.";
RL   J. Biol. Chem. 270:15250-15256(1995).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
RC   TISSUE=T-cell;
RA   Fernandes-Alnemri T., Litwack G., Alnemri E.S.;
RT   "Cloning of human ICE homolog Mih1.";
RL   Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 4 AND 5), AND VARIANT
RP   CYS-134.
RC   TISSUE=Small intestine, 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   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   NIEHS SNPs program;
RL   Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases.
RN   [7]
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   [8]
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   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=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   [10]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 161-263 (ISOFORM 4).
RC   TISSUE=Uterus;
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   [11]
RP   TISSUE SPECIFICITY.
RX   PubMed=10986288; DOI=10.1074/jbc.m007255200;
RA   Lin X.Y., Choi M.S., Porter A.G.;
RT   "Expression analysis of the human caspase-1 subfamily reveals specific
RT   regulation of the CASP5 gene by lipopolysaccharide and interferon-gamma.";
RL   J. Biol. Chem. 275:39920-39926(2000).
RN   [12]
RP   FUNCTION, SUBCELLULAR LOCATION, AND CLEAVAGE IN RESPONSE TO ENDOPLASMIC
RP   RETICULUM STRESS.
RX   PubMed=15123740; DOI=10.1083/jcb.200310015;
RA   Hitomi J., Katayama T., Eguchi Y., Kudo T., Taniguchi M., Koyama Y.,
RA   Manabe T., Yamagishi S., Bando Y., Imaizumi K., Tsujimoto Y., Tohyama M.;
RT   "Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis
RT   and Abeta-induced cell death.";
RL   J. Cell Biol. 165:347-356(2004).
RN   [13]
RP   FUNCTION.
RX   PubMed=15326478; DOI=10.1038/sj.onc.1208036;
RA   Gaggero A., De Ambrosis A., Mezzanzanica D., Piazza T., Rubartelli A.,
RA   Figini M., Canevari S., Ferrini S.;
RT   "A novel isoform of pro-interleukin-18 expressed in ovarian tumors is
RT   resistant to caspase-1 and -4 processing.";
RL   Oncogene 23:7552-7560(2004).
RN   [14]
RP   INDUCTION BY LPS.
RX   PubMed=16893518; DOI=10.1016/j.bbrc.2006.07.104;
RA   Eckhart L., Kittel C., Gawlas S., Gruber F., Mildner M., Jilma B.,
RA   Tschachler E.;
RT   "Identification of a novel exon encoding the amino-terminus of the
RT   predominant caspase-5 variants.";
RL   Biochem. Biophys. Res. Commun. 348:682-688(2006).
RN   [15]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, 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   [16]
RP   INTERACTION WITH NOD2.
RX   PubMed=18511561; DOI=10.1073/pnas.0802726105;
RA   Hsu L.C., Ali S.R., McGillivray S., Tseng P.H., Mariathasan S., Humke E.W.,
RA   Eckmann L., Powell J.J., Nizet V., Dixit V.M., Karin M.;
RT   "A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in
RT   response to Bacillus anthracis infection and muramyl dipeptide.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:7803-7808(2008).
RN   [17]
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   [18]
RP   FUNCTION, INTERACTION WITH CASP1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP   AND MUTAGENESIS OF CYS-258.
RX   PubMed=22246630; DOI=10.4049/jimmunol.1101620;
RA   Sollberger G., Strittmatter G.E., Kistowska M., French L.E., Beer H.D.;
RT   "Caspase-4 is required for activation of inflammasomes.";
RL   J. Immunol. 188:1992-2000(2012).
RN   [19]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF
RP   INITIATOR METHIONINE [LARGE SCALE ANALYSIS] (ISOFORM 2), AND IDENTIFICATION
RP   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   [20]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH TMEM214, AND MUTAGENESIS
RP   OF CYS-258.
RX   PubMed=23661706; DOI=10.1074/jbc.m113.458836;
RA   Li C., Wei J., Li Y., He X., Zhou Q., Yan J., Zhang J., Liu Y., Liu Y.,
RA   Shu H.B.;
RT   "Transmembrane protein 214 (TMEM214) mediates endoplasmic reticulum stress-
RT   induced caspase 4 enzyme activation and apoptosis.";
RL   J. Biol. Chem. 288:17908-17917(2013).
RN   [21]
RP   INTERACTION WITH E.COLI NLEF (MICROBIAL INFECTION), CATALYTIC ACTIVITY,
RP   FUNCTION, AND ACTIVITY REGULATION (MICROBIAL INFECTION).
RX   PubMed=23516580; DOI=10.1371/journal.pone.0058937;
RA   Blasche S., Mortl M., Steuber H., Siszler G., Nisa S., Schwarz F.,
RA   Lavrik I., Gronewold T.M., Maskos K., Donnenberg M.S., Ullmann D., Uetz P.,
RA   Kogl M.;
RT   "The E. coli effector protein NleF is a caspase inhibitor.";
RL   PLoS ONE 8:E58937-E58937(2013).
RN   [22]
RP   FUNCTION, TISSUE SPECIFICITY, AND INDUCTION BY LPS.
RX   PubMed=25121752; DOI=10.1016/j.chom.2014.07.002;
RA   Knodler L.A., Crowley S.M., Sham H.P., Yang H., Wrande M., Ma C.,
RA   Ernst R.K., Steele-Mortimer O., Celli J., Vallance B.A.;
RT   "Noncanonical inflammasome activation of caspase-4/caspase-11 mediates
RT   epithelial defenses against enteric bacterial pathogens.";
RL   Cell Host Microbe 16:249-256(2014).
RN   [23]
RP   FUNCTION, AND INDUCTION BY LPS.
RX   PubMed=24879791; DOI=10.4049/jimmunol.1303424;
RA   Kajiwara Y., Schiff T., Voloudakis G., Gama Sosa M.A., Elder G.,
RA   Bozdagi O., Buxbaum J.D.;
RT   "A critical role for human caspase-4 in endotoxin sensitivity.";
RL   J. Immunol. 193:335-343(2014).
RN   [24]
RP   FUNCTION, OLIGOMERIZATION, INTERACTION WITH LPS, ACTIVITY REGULATION,
RP   SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF CYS-258.
RX   PubMed=25119034; DOI=10.1038/nature13683;
RA   Shi J., Zhao Y., Wang Y., Gao W., Ding J., Li P., Hu L., Shao F.;
RT   "Inflammatory caspases are innate immune receptors for intracellular LPS.";
RL   Nature 514:187-192(2014).
RN   [25]
RP   FUNCTION.
RX   PubMed=26174085; DOI=10.1002/eji.201545523;
RA   Schmid-Burgk J.L., Gaidt M.M., Schmidt T., Ebert T.S., Bartok E.,
RA   Hornung V.;
RT   "Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in
RT   human myeloid cells.";
RL   Eur. J. Immunol. 45:2911-2917(2015).
RN   [26]
RP   FUNCTION.
RX   PubMed=26173988; DOI=10.1002/eji.201545655;
RA   Baker P.J., Boucher D., Bierschenk D., Tebartz C., Whitney P.G.,
RA   D'Silva D.B., Tanzer M.C., Monteleone M., Robertson A.A., Cooper M.A.,
RA   Alvarez-Diaz S., Herold M.J., Bedoui S., Schroder K., Masters S.L.;
RT   "NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by
RT   both caspase-4 and caspase-5.";
RL   Eur. J. Immunol. 45:2918-2926(2015).
RN   [27]
RP   FUNCTION, AND INDUCTION BY LPS.
RX   PubMed=26508369; DOI=10.1038/ncomms9761;
RA   Vigano E., Diamond C.E., Spreafico R., Balachander A., Sobota R.M.,
RA   Mortellaro A.;
RT   "Human caspase-4 and caspase-5 regulate the one-step non-canonical
RT   inflammasome activation in monocytes.";
RL   Nat. Commun. 6:8761-8761(2015).
RN   [28]
RP   FUNCTION, AND GSDMD CLEAVAGE.
RX   PubMed=26375003; DOI=10.1038/nature15514;
RA   Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H., Zhuang Y., Cai T.,
RA   Wang F., Shao F.;
RT   "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell
RT   death.";
RL   Nature 526:660-665(2015).
RN   [29]
RP   INDUCTION BY NF-KAPPA-B.
RX   PubMed=25695505; DOI=10.1371/journal.pone.0117953;
RA   Yang H.J., Wang M., Wang L., Cheng B.F., Lin X.Y., Feng Z.W.;
RT   "NF-kappaB regulates caspase-4 expression and sensitizes neuroblastoma
RT   cells to Fas-induced apoptosis.";
RL   PLoS ONE 10:E0117953-E0117953(2015).
RN   [30]
RP   FUNCTION, AND INDUCTION BY LPS AND IFNB1.
RX   PubMed=25964352; DOI=10.1073/pnas.1421699112;
RA   Casson C.N., Yu J., Reyes V.M., Taschuk F.O., Yadav A., Copenhaver A.M.,
RA   Nguyen H.T., Collman R.G., Shin S.;
RT   "Human caspase-4 mediates noncanonical inflammasome activation against
RT   gram-negative bacterial pathogens.";
RL   Proc. Natl. Acad. Sci. U.S.A. 112:6688-6693(2015).
RN   [31]
RP   FUNCTION, AND MUTAGENESIS OF CYS-258.
RX   PubMed=28314590; DOI=10.1016/j.immuni.2017.02.011;
RA   Wang Y., Ning X., Gao P., Wu S., Sha M., Lv M., Zhou X., Gao J., Fang R.,
RA   Meng G., Su X., Jiang Z.;
RT   "Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to
RT   regulate responses to DNA virus infection.";
RL   Immunity 46:393-404(2017).
RN   [32]
RP   FUNCTION, AND INTERACTION WITH CTSG.
RX   PubMed=29077095; DOI=10.1038/cdd.2017.167;
RA   Jun H.K., Jung Y.J., Ji S., An S.J., Choi B.K.;
RT   "Caspase-4 activation by a bacterial surface protein is mediated by
RT   cathepsin G in human gingival fibroblasts.";
RL   Cell Death Differ. 25:380-391(2018).
RN   [33]
RP   FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=29520027; DOI=10.1038/s41467-018-03409-3;
RA   Chu L.H., Indramohan M., Ratsimandresy R.A., Gangopadhyay A., Morris E.P.,
RA   Monack D.M., Dorfleutner A., Stehlik C.;
RT   "The oxidized phospholipid oxPAPC protects from septic shock by targeting
RT   the non-canonical inflammasome in macrophages.";
RL   Nat. Commun. 9:996-996(2018).
RN   [34]
RP   FUNCTION.
RX   PubMed=31268602; DOI=10.15252/embj.2018100926;
RA   Fisch D., Bando H., Clough B., Hornung V., Yamamoto M., Shenoy A.R.,
RA   Frickel E.M.;
RT   "Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and
RT   pyroptosis.";
RL   EMBO J. 38:e100926-e100926(2019).
RN   [35]
RP   INTERACTION WITH SERPINB1.
RX   PubMed=30692621; DOI=10.1038/s41590-018-0303-z;
RA   Choi Y.J., Kim S., Choi Y., Nielsen T.B., Yan J., Lu A., Ruan J., Lee H.R.,
RA   Wu H., Spellberg B., Jung J.U.;
RT   "SERPINB1-mediated checkpoint of inflammatory caspase activation.";
RL   Nat. Immunol. 20:276-287(2019).
RN   [36]
RP   FUNCTION.
RX   PubMed=32510692; DOI=10.15252/embj.2020104926;
RA   Kutsch M., Sistemich L., Lesser C.F., Goldberg M.B., Herrmann C., Coers J.;
RT   "Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope
RT   functions.";
RL   EMBO J. 39:e104926-e104926(2020).
RN   [37]
RP   FUNCTION.
RX   PubMed=32581219; DOI=10.1038/s41467-020-16889-z;
RA   Santos J.C., Boucher D., Schneider L.K., Demarco B., Dilucca M.,
RA   Shkarina K., Heilig R., Chen K.W., Lim R.Y.H., Broz P.;
RT   "Human GBP1 binds LPS to initiate assembly of a caspase-4 activating
RT   platform on cytosolic bacteria.";
RL   Nat. Commun. 11:3276-3276(2020).
RN   [38]
RP   FUNCTION.
RX   PubMed=33377178; DOI=10.1111/iej.13469;
RA   Tian X.X., Li R., Liu C., Liu F., Yang L.J., Wang S.P., Wang C.L.;
RT   "NLRP6-caspase 4 inflammasome activation in response to cariogenic
RT   bacterial lipoteichoic acid in human dental pulp inflammation.";
RL   Int. Endod. J. 54:916-925(2021).
RN   [39]
RP   FUNCTION, PROTEOLYTIC CLEAVAGE, ADP-RIBOXANATION AT ARG-314 (MICROBIAL
RP   INFECTION), AND MUTAGENESIS OF ARG-314.
RX   PubMed=34671164; DOI=10.1038/s41586-021-04020-1;
RA   Li Z., Liu W., Fu J., Cheng S., Xu Y., Wang Z., Liu X., Shi X., Liu Y.,
RA   Qi X., Liu X., Ding J., Shao F.;
RT   "Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11.";
RL   Nature 599:290-295(2021).
RN   [40]
RP   ADP-RIBOXANATION AT ARG-314 (MICROBIAL INFECTION).
RX   PubMed=35338844; DOI=10.1016/j.molcel.2022.03.010;
RA   Peng T., Tao X., Xia Z., Hu S., Xue J., Zhu Q., Pan X., Zhang Q., Li S.;
RT   "Pathogen hijacks programmed cell death signaling by arginine ADPR-
RT   deacylization of caspases.";
RL   Mol. Cell 82:1806-1820(2022).
RN   [41]
RP   FUNCTION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=37001519; DOI=10.1016/j.immuni.2023.03.003;
RA   Zhu F., Ma J., Li W., Liu Q., Qin X., Qian Y., Wang C., Zhang Y., Li Y.,
RA   Jiang D., Wang S., Xia P.;
RT   "The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-
RT   canonical NLRP3 inflammasome.";
RL   Immunity 56:753-767(2023).
RN   [42]
RP   ADP-RIBOXANATION (MICROBIAL INFECTION).
RX   PubMed=37014865; DOI=10.1073/pnas.2218469120;
RA   Goers L., Kim K., Stedman T.C., Canning P.J., Mou X., Ernst N.H., Coers J.,
RA   Lesser C.F.;
RT   "Shigella IpaH9.8 limits GBP1-dependent LPS release from intracytosolic
RT   bacteria to suppress caspase-4 activation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 120:e2218469120-e2218469120(2023).
RN   [43] {ECO:0007744|PDB:6KMZ}
RP   X-RAY CRYSTALLOGRAPHY (3.61 ANGSTROMS) OF 105-289 AND 290-377 IN COMPLEX
RP   WITH GSDMD, FUNCTION, SUBUNIT, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF
RP   TRP-267; ASP-270 AND VAL-291.
RX   PubMed=32109412; DOI=10.1016/j.cell.2020.02.002;
RA   Wang K., Sun Q., Zhong X., Zeng M., Zeng H., Shi X., Li Z., Wang Y.,
RA   Zhao Q., Shao F., Ding J.;
RT   "Structural mechanism for GSDMD targeting by autoprocessed caspases in
RT   pyroptosis.";
RL   Cell 180:941-955(2020).
RN   [44] {ECO:0007744|PDB:7WR0, ECO:0007744|PDB:7WR1, ECO:0007744|PDB:7WR4, ECO:0007744|PDB:7WR5, ECO:0007744|PDB:7WR6}
RP   X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 102-377 IN COMPLEX WITH
RP   CALMODULIN AND S.FLEXNERI OSPC3, AND ADP-RIBOXANATION AT ARG-314 (MICROBIAL
RP   INFECTION).
RX   PubMed=36624349; DOI=10.1038/s41594-022-00888-3;
RA   Hou Y., Zeng H., Li Z., Feng N., Meng F., Xu Y., Li L., Shao F., Ding J.;
RT   "Structural mechanisms of calmodulin activation of Shigella effector OspC3
RT   to ADP-riboxanate caspase-4/11 and block pyroptosis.";
RL   Nat. Struct. Mol. Biol. 30:261-272(2023).
RN   [45] {ECO:0007744|PDB:8SPB}
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.2 ANGSTROMS) OF 94-270 AND 290-377 IN
RP   COMPLEX WITH IL18, FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND
RP   MUTAGENESIS OF CYS-258; TRP-267; ARG-269 AND LYS-356.
RX   PubMed=37993712; DOI=10.1038/s41586-023-06751-9;
RA   Devant P., Dong Y., Mintseris J., Ma W., Gygi S.P., Wu H., Kagan J.C.;
RT   "Structural insights into cytokine cleavage by inflammatory caspase-4.";
RL   Nature 0:0-0(2023).
RN   [46] {ECO:0007744|PDB:8J6K}
RP   X-RAY CRYSTALLOGRAPHY (3.12 ANGSTROMS) OF 102-270 AND 290-377 IN COMPLEX
RP   WITH IL18 AND S.FLEXNERI OSPC3, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT,
RP   PROTEOLYTIC CLEAVAGE, ACTIVE SITE, AND MUTAGENESIS OF ARG-152; ILE-212;
RP   CYS-258; ALA-261; TRP-267; ASP-289; VAL-291; LYS-293; ARG-314 AND ILE-321.
RX   PubMed=37993714; DOI=10.1038/s41586-023-06742-w;
RA   Shi X., Sun Q., Hou Y., Zeng H., Cao Y., Dong M., Ding J., Shao F.;
RT   "Recognition and maturation of IL-18 by caspase-4 noncanonical
RT   inflammasome.";
RL   Nature 0:0-0(2023).
CC   -!- FUNCTION: Inflammatory caspase that acts as the effector of the non-
CC       canonical inflammasome by mediating lipopolysaccharide (LPS)-induced
CC       pyroptosis (PubMed:25119034, PubMed:26375003, PubMed:32109412,
CC       PubMed:34671164, PubMed:37001519, PubMed:37993712, PubMed:37993714).
CC       Also indirectly activates the NLRP3 and NLRP6 inflammasomes
CC       (PubMed:23516580, PubMed:26375003, PubMed:32109412, PubMed:7797510).
CC       Acts as a thiol protease that cleaves a tetrapeptide after an Asp
CC       residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18
CC       (PubMed:15326478, PubMed:23516580, PubMed:26375003, PubMed:28314590,
CC       PubMed:32109412, PubMed:37993712, PubMed:37993714, PubMed:7797510).
CC       Effector of the non-canonical inflammasome independently of NLRP3
CC       inflammasome and CASP1: the non-canonical inflammasome promotes
CC       pyroptosis through GSDMD cleavage without involving secretion of
CC       cytokine IL1B (PubMed:25119034, PubMed:25121752, PubMed:26375003,
CC       PubMed:31268602, PubMed:32109412, PubMed:37993712, PubMed:37993714). In
CC       the non-canonical inflammasome, CASP4 is activated by direct binding to
CC       the lipid A moiety of LPS without the need of an upstream sensor
CC       (PubMed:25119034, PubMed:25121752, PubMed:29520027, PubMed:32510692,
CC       PubMed:32581219, PubMed:37993712). LPS-binding promotes CASP4
CC       activation and CASP4-mediated cleavage of GSDMD and IL18, followed by
CC       IL18 secretion through the GSDMD pore, pyroptosis of infected cells and
CC       their extrusion into the gut lumen (PubMed:25119034, PubMed:25121752,
CC       PubMed:37993712, PubMed:37993714). Also indirectly promotes secretion
CC       of mature cytokines (IL1A and HMGB1) downstream of GSDMD-mediated
CC       pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes
CC       (PubMed:26375003, PubMed:32109412). Involved in NLRP3-dependent CASP1
CC       activation and IL1B secretion in response to non-canonical activators,
CC       such as UVB radiation or cholera enterotoxin (PubMed:22246630,
CC       PubMed:23516580, PubMed:24879791, PubMed:25964352, PubMed:26173988,
CC       PubMed:26174085, PubMed:26508369). Involved in NLRP6 inflammasome-
CC       dependent activation in response to lipoteichoic acid (LTA), a cell-
CC       wall component of Gram-positive bacteria, which leads to CASP1
CC       activation and IL1B secretion (PubMed:33377178). Involved in LPS-
CC       induced IL6 secretion; this activity may not require caspase enzymatic
CC       activity (PubMed:26508369). The non-canonical inflammasome is required
CC       for innate immunity to cytosolic, but not vacuolar, bacteria (By
CC       similarity). Plays a crucial role in the restriction of S.typhimurium
CC       replication in colonic epithelial cells during infection
CC       (PubMed:25121752, PubMed:25964352). Activation of the non-canonical
CC       inflammasome in brain endothelial cells can lead to excessive
CC       pyroptosis, leading to blood-brain barrier breakdown (By similarity).
CC       Pyroptosis limits bacterial replication, while cytokine secretion
CC       promotes the recruitment and activation of immune cells and triggers
CC       mucosal inflammation (PubMed:25121752, PubMed:25964352,
CC       PubMed:26375003). May also act as an activator of adaptive immunity in
CC       dendritic cells, following activation by oxidized phospholipid 1-
CC       palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized
CC       phospholipid (oxPAPC) (By similarity). Involved in cell death induced
CC       by endoplasmic reticulum stress and by treatment with cytotoxic APP
CC       peptides found in Alzheimer's patient brains (PubMed:15123740,
CC       PubMed:22246630, PubMed:23661706). Cleavage of GSDMD is not strictly
CC       dependent on the consensus cleavage site but depends on an exosite
CC       interface on CASP4 that recognizes and binds the Gasdermin-D, C-
CC       terminal (GSDMD-CT) part (PubMed:32109412). Catalyzes cleavage and
CC       maturation of IL18; IL18 processing also depends of the exosite
CC       interface on CASP4 (PubMed:15326478, PubMed:37993712, PubMed:37993714).
CC       In contrast, it does not directly process IL1B (PubMed:7743998,
CC       PubMed:7797510, PubMed:7797592). During non-canonical inflammasome
CC       activation, cuts CGAS and may play a role in the regulation of
CC       antiviral innate immune activation (PubMed:28314590).
CC       {ECO:0000250|UniProtKB:P70343, ECO:0000269|PubMed:15123740,
CC       ECO:0000269|PubMed:15326478, ECO:0000269|PubMed:22246630,
CC       ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:23661706,
CC       ECO:0000269|PubMed:24879791, ECO:0000269|PubMed:25119034,
CC       ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:25964352,
CC       ECO:0000269|PubMed:26173988, ECO:0000269|PubMed:26174085,
CC       ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26508369,
CC       ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:29520027,
CC       ECO:0000269|PubMed:31268602, ECO:0000269|PubMed:32109412,
CC       ECO:0000269|PubMed:32510692, ECO:0000269|PubMed:32581219,
CC       ECO:0000269|PubMed:33377178, ECO:0000269|PubMed:34671164,
CC       ECO:0000269|PubMed:37001519, ECO:0000269|PubMed:37993714,
CC       ECO:0000269|PubMed:7743998, ECO:0000269|PubMed:7797510,
CC       ECO:0000269|PubMed:7797592}.
CC   -!- FUNCTION: (Microbial infection) In response to the Td92 surface protein
CC       of the periodontal pathogen T.denticola, activated by cathepsin CTSG
CC       which leads to production and secretion of IL1A and pyroptosis of
CC       gingival fibroblasts. {ECO:0000269|PubMed:29077095}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Strict requirement for Asp at the P1 position. It has a
CC         preferred cleavage sequence of Tyr-Val-Ala-Asp-|- but also cleaves at
CC         Asp-Glu-Val-Asp-|-.; EC=3.4.22.57;
CC         Evidence={ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:37993712,
CC         ECO:0000269|PubMed:37993714, ECO:0000269|PubMed:7797510};
CC   -!- ACTIVITY REGULATION: Activated by homooligomerization induced by direct
CC       binding to cytosolic LPS, in a TLR4-independent manner
CC       (PubMed:25119034, PubMed:29520027). In addition to LPS, CASP4/CASP11
CC       may also be activated by oxidized phospholipid 1-palmitoyl-2-
CC       arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid
CC       (oxPAPC), in dendritic cells, promoting adaptive immunity (By
CC       similarity). The role of oxPAPC is however unclear and another report
CC       suggests that oxPAPC competes with LPS-binding and inhibits the non-
CC       canonical inflammasome in macrophages (PubMed:29520027).
CC       {ECO:0000250|UniProtKB:P70343, ECO:0000269|PubMed:25119034,
CC       ECO:0000269|PubMed:29520027}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=681 uM for synthetic peptide acetyl-YVAD-p-nitroanilide
CC         {ECO:0000269|PubMed:7797510};
CC         Note=Values obtained using the partial C-terminal enzyme sequence of
CC         105-377. {ECO:0000269|PubMed:7797510};
CC   -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC       heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a
CC       10 kDa (Caspase-4 subunit p10) subunit (PubMed:32109412). Upon direct
CC       LPS-binding, forms large homooligomers, resulting in its activation (By
CC       similarity). These oligomers are often referred to as 'non-canonical
CC       inflammasomes' (PubMed:25119034). In its precursor form, interacts with
CC       TMEM214; this interaction is required for association with the
CC       endoplasmic reticulum membrane (PubMed:23661706). Interacts with CASP1
CC       (PubMed:22246630). Interacts with NOD2 (PubMed:18511561). Interacts
CC       with SERPINB1; this interaction regulates CASP4 activity
CC       (PubMed:30692621). {ECO:0000250|UniProtKB:P70343,
CC       ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:22246630,
CC       ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034,
CC       ECO:0000269|PubMed:30692621, ECO:0000269|PubMed:32109412}.
CC   -!- SUBUNIT: [Caspase-4 subunit p20]: Heterotetramer that consists of two
CC       anti-parallel arranged heterodimers, each one formed by a 20 kDa
CC       (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit.
CC       {ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:37993714}.
CC   -!- SUBUNIT: [Caspase-4 subunit p10]: Heterotetramer that consists of two
CC       anti-parallel arranged heterodimers, each one formed by a 20 kDa
CC       (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit.
CC       {ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:37993714}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with NleF protein from
CC       pathogenic E.coli; this interaction leads to enzyme inhibition.
CC       {ECO:0000269|PubMed:23516580}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with cathepsin CTSG; the
CC       interaction is promoted by the Td92 surface protein of the periodontal
CC       pathogen T.denticola and leads to CASP4 activation.
CC       {ECO:0000269|PubMed:29077095}.
CC   -!- INTERACTION:
CC       P49662; Q17R89: ARHGAP44; NbExp=2; IntAct=EBI-1057327, EBI-720416;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:23661706}.
CC       Endoplasmic reticulum membrane {ECO:0000269|PubMed:15123740,
CC       ECO:0000269|PubMed:23661706}; Peripheral membrane protein
CC       {ECO:0000269|PubMed:23661706}; Cytoplasmic side
CC       {ECO:0000269|PubMed:23661706}. Mitochondrion
CC       {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:23661706}.
CC       Inflammasome {ECO:0000269|PubMed:25119034,
CC       ECO:0000269|PubMed:26508369}. Secreted {ECO:0000269|PubMed:22246630}.
CC       Note=Predominantly localizes to the endoplasmic reticulum (ER).
CC       Association with the ER membrane requires TMEM214 (PubMed:15123740).
CC       Released in the extracellular milieu by keratinocytes following UVB
CC       irradiation (PubMed:22246630). {ECO:0000269|PubMed:15123740,
CC       ECO:0000269|PubMed:22246630}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=5;
CC       Name=1; Synonyms=Alpha;
CC         IsoId=P49662-1; Sequence=Displayed;
CC       Name=2; Synonyms=Gamma, mih1-beta;
CC         IsoId=P49662-2; Sequence=VSP_043495;
CC       Name=3; Synonyms=mih1-delta;
CC         IsoId=P49662-3; Sequence=VSP_058177, VSP_058178;
CC       Name=4;
CC         IsoId=P49662-4; Sequence=VSP_058181, VSP_058182;
CC       Name=5;
CC         IsoId=P49662-5; Sequence=VSP_058179, VSP_058180;
CC   -!- TISSUE SPECIFICITY: Widely expressed, including in keratinocytes and
CC       colonic and small intestinal epithelial cells (at protein level). Not
CC       detected in brain. {ECO:0000269|PubMed:10986288,
CC       ECO:0000269|PubMed:22246630, ECO:0000269|PubMed:25121752,
CC       ECO:0000269|PubMed:7743998, ECO:0000269|PubMed:7797510,
CC       ECO:0000269|PubMed:7797592}.
CC   -!- INDUCTION: In peripheral blood mononuclear cells and purified
CC       monocytes, up-regulated by bacterial lipopolysaccharides (LPS) and
CC       interferon-beta/IFNB1 at the mRNA level (PubMed:16893518,
CC       PubMed:24879791). However, this increase is not observed at the protein
CC       level, which remains constant in monocytes and other cell types
CC       following LPS treatment (PubMed:25121752, PubMed:26508369). In
CC       monocyte-derived macrophages, some up-regulation at the protein level
CC       is observed following treatment with LPS and IFNB1 (PubMed:25964352).
CC       In SH-EP1 neuroblastoma cell line, up-regulated by NF-kappa-B RELA/p65
CC       at both mRNA and protein levels. {ECO:0000269|PubMed:16893518,
CC       ECO:0000269|PubMed:24879791, ECO:0000269|PubMed:25695505}.
CC   -!- DOMAIN: The CARD domain mediates LPS recognition and
CC       homooligomerization. {ECO:0000269|PubMed:25119034}.
CC   -!- PTM: In response to activation signals, undergoes autoproteolytic
CC       cleavage and activation. {ECO:0000269|PubMed:15123740,
CC       ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:34671164,
CC       ECO:0000269|PubMed:37993714, ECO:0000269|PubMed:7743998,
CC       ECO:0000269|PubMed:7797510}.
CC   -!- PTM: (Microbial infection) ADP-riboxanation by S.flexneri OspC3 blocks
CC       CASP4 autoprocessing, preventing CASP4 activation and ability to
CC       recognize and cleave GSDMD, thereby thwarting the
CC       inflammasome/pyroptosis-mediated defense. {ECO:0000269|PubMed:34671164,
CC       ECO:0000269|PubMed:35338844, ECO:0000269|PubMed:36624349,
CC       ECO:0000269|PubMed:37014865}.
CC   -!- MISCELLANEOUS: [Isoform 3]: May be due to competing acceptor splice
CC       site. May be produced at very low levels due to a premature stop codon
CC       in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAC99854.1; Type=Erroneous translation; Note=Erroneous CDS prediction.; Evidence={ECO:0000305};
CC       Sequence=EAW67050.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC   -!- SEQUENCE CAUTION: [Isoform 2]:
CC       Sequence=AAC99851.1; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; Z48810; CAA88750.1; -; mRNA.
DR   EMBL; U28014; AAA75171.1; -; mRNA.
DR   EMBL; U25804; AAA86890.1; -; mRNA.
DR   EMBL; U28976; AAC99850.1; -; mRNA.
DR   EMBL; U28977; AAC99851.1; ALT_FRAME; mRNA.
DR   EMBL; U28978; AAC99852.1; -; mRNA.
DR   EMBL; U28979; AAC99853.1; -; mRNA.
DR   EMBL; U28979; AAC99854.1; ALT_SEQ; mRNA.
DR   EMBL; AK057094; BAG51861.1; -; mRNA.
DR   EMBL; AK296081; BAG58837.1; -; mRNA.
DR   EMBL; AK304222; BAG65094.1; -; mRNA.
DR   EMBL; EF636667; ABR09278.1; -; Genomic_DNA.
DR   EMBL; AP001153; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AP002004; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471065; EAW67050.1; ALT_SEQ; Genomic_DNA.
DR   EMBL; CH471065; EAW67051.1; -; Genomic_DNA.
DR   EMBL; CH471065; EAW67052.1; -; Genomic_DNA.
DR   EMBL; BC017839; AAH17839.1; -; mRNA.
DR   EMBL; AL050391; CAB43686.2; -; mRNA.
DR   CCDS; CCDS41704.1; -. [P49662-2]
DR   CCDS; CCDS8327.1; -. [P49662-1]
DR   PIR; A57511; A57511.
DR   RefSeq; NP_001216.1; NM_001225.4. [P49662-1]
DR   RefSeq; NP_150649.1; NM_033306.3. [P49662-2]
DR   RefSeq; XP_011541321.1; XM_011543019.1.
DR   PDB; 6KMZ; X-ray; 3.61 A; A/B/C/D=105-377.
DR   PDB; 6NRY; X-ray; 2.18 A; A=92-377.
DR   PDB; 7WR0; X-ray; 2.80 A; A=102-377.
DR   PDB; 7WR1; X-ray; 2.13 A; A/B=102-377.
DR   PDB; 7WR4; X-ray; 2.75 A; C=102-377.
DR   PDB; 7WR5; X-ray; 3.10 A; C=102-377.
DR   PDB; 7WR6; X-ray; 1.96 A; A=102-377.
DR   PDB; 8J6K; X-ray; 3.12 A; A=102-270, a=290-377.
DR   PDB; 8SPB; EM; 3.20 A; A/a=94-270, B/b=290-377.
DR   PDBsum; 6KMZ; -.
DR   PDBsum; 6NRY; -.
DR   PDBsum; 7WR0; -.
DR   PDBsum; 7WR1; -.
DR   PDBsum; 7WR4; -.
DR   PDBsum; 7WR5; -.
DR   PDBsum; 7WR6; -.
DR   PDBsum; 8J6K; -.
DR   PDBsum; 8SPB; -.
DR   AlphaFoldDB; P49662; -.
DR   EMDB; EMD-40678; -.
DR   SMR; P49662; -.
DR   BioGRID; 107287; 48.
DR   DIP; DIP-44806N; -.
DR   FunCoup; P49662; 728.
DR   IntAct; P49662; 47.
DR   MINT; P49662; -.
DR   STRING; 9606.ENSP00000388566; -.
DR   BindingDB; P49662; -.
DR   ChEMBL; CHEMBL2226; -.
DR   DrugBank; DB06255; Incadronic acid.
DR   GuidetoPHARMACOLOGY; 1620; -.
DR   MEROPS; C14.007; -.
DR   iPTMnet; P49662; -.
DR   MetOSite; P49662; -.
DR   PhosphoSitePlus; P49662; -.
DR   BioMuta; CASP4; -.
DR   DMDM; 1352420; -.
DR   jPOST; P49662; -.
DR   MassIVE; P49662; -.
DR   PaxDb; 9606-ENSP00000388566; -.
DR   PeptideAtlas; P49662; -.
DR   ProteomicsDB; 56043; -. [P49662-1]
DR   ProteomicsDB; 56044; -. [P49662-2]
DR   Pumba; P49662; -.
DR   Antibodypedia; 18094; 734 antibodies from 42 providers.
DR   DNASU; 837; -.
DR   Ensembl; ENST00000393150.7; ENSP00000376857.3; ENSG00000196954.14. [P49662-2]
DR   Ensembl; ENST00000444739.7; ENSP00000388566.2; ENSG00000196954.14. [P49662-1]
DR   GeneID; 837; -.
DR   KEGG; hsa:837; -.
DR   MANE-Select; ENST00000444739.7; ENSP00000388566.2; NM_001225.4; NP_001216.1.
DR   UCSC; uc001pib.2; human. [P49662-1]
DR   AGR; HGNC:1505; -.
DR   ClinPGx; PA26088; -.
DR   CTD; 837; -.
DR   DisGeNET; 837; -.
DR   GeneCards; CASP4; -.
DR   HGNC; HGNC:1505; CASP4.
DR   HPA; ENSG00000196954; Low tissue specificity.
DR   MIM; 602664; gene.
DR   OpenTargets; ENSG00000196954; -.
DR   VEuPathDB; HostDB:ENSG00000196954; -.
DR   eggNOG; KOG3573; Eukaryota.
DR   GeneTree; ENSGT00940000161497; -.
DR   HOGENOM; CLU_036904_0_1_1; -.
DR   InParanoid; P49662; -.
DR   OMA; ACRGANH; -.
DR   OrthoDB; 6097640at2759; -.
DR   PAN-GO; P49662; 6 GO annotations based on evolutionary models.
DR   PhylomeDB; P49662; -.
DR   BioCyc; MetaCyc:HS06388-MONOMER; -.
DR   BRENDA; 3.4.22.57; 2681.
DR   PathwayCommons; P49662; -.
DR   Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR   Reactome; R-HSA-5620971; Pyroptosis.
DR   SABIO-RK; P49662; -.
DR   SignaLink; P49662; -.
DR   SIGNOR; P49662; -.
DR   Agora; ENSG00000196954; -.
DR   BioGRID-ORCS; 837; 15 hits in 1158 CRISPR screens.
DR   ChiTaRS; CASP4; human.
DR   GenomeRNAi; 837; -.
DR   Pharos; P49662; Tchem.
DR   PRO; PR:P49662; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; P49662; protein.
DR   Bgee; ENSG00000196954; Expressed in monocyte and 178 other cell types or tissues.
DR   ExpressionAtlas; P49662; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
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; IEA:UniProtKB-SubCell.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0072558; C:NLRP1 inflammasome complex; IBA:GO_Central.
DR   GO; GO:0160074; C:non-canonical inflammasome complex; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR   GO; GO:0050700; F:CARD domain binding; IPI:UniProtKB.
DR   GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0008289; F:lipid binding; IDA:UniProtKB.
DR   GO; GO:0001530; F:lipopolysaccharide binding; IDA:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0042742; P:defense response to bacterium; IDA:UniProtKB.
DR   GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB.
DR   GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR   GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0160075; P:non-canonical inflammasome complex assembly; IDA:UniProtKB.
DR   GO; GO:0050729; P:positive regulation of inflammatory response; IDA:UniProtKB.
DR   GO; GO:2000494; P:positive regulation of interleukin-18-mediated signaling pathway; IDA:UniProtKB.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB.
DR   GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB.
DR   GO; GO:0051604; P:protein maturation; IDA:UniProt.
DR   GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR   GO; GO:0070269; P:pyroptotic inflammatory response; IDA:UniProtKB.
DR   GO; GO:0050727; P:regulation of inflammatory response; IDA:UniProtKB.
DR   CDD; cd08325; CARD_CASP1-like; 1.
DR   CDD; cd00032; CASc; 1.
DR   FunFam; 3.30.70.1470:FF:000003; Caspase-1; 1.
DR   FunFam; 3.40.50.1460:FF:000007; Caspase-1; 1.
DR   FunFam; 1.10.533.10:FF:000073; Inactive caspase-12; 1.
DR   Gene3D; 3.40.50.1460; -; 1.
DR   Gene3D; 1.10.533.10; Death Domain, Fas; 1.
DR   InterPro; IPR001315; CARD.
DR   InterPro; IPR029030; Caspase-like_dom_sf.
DR   InterPro; IPR033139; Caspase_cys_AS.
DR   InterPro; IPR016129; Caspase_his_AS.
DR   InterPro; IPR011029; DEATH-like_dom_sf.
DR   InterPro; IPR002398; Pept_C14.
DR   InterPro; IPR011600; Pept_C14_caspase.
DR   InterPro; IPR002138; Pept_C14_p10.
DR   InterPro; IPR001309; Pept_C14_p20.
DR   InterPro; IPR015917; Pept_C14A.
DR   PANTHER; PTHR47901; CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 18; 1.
DR   PANTHER; PTHR47901:SF3; CASPASE-1; 1.
DR   Pfam; PF00619; CARD; 1.
DR   Pfam; PF00656; Peptidase_C14; 1.
DR   PIRSF; PIRSF038001; Caspase_ICE; 1.
DR   PRINTS; PR00376; IL1BCENZYME.
DR   SMART; SM00114; CARD; 1.
DR   SMART; SM00115; CASc; 1.
DR   SUPFAM; SSF52129; Caspase-like; 1.
DR   SUPFAM; SSF47986; DEATH domain; 1.
DR   PROSITE; PS50209; CARD; 1.
DR   PROSITE; PS01122; CASPASE_CYS; 1.
DR   PROSITE; PS01121; CASPASE_HIS; 1.
DR   PROSITE; PS50207; CASPASE_P10; 1.
DR   PROSITE; PS50208; CASPASE_P20; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Cytoplasm;
KW   Endoplasmic reticulum; Hydrolase; Immunity; Inflammasome;
KW   Inflammatory response; Innate immunity; Membrane; Mitochondrion; Necrosis;
KW   Phosphoprotein; Protease; Proteomics identification; Reference proteome;
KW   Secreted; Thiol protease; Zymogen.
FT   PROPEP          1..?80
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000004596"
FT   CHAIN           ?81..270
FT                   /note="Caspase-4 subunit p20"
FT                   /evidence="ECO:0000305|PubMed:32109412,
FT                   ECO:0000305|PubMed:37993714"
FT                   /id="PRO_0000004597"
FT   PROPEP          271..289
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:7797510"
FT                   /id="PRO_0000004598"
FT   CHAIN           290..377
FT                   /note="Caspase-4 subunit p10"
FT                   /evidence="ECO:0000305|PubMed:32109412,
FT                   ECO:0000305|PubMed:37993714"
FT                   /id="PRO_0000004599"
FT   DOMAIN          1..91
FT                   /note="CARD"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT   REGION          1..59
FT                   /note="Required for LPS-binding"
FT                   /evidence="ECO:0000250|UniProtKB:P70343"
FT   REGION          84..104
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        210
FT                   /evidence="ECO:0000250|UniProtKB:P29466"
FT   ACT_SITE        258
FT                   /evidence="ECO:0000269|PubMed:22246630,
FT                   ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034,
FT                   ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714,
FT                   ECO:0000269|PubMed:7743998"
FT   SITE            289..290
FT                   /note="Cleavage; by autolysis"
FT                   /evidence="ECO:0000269|PubMed:37993714,
FT                   ECO:0000269|PubMed:7797510"
FT   MOD_RES         83
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:20068231"
FT   MOD_RES         314
FT                   /note="(Microbial infection) ADP-riboxanated arginine"
FT                   /evidence="ECO:0000269|PubMed:34671164,
FT                   ECO:0000269|PubMed:35338844, ECO:0000269|PubMed:36624349"
FT   VAR_SEQ         1..56
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.4"
FT                   /id="VSP_043495"
FT   VAR_SEQ         88..116
FT                   /note="AHPNMEAGPPESGESTDALKLCPHEEFLR -> GDKLGHRGRNHNLCSAISC
FT                   SSSEYGGWTT (in isoform 3)"
FT                   /evidence="ECO:0000303|Ref.4"
FT                   /id="VSP_058177"
FT   VAR_SEQ         117..377
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|Ref.4"
FT                   /id="VSP_058178"
FT   VAR_SEQ         125..157
FT                   /note="IYPIKERNNRTRLALIICNTEFDHLPPRNGADF -> VLCYLYEIEKKEEIS
FT                   LLSFSAPFLTALNDWGWG (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_058179"
FT   VAR_SEQ         158..377
FT                   /note="Missing (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_058180"
FT   VAR_SEQ         261..263
FT                   /note="ANR -> GEC (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:11230166,
FT                   ECO:0000303|PubMed:14702039"
FT                   /id="VSP_058181"
FT   VAR_SEQ         264..377
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:11230166,
FT                   ECO:0000303|PubMed:14702039"
FT                   /id="VSP_058182"
FT   VARIANT         47
FT                   /note="D -> N (in dbSNP:rs56226603)"
FT                   /id="VAR_061081"
FT   VARIANT         134
FT                   /note="R -> C (in dbSNP:rs181090259)"
FT                   /evidence="ECO:0000269|PubMed:14702039"
FT                   /id="VAR_075654"
FT   VARIANT         284
FT                   /note="E -> D (in dbSNP:rs55901059)"
FT                   /id="VAR_061082"
FT   MUTAGEN         152
FT                   /note="R->A: Abolished ability to cleave IL18."
FT                   /evidence="ECO:0000269|PubMed:37993714"
FT   MUTAGEN         212
FT                   /note="I->D: Abolished ability to cleave IL18; when
FT                   associated with D-261."
FT                   /evidence="ECO:0000269|PubMed:37993714"
FT   MUTAGEN         258
FT                   /note="C->A: Loss of enzymatic activity. Loss of LPS-
FT                   induced pyroptosis. No effect on the interaction with LPS.
FT                   Decrease in cell death induced by TMEM214 overexpression.
FT                   Does not support IL1B and IL18 secretion following UVB
FT                   irradiation."
FT                   /evidence="ECO:0000269|PubMed:22246630,
FT                   ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034,
FT                   ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:37993712,
FT                   ECO:0000269|PubMed:37993714"
FT   MUTAGEN         258
FT                   /note="C->S: Loss of autocatalysis."
FT                   /evidence="ECO:0000269|PubMed:7743998"
FT   MUTAGEN         261
FT                   /note="A->D: Abolished ability to cleave IL18; when
FT                   associated with D-212."
FT                   /evidence="ECO:0000269|PubMed:37993714"
FT   MUTAGEN         267
FT                   /note="W->L,N: Abolished interaction with Gasdermin-D
FT                   (GSDMD) and ability to mediate its cleavage. Abolished
FT                   binding to IL18 and ability to mediate its cleavage."
FT                   /evidence="ECO:0000269|PubMed:32109412,
FT                   ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714"
FT   MUTAGEN         269
FT                   /note="R->D: Abolished binding to IL18 and ability to
FT                   mediate its cleavage."
FT                   /evidence="ECO:0000269|PubMed:37993712"
FT   MUTAGEN         270
FT                   /note="D->A: Abolished autoprocessing and ability to form a
FT                   heterotetramer composed of Caspase-4 subunit p10 and
FT                   Caspase-4 subunit p20, preventing ability to cleave GSDMD
FT                   and induce pyroptosis."
FT                   /evidence="ECO:0000269|PubMed:32109412"
FT   MUTAGEN         289
FT                   /note="D->A: Abolished autoprocessing."
FT                   /evidence="ECO:0000269|PubMed:37993714"
FT   MUTAGEN         291
FT                   /note="V->N: Abolished interaction with Gasdermin-D (GSDMD)
FT                   and ability to mediate its cleavage. Strongly decreased
FT                   ability to cleave IL18."
FT                   /evidence="ECO:0000269|PubMed:32109412,
FT                   ECO:0000269|PubMed:37993714"
FT   MUTAGEN         293
FT                   /note="K->A: Strongly decreased ability to cleave IL18."
FT                   /evidence="ECO:0000269|PubMed:37993714"
FT   MUTAGEN         314
FT                   /note="R->A: Abolished ability to cleave Gasdermin-D
FT                   (GSDMD). Abolished ability to cleave IL18."
FT                   /evidence="ECO:0000269|PubMed:34671164,
FT                   ECO:0000269|PubMed:37993714"
FT   MUTAGEN         321
FT                   /note="I->D: Abolished ability to cleave IL18."
FT                   /evidence="ECO:0000269|PubMed:37993714"
FT   MUTAGEN         356
FT                   /note="K->D: Abolished binding to IL18 and ability to
FT                   mediate its cleavage."
FT                   /evidence="ECO:0000269|PubMed:37993712"
FT   HELIX           111..120
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           122..124
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           131..133
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          136..142
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          147..149
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           155..168
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          171..178
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           181..192
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           195..197
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          203..211
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          213..217
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          223..225
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          228..230
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           231..237
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   TURN            240..242
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           244..246
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          251..259
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          266..269
FT                   /evidence="ECO:0007829|PDB:8SPB"
FT   HELIX           293..296
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          299..305
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           309..311
FT                   /evidence="ECO:0007829|PDB:7WR0"
FT   HELIX           313..316
FT                   /evidence="ECO:0007829|PDB:6NRY"
FT   STRAND          317..320
FT                   /evidence="ECO:0007829|PDB:7WR0"
FT   HELIX           321..333
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   TURN            334..336
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           339..349
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   TURN            353..355
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   HELIX           356..358
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          361..364
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   STRAND          368..370
FT                   /evidence="ECO:0007829|PDB:7WR6"
FT   INIT_MET        P49662-2:1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:22814378"
FT   MOD_RES         P49662-2:2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:22814378"
SQ   SEQUENCE   377 AA;  43262 MW;  DC7CCEC6E9D483EB CRC64;
     MAEGNHRKKP LKVLESLGKD FLTGVLDNLV EQNVLNWKEE EKKKYYDAKT EDKVRVMADS
     MQEKQRMAGQ MLLQTFFNID QISPNKKAHP NMEAGPPESG ESTDALKLCP HEEFLRLCKE
     RAEEIYPIKE RNNRTRLALI ICNTEFDHLP PRNGADFDIT GMKELLEGLD YSVDVEENLT
     ARDMESALRA FATRPEHKSS DSTFLVLMSH GILEGICGTV HDEKKPDVLL YDTIFQIFNN
     RNCLSLKDKP KVIIVQACRG ANRGELWVRD SPASLEVASS QSSENLEEDA VYKTHVEKDF
     IAFCSSTPHN VSWRDSTMGS IFITQLITCF QKYSWCCHLE EVFRKVQQSF ETPRAKAQMP
     TIERLSMTRY FYLFPGN
//
ID   CNR1_HUMAN              Reviewed;         472 AA.
AC   P21554; B2R9T4; E1P512; Q13949; Q495Z0; Q4PLI4; Q4VBM6; Q5JVL5; Q5UB37;
AC   Q9UNN0;
DT   01-MAY-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1991, sequence version 1.
DT   28-JAN-2026, entry version 234.
DE   RecName: Full=Cannabinoid receptor 1;
DE            Short=CB-R;
DE            Short=CB1;
DE   AltName: Full=CANN6;
GN   Name=CNR1; Synonyms=CNR;
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=Brain stem;
RX   PubMed=2263478; DOI=10.1093/nar/18.23.7142;
RA   Gerard C., Mollereau C., Vassart G., Parmentier M.;
RT   "Nucleotide sequence of a human cannabinoid receptor cDNA.";
RL   Nucleic Acids Res. 18:7142-7142(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RC   TISSUE=Brain stem;
RX   PubMed=1718258; DOI=10.1042/bj2790129;
RA   Gerard C., Mollereau C., Vassart G., Parmentier M.;
RT   "Molecular cloning of a human cannabinoid receptor which is also expressed
RT   in testis.";
RL   Biochem. J. 279:129-134(1991).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Lung;
RX   PubMed=7876112; DOI=10.1074/jbc.270.8.3726;
RA   Shire D., Carillon C., Kaghad M., Calandra B., Rinaldi-Carmona M.,
RA   Le Fur G., Caput D., Ferrara P.;
RT   "An amino-terminal variant of the central cannabinoid receptor resulting
RT   from alternative splicing.";
RL   J. Biol. Chem. 270:3726-3731(1995).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION (ISOFORMS 1; 2 AND 3), AND
RP   TISSUE SPECIFICITY.
RC   TISSUE=Fetal brain;
RX   PubMed=15620723; DOI=10.1016/j.febslet.2004.11.085;
RA   Ryberg E., Vu H.K., Larsson N., Groblewski T., Hjorth S., Elebring T.,
RA   Sjoegren S., Greasley P.J.;
RT   "Identification and characterisation of a novel splice variant of the human
RT   CB1 receptor.";
RL   FEBS Lett. 579:259-264(2005).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Hippocampus;
RA   Kathmann M., Schlicker E.;
RL   Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Bonner T.I.;
RL   Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Brain tumor;
RA   Kumar S., Gupta S., Sharma G.;
RL   Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Kopatz S.A., Aronstam R.S., Sharma S.V.;
RT   "cDNA clones of human proteins involved in signal transduction sequenced by
RT   the Guthrie cDNA resource center (www.cdna.org).";
RL   Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=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 [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   [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=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   [13]
RP   REVIEW ON INVOLVEMENT IN NERVOUS SYSTEM DISORDERS.
RX   PubMed=32549916; DOI=10.1007/s13167-020-00203-4;
RA   Reddy V., Grogan D., Ahluwalia M., Salles E.L., Ahluwalia P., Khodadadi H.,
RA   Alverson K., Nguyen A., Raju S.P., Gaur P., Braun M., Vale F.L.,
RA   Costigliola V., Dhandapani K., Baban B., Vaibhav K.;
RT   "Targeting the endocannabinoid system: a predictive, preventive, and
RT   personalized medicine-directed approach to the management of brain
RT   pathologies.";
RL   EPMA J. 11:217-250(2020).
RN   [14]
RP   INVOLVEMENT IN HUNTINGTON DISEASE.
RX   PubMed=8255419; DOI=10.1016/0306-4522(93)90352-g;
RA   Glass M., Faull R.L., Dragunow M.;
RT   "Loss of cannabinoid receptors in the substantia nigra in Huntington's
RT   disease.";
RL   Neuroscience 56:523-527(1993).
RN   [15]
RP   INVOLVEMENT IN HUNTINGTON DISEASE.
RX   PubMed=10828533; DOI=10.1016/s0306-4522(00)00008-7;
RA   Glass M., Dragunow M., Faull R.L.;
RT   "The pattern of neurodegeneration in Huntington's disease: a comparative
RT   study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations
RT   in the human basal ganglia in Huntington's disease.";
RL   Neuroscience 97:505-519(2000).
RN   [16]
RP   FUNCTION, AND INTERACTION WITH CNRIP1.
RC   TISSUE=Brain;
RX   PubMed=17895407; DOI=10.1124/mol.107.039263;
RA   Niehaus J.L., Liu Y., Wallis K.T., Egertova M., Bhartur S.G.,
RA   Mukhopadhyay S., Shi S., He H., Selley D.E., Howlett A.C., Elphick M.R.,
RA   Lewis D.L.;
RT   "CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor
RT   interacting protein CRIP 1a.";
RL   Mol. Pharmacol. 72:1557-1566(2007).
RN   [17]
RP   ACTIVITY REGULATION.
RX   PubMed=18077343; DOI=10.1073/pnas.0706980105;
RA   Heimann A.S., Gomes I., Dale C.S., Pagano R.L., Gupta A., de Souza L.L.,
RA   Luchessi A.D., Castro L.M., Giorgi R., Rioli V., Ferro E.S., Devi L.A.;
RT   "Hemopressin is an inverse agonist of CB1 cannabinoid receptors.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:20588-20593(2007).
RN   [18]
RP   FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-415, AND MUTAGENESIS
RP   OF CYS-415.
RX   PubMed=21895628; DOI=10.1111/j.1476-5381.2011.01658.x;
RA   Oddi S., Dainese E., Sandiford S., Fezza F., Lanuti M., Chiurchiu V.,
RA   Totaro A., Catanzaro G., Barcaroli D., De Laurenzi V., Centonze D.,
RA   Mukhopadhyay S., Selent J., Howlett A.C., Maccarrone M.;
RT   "Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid
RT   receptor on membrane localization and signalling.";
RL   Br. J. Pharmacol. 165:2635-2651(2012).
RN   [19]
RP   INVOLVEMENT IN OBESITY.
RX   PubMed=18177726; DOI=10.1016/j.cmet.2007.11.012;
RA   Addy C., Wright H., Van Laere K., Gantz I., Erondu N., Musser B.J., Lu K.,
RA   Yuan J., Sanabria-Bohorquez S.M., Stoch A., Stevens C., Fong T.M.,
RA   De Lepeleire I., Cilissen C., Cote J., Rosko K., Gendrano I.N. III,
RA   Nguyen A.M., Gumbiner B., Rothenberg P., de Hoon J., Bormans G., Depre M.,
RA   Eng W.S., Ravussin E., Klein S., Blundell J., Herman G.A., Burns H.D.,
RA   Hargreaves R.J., Wagner J., Gottesdiener K., Amatruda J.M.,
RA   Heymsfield S.B.;
RT   "The acyclic CB1R inverse agonist taranabant mediates weight loss by
RT   increasing energy expenditure and decreasing caloric intake.";
RL   Cell Metab. 7:68-78(2008).
RN   [20]
RP   INVOLVEMENT IN HUNTINGTON DISEASE.
RX   PubMed=19524019; DOI=10.1016/j.neuroscience.2009.06.014;
RA   Dowie M.J., Bradshaw H.B., Howard M.L., Nicholson L.F., Faull R.L.,
RA   Hannan A.J., Glass M.;
RT   "Altered CB1 receptor and endocannabinoid levels precede motor symptom
RT   onset in a transgenic mouse model of Huntington's disease.";
RL   Neuroscience 163:456-465(2009).
RN   [21]
RP   FUNCTION, AND INDUCTION BY ENDOCANNABINOID ANANDAMIDE.
RX   PubMed=23955712; DOI=10.1038/nm.3265;
RA   Jourdan T., Godlewski G., Cinar R., Bertola A., Szanda G., Liu J., Tam J.,
RA   Han T., Mukhopadhyay B., Skarulis M.C., Ju C., Aouadi M., Czech M.P.,
RA   Kunos G.;
RT   "Activation of the Nlrp3 inflammasome in infiltrating macrophages by
RT   endocannabinoids mediates beta cell loss in type 2 diabetes.";
RL   Nat. Med. 19:1132-1140(2013).
RN   [22]
RP   INVOLVEMENT IN ALZHEIMER DISEASE.
RX   PubMed=30096288; DOI=10.1016/j.bcp.2018.08.007;
RA   Aso E., Andres-Benito P., Ferrer I.;
RT   "Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-
RT   like symptoms in a transgenic animal model.";
RL   Biochem. Pharmacol. 157:210-216(2018).
RN   [23]
RP   INVOLVEMENT IN PARKINSON DISEASE.
RX   PubMed=31342135; DOI=10.1007/s00259-019-04445-x;
RA   Ceccarini J., Casteels C., Ahmad R., Crabbe M., Van de Vliet L.,
RA   Vanhaute H., Vandenbulcke M., Vandenberghe W., Van Laere K.;
RT   "Regional changes in the type 1 cannabinoid receptor are associated with
RT   cognitive dysfunction in Parkinson's disease.";
RL   Eur. J. Nucl. Med. Mol. Imaging 46:2348-2357(2019).
RN   [24]
RP   STRUCTURE BY NMR OF 338-346, INTERACTION WITH GNAI1, AND MUTAGENESIS OF
RP   341-LEU-ALA-342.
RX   PubMed=12237474; DOI=10.1110/ps.0218402;
RA   Ulfers A.L., McMurry J.L., Miller A., Wang L., Kendall D.A., Mierke D.F.;
RT   "Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures
RT   of IC3 and a mutant with altered G protein specificity.";
RL   Protein Sci. 11:2526-2531(2002).
RN   [25] {ECO:0007744|PDB:5TGZ}
RP   X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 99-306 AND 332-414, FUNCTION, AND
RP   TOPOLOGY.
RX   PubMed=27768894; DOI=10.1016/j.cell.2016.10.004;
RA   Hua T., Vemuri K., Pu M., Qu L., Han G.W., Wu Y., Zhao S., Shui W., Li S.,
RA   Korde A., Laprairie R.B., Stahl E.L., Ho J.H., Zvonok N., Zhou H.,
RA   Kufareva I., Wu B., Zhao Q., Hanson M.A., Bohn L.M., Makriyannis A.,
RA   Stevens R.C., Liu Z.J.;
RT   "Crystal structure of the human cannabinoid receptor CB1.";
RL   Cell 167:750-762(2016).
RN   [26] {ECO:0007744|PDB:5U09}
RP   X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 90-301 AND 334-421 IN COMPLEX
RP   WITH INVERSE AGONIST TARANABANT, MUTAGENESIS OF THR-210, TOPOLOGY, AND
RP   FUNCTION.
RX   PubMed=27851727; DOI=10.1038/nature20613;
RA   Shao Z., Yin J., Chapman K., Grzemska M., Clark L., Wang J.,
RA   Rosenbaum D.M.;
RT   "High-resolution crystal structure of the human CB1 cannabinoid receptor.";
RL   Nature 540:602-606(2016).
RN   [27] {ECO:0007744|PDB:7FEE, ECO:0007744|PDB:7WV9}
RP   X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 74-305 AND 333-414, INTERACTION
RP   WITH GNAI2, FUNCTION, AND MUTAGENESIS OF PHE-155.
RX   PubMed=35637350; DOI=10.1038/s41589-022-01038-y;
RA   Yang X., Wang X., Xu Z., Wu C., Zhou Y., Wang Y., Lin G., Li K., Wu M.,
RA   Xia A., Liu J., Cheng L., Zou J., Yan W., Shao Z., Yang S.;
RT   "Molecular mechanism of allosteric modulation for the cannabinoid receptor
RT   CB1.";
RL   Nat. Chem. Biol. 18:831-840(2022).
CC   -!- FUNCTION: G-protein coupled receptor for endogenous cannabinoids
CC       (eCBs), including N-arachidonoylethanolamide (also called anandamide or
CC       AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids,
CC       such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723,
CC       PubMed:27768894, PubMed:27851727, PubMed:35637350). Mediates many
CC       cannabinoid-induced effects, acting, among others, on food intake,
CC       memory loss, gastrointestinal motility, catalepsy, ambulatory activity,
CC       anxiety, chronic pain. Signaling typically involves reduction in cyclic
CC       AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the
CC       hypothalamus, may have a dual effect on mitochondrial respiration
CC       depending upon the agonist dose and possibly upon the cell type.
CC       Increases respiration at low doses, while decreases respiration at high
CC       doses. At high doses, CNR1 signal transduction involves G-protein
CC       alpha-i protein activation and subsequent inhibition of mitochondrial
CC       soluble adenylate cyclase, decrease in cyclic AMP concentration,
CC       inhibition of protein kinase A (PKA)-dependent phosphorylation of
CC       specific subunits of the mitochondrial electron transport system,
CC       including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive
CC       oxygen species (ROS) formation and mediates cannabinoid-induced
CC       increase in SREBF1 and FASN gene expression. In response to
CC       cannabinoids, drives the release of orexigenic beta-endorphin, but not
CC       that of melanocyte-stimulating hormone alpha/alpha-MSH, from
CC       hypothalamic POMC neurons, hence promoting food intake. In the
CC       hippocampus, regulates cellular respiration and energy production in
CC       response to cannabinoids. Involved in cannabinoid-dependent
CC       depolarization-induced suppression of inhibition (DSI), a process in
CC       which depolarization of CA1 postsynaptic pyramidal neurons mobilizes
CC       eCBs, which retrogradely activate presynaptic CB1 receptors,
CC       transiently decreasing GABAergic inhibitory neurotransmission. Also
CC       reduces excitatory synaptic transmission (By similarity). In superior
CC       cervical ganglions and cerebral vascular smooth muscle cells, inhibits
CC       voltage-gated Ca(2+) channels in a constitutive, as well as agonist-
CC       dependent manner (PubMed:17895407). In cerebral vascular smooth muscle
CC       cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels
CC       leads to vasodilation and decreased vascular tone (By similarity).
CC       Induces leptin production in adipocytes and reduces LRP2-mediated
CC       leptin clearance in the kidney, hence participating in hyperleptinemia.
CC       In adipose tissue, CNR1 signaling leads to increased expression of
CC       SREBF1, ACACA and FASN genes (By similarity). In the liver, activation
CC       by endocannabinoids leads to increased de novo lipogenesis and reduced
CC       fatty acid catabolism, associated with increased expression of
CC       SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de
CC       novo cholesterol synthesis and HDL-cholesteryl ether uptake.
CC       Peripherally modulates energy metabolism (By similarity). In high
CC       carbohydrate diet-induced obesity, may decrease the expression of
CC       mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as
CC       well as that of selected glucose/ pyruvate metabolic enzymes, hence
CC       affecting energy expenditure through mitochondrial metabolism (By
CC       similarity). In response to cannabinoid anandamide, elicits a pro-
CC       inflammatory response in macrophages, which involves NLRP3 inflammasome
CC       activation and IL1B and IL18 secretion (By similarity). In macrophages
CC       infiltrating pancreatic islets, this process may participate in the
CC       progression of type-2 diabetes and associated loss of pancreatic beta-
CC       cells (PubMed:23955712). {ECO:0000250|UniProtKB:O02777,
CC       ECO:0000250|UniProtKB:P47746, ECO:0000269|PubMed:15620723,
CC       ECO:0000269|PubMed:1718258, ECO:0000269|PubMed:17895407,
CC       ECO:0000269|PubMed:21895628, ECO:0000269|PubMed:23955712,
CC       ECO:0000269|PubMed:27768894, ECO:0000269|PubMed:27851727,
CC       ECO:0000269|PubMed:35637350}.
CC   -!- FUNCTION: [Isoform 1]: Binds both 2-arachidonoylglycerol (2-AG) and
CC       anandamide. {ECO:0000269|PubMed:15620723}.
CC   -!- FUNCTION: [Isoform 2]: Only binds 2-arachidonoylglycerol (2-AG) with
CC       high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an
CC       inverse agonist on isoform 2 in assays measuring GTP binding to
CC       membranes. {ECO:0000269|PubMed:15620723}.
CC   -!- FUNCTION: [Isoform 3]: Only binds 2-arachidonoylglycerol (2-AG) with
CC       high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an
CC       inverse agonist on isoform 3 in assays measuring GTP binding to
CC       membranes. {ECO:0000269|PubMed:15620723}.
CC   -!- ACTIVITY REGULATION: Hemopressin, a peptide derived from hemoglobin
CC       subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide:
CC       hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and
CC       subsequent signaling. {ECO:0000269|PubMed:18077343}.
CC   -!- SUBUNIT: Interacts (via C-terminus) with CNRIP1; this interaction
CC       attenuates constitutive, but not agonist-dependent, inhibition of
CC       voltage-gated Ca(2+) channels in neurons (PubMed:17895407). Associates
CC       with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i)
CC       alpha-2/GNAI2, G(i) alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation
CC       is important for interaction with GNAI3 and GNAO1 (PubMed:12237474).
CC       {ECO:0000269|PubMed:12237474, ECO:0000269|PubMed:17895407,
CC       ECO:0000269|PubMed:35637350}.
CC   -!- INTERACTION:
CC       P21554; P29274: ADORA2A; NbExp=8; IntAct=EBI-2909859, EBI-2902702;
CC       P21554; P21554: CNR1; NbExp=8; IntAct=EBI-2909859, EBI-2909859;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21895628};
CC       Multi-pass membrane protein {ECO:0000269|PubMed:27768894,
CC       ECO:0000269|PubMed:27851727}. Membrane raft
CC       {ECO:0000269|PubMed:21895628}. Mitochondrion outer membrane
CC       {ECO:0000250|UniProtKB:P47746}. Cell projection, axon
CC       {ECO:0000250|UniProtKB:P20272}. Presynapse
CC       {ECO:0000250|UniProtKB:P20272}. Note=Unexpectedly, in the mitochondria,
CC       the C-terminus is located in the mitochondrial intermembrane space, a
CC       compartment topologically considered as extracellular. In canonical
CC       seven-transmembrane G-protein coupled receptors, the C-terminus is
CC       cytosolic (By similarity). Found on presynaptic axon terminals in some
CC       GABAergic neurons in the somatosensory cortex (By similarity).
CC       {ECO:0000250|UniProtKB:P20272, ECO:0000250|UniProtKB:P47746}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=Long;
CC         IsoId=P21554-1; Sequence=Displayed;
CC       Name=2; Synonyms=CB1a {ECO:0000303|PubMed:15620723}, Short;
CC         IsoId=P21554-2; Sequence=VSP_001868;
CC       Name=3; Synonyms=CB1b {ECO:0000303|PubMed:15620723};
CC         IsoId=P21554-3; Sequence=VSP_016529;
CC   -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in fetal and
CC       adult brain. Expression levels of isoform 2 and isoform 3 are much
CC       lower than those of isoform 1. {ECO:0000269|PubMed:15620723}.
CC   -!- INDUCTION: Up-regulated by endocannabinoid anandamide.
CC       {ECO:0000269|PubMed:23955712}.
CC   -!- PTM: Palmitoylation at Cys-415 is important for recruitment at plasma
CC       membrane and lipid rafts and association with G protein alpha subunits.
CC       {ECO:0000269|PubMed:21895628}.
CC   -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by
CC       an increase of body weight beyond the limitation of skeletal and
CC       physical requirements, as the result of excessive accumulation of body
CC       fat. {ECO:0000269|PubMed:18177726}. Note=The protein represented in
CC       this entry may be involved in disease pathogenesis. May contribute to
CC       the development of diet-induced obesity and several obesity-associated
CC       features, such as dyslipidemia and liver steatosis, regulating
CC       peripheral lipogenesis, energy expenditure and feeding behavior. CNR1
CC       inverse agonists have been shown to reduce body weight and improve
CC       metabolic abnormalities in obese subjects, although adverse
CC       neuropsychiatric effects, including anxiety, irritability, and
CC       depressed mood, halted their therapeutic development (PubMed:18177726).
CC       In obese mice, peripherally restricted CNR1 inverse agonists have been
CC       shown to normalize metabolic abnormalities, including insulin
CC       resistance and fatty liver, and to reverse leptin resistance.
CC       {ECO:0000269|PubMed:18177726}.
CC   -!- DISEASE: Note=Dysfunction of the endogenous cannabinoid system
CC       including CNR1 has been implicated in the pathogenesis of a number of
CC       central nervous system disorders, including Huntington disease,
CC       Parkinson disease, and Alzheimer disease (PubMed:32549916). In post-
CC       mortem brains from Huntington disease patients, a progressive CNR1 loss
CC       has been observed in the caudate nucleus, putamen, and substantia nigra
CC       pars reticulata, and altered expression and abnormal endocannabinoid
CC       levels precede motor symptoms in a disease mouse model
CC       (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson
CC       disease, low CNR1 expression in mid-superior frontal gyrus and mid-
CC       cingulate cortex has been associated with poor mind, poor executive
CC       functioning and poor episode memory, while patients with more severe
CC       visuospatial dysfunction showed decreased receptor availability in the
CC       precuneus, mid-cingulate, supplementary motor cortex, inferior
CC       orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model
CC       for Alzheimer disease, CNR1 heterozygous deletion has been associated
CC       with decreased levels of postsynaptic density protein 95 (DLG4/PSD95)
CC       and accelerated memory impairment, suggesting synaptic dysfunction and
CC       a crucial role for CNR1 in the progression of disease symptoms
CC       (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135,
CC       PubMed:8255419). {ECO:0000269|PubMed:10828533,
CC       ECO:0000269|PubMed:19524019, ECO:0000269|PubMed:30096288,
CC       ECO:0000269|PubMed:31342135, ECO:0000269|PubMed:32549916,
CC       ECO:0000269|PubMed:8255419}.
CC   -!- MISCELLANEOUS: High-fat diet also increases the hepatic levels of CNR1
CC       ligand anandamide, but not that of 2-arachidonoylglycerol.
CC       {ECO:0000250|UniProtKB:P47746}.
CC   -!- MISCELLANEOUS: [Isoform 2]: Dubious isoform. A putative downstream
CC       initiation AUG is used to produce isoform 2 (PubMed:1718258). The use
CC       of the first AUG (same as isoform 1) gives a truncated protein of 36
CC       AA. {ECO:0000305|PubMed:1718258}.
CC   -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC       {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR   EMBL; X54937; CAA38699.1; -; mRNA.
DR   EMBL; X81120; CAA57018.1; -; mRNA.
DR   EMBL; X81121; CAA57019.1; -; mRNA.
DR   EMBL; AY766182; AAV35030.1; -; mRNA.
DR   EMBL; AF107262; AAD34320.1; -; mRNA.
DR   EMBL; U73304; AAB18200.1; -; Genomic_DNA.
DR   EMBL; DQ067455; AAY68486.1; -; mRNA.
DR   EMBL; AY225225; AAO67710.1; -; Genomic_DNA.
DR   EMBL; AL136096; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AK313908; BAG36631.1; -; mRNA.
DR   EMBL; CH471051; EAW48574.1; -; Genomic_DNA.
DR   EMBL; CH471051; EAW48575.1; -; Genomic_DNA.
DR   EMBL; CH471051; EAW48576.1; -; Genomic_DNA.
DR   EMBL; BC074811; AAH74811.1; -; mRNA.
DR   EMBL; BC074812; AAH74812.1; -; mRNA.
DR   EMBL; BC095513; AAH95513.1; -; mRNA.
DR   EMBL; BC100968; AAI00969.1; -; mRNA.
DR   EMBL; BC100969; AAI00970.1; -; mRNA.
DR   EMBL; BC100970; AAI00971.1; -; mRNA.
DR   EMBL; BC100971; AAI00972.1; -; mRNA.
DR   CCDS; CCDS5015.1; -. [P21554-1]
DR   CCDS; CCDS5016.2; -. [P21554-3]
DR   PIR; S17595; S17595.
DR   RefSeq; NP_001153698.1; NM_001160226.3. [P21554-1]
DR   RefSeq; NP_001153730.1; NM_001160258.3. [P21554-1]
DR   RefSeq; NP_001153731.1; NM_001160259.3. [P21554-1]
DR   RefSeq; NP_001352798.1; NM_001365869.2. [P21554-1]
DR   RefSeq; NP_001352799.1; NM_001365870.2. [P21554-1]
DR   RefSeq; NP_001352801.1; NM_001365872.2. [P21554-1]
DR   RefSeq; NP_001352803.1; NM_001365874.3. [P21554-1]
DR   RefSeq; NP_001357474.1; NM_001370545.1. [P21554-1]
DR   RefSeq; NP_001357475.1; NM_001370546.1. [P21554-1]
DR   RefSeq; NP_001357476.1; NM_001370547.1. [P21554-1]
DR   RefSeq; NP_001411023.1; NM_001424094.1. [P21554-1]
DR   RefSeq; NP_001411024.1; NM_001424095.1. [P21554-1]
DR   RefSeq; NP_001411025.1; NM_001424096.1. [P21554-1]
DR   RefSeq; NP_001411026.1; NM_001424097.1. [P21554-1]
DR   RefSeq; NP_001411027.1; NM_001424098.1. [P21554-1]
DR   RefSeq; NP_057167.2; NM_016083.4. [P21554-1]
DR   RefSeq; NP_149421.2; NM_033181.4. [P21554-3]
DR   RefSeq; XP_047274127.1; XM_047418171.1. [P21554-1]
DR   RefSeq; XP_047274128.1; XM_047418172.1. [P21554-1]
DR   RefSeq; XP_047274129.1; XM_047418173.1. [P21554-1]
DR   RefSeq; XP_054210179.1; XM_054354204.1. [P21554-1]
DR   RefSeq; XP_054210180.1; XM_054354205.1. [P21554-1]
DR   RefSeq; XP_054210181.1; XM_054354206.1. [P21554-1]
DR   PDB; 1LVQ; NMR; -; A=338-346.
DR   PDB; 1LVR; NMR; -; A=338-346.
DR   PDB; 2B0Y; NMR; -; A=400-414.
DR   PDB; 2KOE; NMR; -; A=377-414.
DR   PDB; 2MZ2; NMR; -; A=400-414.
DR   PDB; 2MZ3; NMR; -; A=400-414.
DR   PDB; 2MZA; NMR; -; A=400-414.
DR   PDB; 5TGZ; X-ray; 2.80 A; A=99-306, A=332-414.
DR   PDB; 5U09; X-ray; 2.60 A; A=90-301, A=333-421.
DR   PDB; 5XR8; X-ray; 2.95 A; A=99-306, A=332-414.
DR   PDB; 5XRA; X-ray; 2.80 A; A=99-306, A=332-414.
DR   PDB; 6KPG; EM; 3.00 A; R=71-425.
DR   PDB; 6KQI; X-ray; 3.25 A; A=94-301, A=334-413.
DR   PDB; 6N4B; EM; 3.00 A; R=1-472.
DR   PDB; 7FEE; X-ray; 2.70 A; A=74-305, A=333-414.
DR   PDB; 7V3Z; X-ray; 3.29 A; A=102-306, A=336-414.
DR   PDB; 7WV9; EM; 3.36 A; R=1-472.
DR   PDB; 8GAG; EM; 3.30 A; R=1-472.
DR   PDB; 8GHV; EM; 2.80 A; D=1-472.
DR   PDB; 8IKG; EM; 3.40 A; R=99-408.
DR   PDB; 8IKH; EM; 3.30 A; R=99-408.
DR   PDB; 8K8J; EM; 2.88 A; R=71-425.
DR   PDB; 8WRZ; EM; 3.60 A; R=71-432.
DR   PDB; 8WU1; EM; 3.20 A; R=1-413.
DR   PDB; 9B54; EM; 2.86 A; R=1-472.
DR   PDB; 9B65; EM; 3.03 A; R=1-472.
DR   PDB; 9B9Y; EM; 3.50 A; R=96-301, R=334-416.
DR   PDB; 9B9Z; EM; 3.30 A; R=96-301, R=334-416.
DR   PDB; 9BA0; EM; 3.13 A; R=96-301, R=334-416.
DR   PDB; 9DGI; EM; 3.35 A; R=1-472.
DR   PDB; 9EGO; EM; 3.20 A; R=1-472.
DR   PDB; 9ERX; EM; 2.90 A; R=2-472.
DR   PDBsum; 1LVQ; -.
DR   PDBsum; 1LVR; -.
DR   PDBsum; 2B0Y; -.
DR   PDBsum; 2KOE; -.
DR   PDBsum; 2MZ2; -.
DR   PDBsum; 2MZ3; -.
DR   PDBsum; 2MZA; -.
DR   PDBsum; 5TGZ; -.
DR   PDBsum; 5U09; -.
DR   PDBsum; 5XR8; -.
DR   PDBsum; 5XRA; -.
DR   PDBsum; 6KPG; -.
DR   PDBsum; 6KQI; -.
DR   PDBsum; 6N4B; -.
DR   PDBsum; 7FEE; -.
DR   PDBsum; 7V3Z; -.
DR   PDBsum; 7WV9; -.
DR   PDBsum; 8GAG; -.
DR   PDBsum; 8GHV; -.
DR   PDBsum; 8IKG; -.
DR   PDBsum; 8IKH; -.
DR   PDBsum; 8K8J; -.
DR   PDBsum; 8WRZ; -.
DR   PDBsum; 8WU1; -.
DR   PDBsum; 9B54; -.
DR   PDBsum; 9B65; -.
DR   PDBsum; 9B9Y; -.
DR   PDBsum; 9B9Z; -.
DR   PDBsum; 9BA0; -.
DR   PDBsum; 9DGI; -.
DR   PDBsum; 9EGO; -.
DR   PDBsum; 9ERX; -.
DR   AlphaFoldDB; P21554; -.
DR   EMDB; EMD-0339; -.
DR   EMDB; EMD-0745; -.
DR   EMDB; EMD-19929; -.
DR   EMDB; EMD-29898; -.
DR   EMDB; EMD-32850; -.
DR   EMDB; EMD-35511; -.
DR   EMDB; EMD-35512; -.
DR   EMDB; EMD-36951; -.
DR   EMDB; EMD-37795; -.
DR   EMDB; EMD-40052; -.
DR   EMDB; EMD-44199; -.
DR   EMDB; EMD-44247; -.
DR   EMDB; EMD-44392; -.
DR   EMDB; EMD-44393; -.
DR   EMDB; EMD-44394; -.
DR   EMDB; EMD-46828; -.
DR   EMDB; EMD-47992; -.
DR   SMR; P21554; -.
DR   BioGRID; 107668; 11.
DR   CORUM; P21554; -.
DR   DIP; DIP-61575N; -.
DR   FunCoup; P21554; 1275.
DR   IntAct; P21554; 12.
DR   STRING; 9606.ENSP00000358513; -.
DR   BindingDB; P21554; -.
DR   ChEMBL; CHEMBL218; -.
DR   DrugBank; DB09061; Cannabidiol.
DR   DrugBank; DB14737; Cannabinol.
DR   DrugBank; DB05750; Drinabant.
DR   DrugBank; DB00470; Dronabinol.
DR   DrugBank; DB14009; Medical Cannabis.
DR   DrugBank; DB00486; Nabilone.
DR   DrugBank; DB14011; Nabiximols.
DR   DrugBank; DB16495; Oleic monoethanolamide.
DR   DrugBank; DB01083; Orlistat.
DR   DrugBank; DB11745; Otenabant.
DR   DrugBank; DB13495; Paraoxon.
DR   DrugBank; DB09288; Propacetamol.
DR   DrugBank; DB02955; Ricinoleic acid.
DR   DrugBank; DB06155; Rimonabant.
DR   DrugBank; DB05077; SLV319.
DR   DrugBank; DB13070; Surinabant.
DR   DrugBank; DB06624; Taranabant.
DR   DrugBank; DB11755; Tetrahydrocannabivarin.
DR   DrugBank; DB05201; V24343.
DR   DrugBank; DB13950; WIN 55212-2.
DR   DrugCentral; P21554; -.
DR   GuidetoPHARMACOLOGY; 56; -.
DR   SwissLipids; SLP:000001607; -.
DR   TCDB; 9.A.14.2.2; the g-protein-coupled receptor (gpcr) family.
DR   GlyCosmos; P21554; 2 sites, No reported glycans.
DR   GlyGen; P21554; 2 sites.
DR   iPTMnet; P21554; -.
DR   PhosphoSitePlus; P21554; -.
DR   SwissPalm; P21554; -.
DR   BioMuta; CNR1; -.
DR   DMDM; 115562; -.
DR   MassIVE; P21554; -.
DR   PaxDb; 9606-ENSP00000358513; -.
DR   PeptideAtlas; P21554; -.
DR   ProteomicsDB; 53875; -. [P21554-1]
DR   ProteomicsDB; 53876; -. [P21554-2]
DR   ProteomicsDB; 53877; -. [P21554-3]
DR   ABCD; P21554; 62 sequenced antibodies.
DR   Antibodypedia; 3355; 718 antibodies from 42 providers.
DR   DNASU; 1268; -.
DR   Ensembl; ENST00000369499.3; ENSP00000358511.2; ENSG00000118432.14. [P21554-1]
DR   Ensembl; ENST00000369501.3; ENSP00000358513.2; ENSG00000118432.14. [P21554-1]
DR   Ensembl; ENST00000428600.3; ENSP00000412192.2; ENSG00000118432.14. [P21554-1]
DR   Ensembl; ENST00000468898.2; ENSP00000420188.1; ENSG00000118432.14. [P21554-3]
DR   Ensembl; ENST00000549890.2; ENSP00000446819.1; ENSG00000118432.14. [P21554-1]
DR   Ensembl; ENST00000551417.2; ENSP00000446702.2; ENSG00000118432.14. [P21554-1]
DR   GeneID; 1268; -.
DR   KEGG; hsa:1268; -.
DR   MANE-Select; ENST00000369501.3; ENSP00000358513.2; NM_016083.6; NP_057167.2.
DR   AGR; HGNC:2159; -.
DR   ClinPGx; PA26681; -.
DR   CTD; 1268; -.
DR   DisGeNET; 1268; -.
DR   GeneCards; CNR1; -.
DR   HGNC; HGNC:2159; CNR1.
DR   HPA; ENSG00000118432; Tissue enhanced (adipose tissue, pituitary gland).
DR   MIM; 114610; gene.
DR   MIM; 601665; phenotype.
DR   OpenTargets; ENSG00000118432; -.
DR   VEuPathDB; HostDB:ENSG00000118432; -.
DR   eggNOG; KOG3656; Eukaryota.
DR   GeneTree; ENSGT01140000282530; -.
DR   HOGENOM; CLU_009579_7_0_1; -.
DR   InParanoid; P21554; -.
DR   OMA; HKHANSA; -.
DR   OrthoDB; 5966748at2759; -.
DR   PAN-GO; P21554; 6 GO annotations based on evolutionary models.
DR   PhylomeDB; P21554; -.
DR   PathwayCommons; P21554; -.
DR   Reactome; R-HSA-373076; Class A/1 (Rhodopsin-like receptors).
DR   Reactome; R-HSA-418594; G alpha (i) signalling events.
DR   SignaLink; P21554; -.
DR   SIGNOR; P21554; -.
DR   Agora; ENSG00000118432; -.
DR   BioGRID-ORCS; 1268; 19 hits in 1157 CRISPR screens.
DR   ChiTaRS; CNR1; human.
DR   EvolutionaryTrace; P21554; -.
DR   GeneWiki; Cannabinoid_receptor_type_1; -.
DR   GenomeRNAi; 1268; -.
DR   Pharos; P21554; Tclin.
DR   PRO; PR:P21554; -.
DR   Proteomes; UP000005640; Chromosome 6.
DR   RNAct; P21554; protein.
DR   Bgee; ENSG00000118432; Expressed in ganglionic eminence and 150 other cell types or tissues.
DR   ExpressionAtlas; P21554; baseline and differential.
DR   GO; GO:0015629; C:actin cytoskeleton; IDA:HPA.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0030426; C:growth cone; IEA:Ensembl.
DR   GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR   GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl.
DR   GO; GO:0004949; F:cannabinoid receptor activity; IDA:UniProtKB.
DR   GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR   GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0007413; P:axonal fasciculation; IEA:Ensembl.
DR   GO; GO:0038171; P:cannabinoid signaling pathway; IDA:UniProtKB.
DR   GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc.
DR   GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl.
DR   GO; GO:0099509; P:regulation of presynaptic cytosolic calcium ion concentration; IEA:Ensembl.
DR   GO; GO:0098921; P:retrograde trans-synaptic signaling by endocannabinoid; IEA:Ensembl.
DR   CDD; cd15340; 7tmA_CB1; 1.
DR   FunFam; 1.20.1070.10:FF:000072; Cannabinoid receptor 1; 1.
DR   Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1.
DR   InterPro; IPR000810; Canbinoid_rcpt_1.
DR   InterPro; IPR002230; Cnbnoid_rcpt.
DR   InterPro; IPR000276; GPCR_Rhodpsn.
DR   InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR   PANTHER; PTHR22750; G-PROTEIN COUPLED RECEPTOR; 1.
DR   Pfam; PF00001; 7tm_1; 1.
DR   PIRSF; PIRSF037995; Cnoid_rcpt_1; 1.
DR   PRINTS; PR00522; CANABINOID1R.
DR   PRINTS; PR00362; CANNABINOIDR.
DR   PRINTS; PR00237; GPCRRHODOPSN.
DR   SMART; SM01381; 7TM_GPCR_Srsx; 1.
DR   SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1.
DR   PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR   PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cell membrane; Cell projection;
KW   G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane;
KW   Mitochondrion; Mitochondrion outer membrane; Neurodegeneration; Obesity;
KW   Palmitate; Phosphoprotein; Proteomics identification; Receptor;
KW   Reference proteome; Synapse; Transducer; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..472
FT                   /note="Cannabinoid receptor 1"
FT                   /id="PRO_0000069314"
FT   TOPO_DOM        1..116
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TRANSMEM        117..142
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TOPO_DOM        143..154
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TRANSMEM        155..175
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TOPO_DOM        176..187
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TRANSMEM        188..212
FT                   /note="Helical; Name=3"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TOPO_DOM        213..232
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TRANSMEM        233..255
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TOPO_DOM        256..273
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TRANSMEM        274..299
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TOPO_DOM        300..344
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TRANSMEM        345..365
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TOPO_DOM        366..377
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TRANSMEM        378..399
FT                   /note="Helical; Name=7"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   TOPO_DOM        400..472
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:27768894,
FT                   ECO:0000269|PubMed:27851727"
FT   REGION          2..23
FT                   /note="Required for mitochondrial localization"
FT                   /evidence="ECO:0000250|UniProtKB:P47746"
FT   MOD_RES         425
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P47746"
FT   MOD_RES         429
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P47746"
FT   LIPID           415
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:21895628"
FT   CARBOHYD        77
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        83
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         1..89
FT                   /note="MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTS
FT                   FRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF -> MALQIPPSAPSPLTSCTW
FT                   AQMTFSTKTS (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:7876112"
FT                   /id="VSP_001868"
FT   VAR_SEQ         22..54
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15620723"
FT                   /id="VSP_016529"
FT   MUTAGEN         155
FT                   /note="F->V: Enhanced G(i) signaling activation ability."
FT                   /evidence="ECO:0000269|PubMed:35637350"
FT   MUTAGEN         155
FT                   /note="F->W: Reduced agonist-induced receptor activation."
FT                   /evidence="ECO:0000269|PubMed:35637350"
FT   MUTAGEN         210
FT                   /note="T->A: 7-fold lower affinity for a synthetic agonist,
FT                   CP55940, possibly due the stabilization of an inactive
FT                   conformation."
FT                   /evidence="ECO:0000269|PubMed:27851727"
FT   MUTAGEN         341..342
FT                   /note="LA->AL: Loss of activity, when assayed for GNAI1
FT                   GTPase stimulatory activity."
FT                   /evidence="ECO:0000269|PubMed:12237474"
FT   MUTAGEN         415
FT                   /note="C->A: Loss of palmitoylation, marked loss of
FT                   association with lipid rafts on the plasma membrane and
FT                   loss of activity, when assayed for downstream GTP-binding
FT                   and reduction in cAMP levels."
FT                   /evidence="ECO:0000269|PubMed:21895628"
FT   CONFLICT        94
FT                   /note="E -> G (in Ref. 12; AAH95513)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        103
FT                   /note="M -> I (in Ref. 12; AAH95513)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        149
FT                   /note="C -> R (in Ref. 12; AAH95513)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        200
FT                   /note="F -> L (in Ref. 5; AAD34320)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        216
FT                   /note="I -> V (in Ref. 5; AAD34320)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        246
FT                   /note="V -> A (in Ref. 5; AAD34320)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        298
FT                   /note="L -> P (in Ref. 12; AAH95513)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        332
FT                   /note="P -> S (in Ref. 12; AAI00972)"
FT                   /evidence="ECO:0000305"
FT   STRAND          100..102
FT                   /evidence="ECO:0007829|PDB:7FEE"
FT   HELIX           105..107
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           113..143
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           145..148
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           151..153
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           154..178
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           186..219
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   TURN            221..223
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           224..227
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           230..249
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           250..253
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           257..260
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   STRAND          266..268
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           273..300
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           302..305
FT                   /evidence="ECO:0007829|PDB:6KPG"
FT   HELIX           306..309
FT                   /evidence="ECO:0007829|PDB:8K8J"
FT   HELIX           334..367
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           375..400
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           402..409
FT                   /evidence="ECO:0007829|PDB:5U09"
FT   HELIX           411..415
FT                   /evidence="ECO:0007829|PDB:2B0Y"
SQ   SEQUENCE   472 AA;  52858 MW;  1D2E49061D12ABF2 CRC64;
     MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE
     KMTAGDNPQL VPADQVNITE FYNKSLSSFK ENEENIQCGE NFMDIECFMV LNPSQQLAIA
     VLSLTLGTFT VLENLLVLCV ILHSRSLRCR PSYHFIGSLA VADLLGSVIF VYSFIDFHVF
     HRKDSRNVFL FKLGGVTASF TASVGSLFLT AIDRYISIHR PLAYKRIVTR PKAVVAFCLM
     WTIAIVIAVL PLLGWNCEKL QSVCSDIFPH IDETYLMFWI GVTSVLLLFI VYAYMYILWK
     AHSHAVRMIQ RGTQKSIIIH TSEDGKVQVT RPDQARMDIR LAKTLVLILV VLIICWGPLL
     AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR SKDLRHAFRS MFPSCEGTAQ
     PLDNSMGDSD CLHKHANNAA SVHRAAESCI KSTVKIAKVT MSVSTDTSAE AL
//
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   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   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}.
CC   ---------------------------------------------------------------------------
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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   NU1M_HUMAN              Reviewed;         318 AA.
AC   P03886; C0JKH6; Q37523;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   21-JUL-1986, sequence version 1.
DT   28-JAN-2026, entry version 222.
DE   RecName: Full=NADH-ubiquinone oxidoreductase chain 1;
DE            EC=7.1.1.2 {ECO:0000269|PubMed:1959619};
DE   AltName: Full=NADH dehydrogenase subunit 1;
GN   Name=MT-ND1; Synonyms=MTND1, NADH1, ND1;
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 [LARGE SCALE GENOMIC DNA].
RX   PubMed=7219534; DOI=10.1038/290457a0;
RA   Anderson S., Bankier A.T., Barrell B.G., de Bruijn M.H.L., Coulson A.R.,
RA   Drouin J., Eperon I.C., Nierlich D.P., Roe B.A., Sanger F., Schreier P.H.,
RA   Smith A.J.H., Staden R., Young I.G.;
RT   "Sequence and organization of the human mitochondrial genome.";
RL   Nature 290:457-465(1981).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ALA-87 AND ALA-168.
RC   TISSUE=Placenta;
RX   PubMed=7530363; DOI=10.1073/pnas.92.2.532;
RA   Horai S., Hayasaka K., Kondo R., Tsugane K., Takahata N.;
RT   "Recent African origin of modern humans revealed by complete sequences of
RT   hominoid mitochondrial DNAs.";
RL   Proc. Natl. Acad. Sci. U.S.A. 92:532-536(1995).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=12949126; DOI=10.1093/molbev/msg230;
RA   Moilanen J.S., Finnila S., Majamaa K.;
RT   "Lineage-specific selection in human mtDNA: lack of polymorphisms in a
RT   segment of MTND5 gene in haplogroup J.";
RL   Mol. Biol. Evol. 20:2132-2142(2003).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=11130070; DOI=10.1038/35047064;
RA   Ingman M., Kaessmann H., Paeaebo S., Gyllensten U.;
RT   "Mitochondrial genome variation and the origin of modern humans.";
RL   Nature 408:708-713(2000).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=12840039; DOI=10.1101/gr.686603;
RA   Ingman M., Gyllensten U.;
RT   "Mitochondrial genome variation and evolutionary history of Australian and
RT   New Guinean aborigines.";
RL   Genome Res. 13:1600-1606(2003).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=14760490; DOI=10.1007/s00414-004-0427-6;
RA   Coble M.D., Just R.S., O'Callaghan J.E., Letmanyi I.H., Peterson C.T.,
RA   Irwin J.A., Parsons T.J.;
RT   "Single nucleotide polymorphisms over the entire mtDNA genome that increase
RT   the power of forensic testing in Caucasians.";
RL   Int. J. Legal Med. 118:137-146(2004).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=19243582; DOI=10.1186/1471-2156-10-8;
RA   Ennafaa H., Cabrera V.M., Abu-Amero K.K., Gonzalez A.M., Amor M.B.,
RA   Bouhaha R., Dzimiri N., Elgaaied A.B., Larruga J.M.;
RT   "Mitochondrial DNA haplogroup H structure in North Africa.";
RL   BMC Genet. 10:8-8(2009).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 130-318.
RX   PubMed=6260957; DOI=10.1016/0022-2836(80)90196-5;
RA   Sanger F., Coulson A.R., Barrell B.G., Smith A.J.H., Roe B.A.;
RT   "Cloning in single-stranded bacteriophage as an aid to rapid DNA
RT   sequencing.";
RL   J. Mol. Biol. 143:161-178(1980).
RN   [9]
RP   IDENTIFICATION OF PROTEIN.
RX   PubMed=3921850; DOI=10.1038/314592a0;
RA   Chomyn A., Mariottini P., Cleeter M.W.J., Ragan C.I., Matsuno-Yagi A.,
RA   Hatefi Y., Doolittle R.F., Attardi G.;
RT   "Six unidentified reading frames of human mitochondrial DNA encode
RT   components of the respiratory-chain NADH dehydrogenase.";
RL   Nature 314:592-597(1985).
RN   [10]
RP   IDENTIFICATION IN THE NADH-UBIQUINONE OXIDOREDUCTASE COMPLEX, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=12611891; DOI=10.1074/jbc.c300064200;
RA   Murray J., Zhang B., Taylor S.W., Oglesbee D., Fahy E., Marusich M.F.,
RA   Ghosh S.S., Capaldi R.A.;
RT   "The subunit composition of the human NADH dehydrogenase obtained by rapid
RT   one-step immunopurification.";
RL   J. Biol. Chem. 278:13619-13622(2003).
RN   [11]
RP   POSSIBLE INVOLVEMENT IN SUSCEPTIBILITY TO T2D.
RX   PubMed=15265369;
RA   Yu P., Yu D.M., Liu D.M., Wang K., Tang X.Z.;
RT   "Relationship between mutations of mitochondrial DNA ND1 gene and type 2
RT   diabetes.";
RL   Chin. Med. J. 117:985-989(2004).
RN   [12]
RP   FUNCTION.
RX   PubMed=26929434; DOI=10.1096/fj.201500137r;
RA   Lim S.C., Hroudova J., Van Bergen N.J., Lopez Sanchez M.I., Trounce I.A.,
RA   McKenzie M.;
RT   "Loss of mitochondrial DNA-encoded protein ND1 results in disruption of
RT   complex I biogenesis during early stages of assembly.";
RL   FASEB J. 30:2236-2248(2016).
RN   [13]
RP   VARIANT LYS-214.
RX   PubMed=24105702; DOI=10.1002/humu.22445;
RA   Delmiro A., Rivera H., Garcia-Silva M.T., Garcia-Consuegra I.,
RA   Martin-Hernandez E., Quijada-Fraile P., de Las Heras R.S.,
RA   Moreno-Izquierdo A., Martin M.A., Arenas J., Martinez-Azorin F.;
RT   "Whole-exome sequencing identifies a variant of the mitochondrial MT-ND1
RT   gene associated with epileptic encephalopathy: west syndrome evolving to
RT   Lennox-Gastaut syndrome.";
RL   Hum. Mutat. 34:1623-1627(2013).
RN   [14]
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   [15]
RP   VARIANT LHON THR-52.
RX   PubMed=1928099;
RA   Howell N., Bindoff L.A., McCullough D.A., Kubacka I., Poulton J.,
RA   Mackey D., Taylor L., Turnbull D.M.;
RT   "Leber hereditary optic neuropathy: identification of the same
RT   mitochondrial ND1 mutation in six pedigrees.";
RL   Am. J. Hum. Genet. 49:939-950(1991).
RN   [16]
RP   VARIANT LHON THR-52.
RX   PubMed=1674640;
RA   Huoponen K., Vilkki J., Aula P., Nikoskelainen E.K., Savontaus M.L.;
RT   "A new mtDNA mutation associated with Leber hereditary optic
RT   neuroretinopathy.";
RL   Am. J. Hum. Genet. 48:1147-1153(1991).
RN   [17]
RP   VARIANT LHON PRO-285, AND VARIANT CYS-277.
RX   PubMed=2018041;
RA   Howell N., Kubacka I., Xu M., McCullough D.A.;
RT   "Leber hereditary optic neuropathy: involvement of the mitochondrial ND1
RT   gene and evidence for an intragenic suppressor mutation.";
RL   Am. J. Hum. Genet. 48:935-942(1991).
RN   [18]
RP   VARIANT LHON HIS-304.
RX   PubMed=1900003; DOI=10.1016/0006-291x(91)91567-v;
RA   Johns D.R., Berman J.;
RT   "Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's
RT   hereditary optic neuropathy.";
RL   Biochem. Biophys. Res. Commun. 174:1324-1330(1991).
RN   [19]
RP   CHARACTERIZATION OF VARIANT LHON THR-52, FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=1959619; DOI=10.1016/0014-5793(91)80886-8;
RA   Majander A., Huoponen K., Savontaus M.-L., Nikoskelainen E., Wikstroem M.;
RT   "Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460
RT   and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy
RT   (LHON).";
RL   FEBS Lett. 292:289-292(1991).
RN   [20]
RP   VARIANTS PRO-205; CYS-255 AND PRO-288.
RX   PubMed=1757091; DOI=10.1007/bf00206061;
RA   Marzuki S., Noer A.S., Lertrit P., Thyagarajan D., Kapsa R.,
RA   Utthanaphol P., Byrne E.;
RT   "Normal variants of human mitochondrial DNA and translation products: the
RT   building of a reference data base.";
RL   Hum. Genet. 88:139-145(1991).
RN   [21]
RP   VARIANT LHON HIS-30.
RX   PubMed=1417830; DOI=10.1016/0006-291x(92)90479-5;
RA   Johns D.R., Neufeld M.J., Park R.D.;
RT   "An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic
RT   neuropathy.";
RL   Biochem. Biophys. Res. Commun. 187:1551-1557(1992).
RN   [22]
RP   POSSIBLE INVOLVEMENT IN AD-MT, AND VARIANT AD-MT VAL-31.
RX   PubMed=8104867; DOI=10.1006/geno.1993.1299;
RA   Shoffner J.M., Brown M.D., Torroni A., Lott M.T., Cabell M.F., Mirra S.S.,
RA   Beal M.F., Yang C.-C., Gearing M., Salvo R., Watts R.L., Juncos J.L.,
RA   Hansen L.A., Crain B.J., Fayad M., Reckord C.L., Wallace D.C.;
RT   "Mitochondrial DNA variants observed in Alzheimer disease and Parkinson
RT   disease patients.";
RL   Genomics 17:171-184(1993).
RN   [23]
RP   VARIANT MELAS THR-31.
RX   PubMed=8723687;
RX   DOI=10.1002/(sici)1098-1004(1996)7:4<358::aid-humu11>3.0.co;2-1;
RA   Jaksch M., Hofmann S., Kaufhold P., Obermaier-Kusser B., Zierz S.,
RA   Gerbitz K.-D.;
RT   "A novel combination of mitochondrial tRNA and ND1 gene mutations in a
RT   syndrome with MELAS, cardiomyopathy, and diabetes mellitus.";
RL   Hum. Mutat. 7:358-360(1996).
RN   [24]
RP   VARIANT THR-4, AND POSSIBLE INVOLVEMENT IN SUSCEPTIBILITY TO T2D.
RX   PubMed=7733935; DOI=10.1006/bbrc.1995.1550;
RA   Nakagawa Y., Ikegami H., Yamato E., Takekawa K., Fujisawa T., Hamada Y.,
RA   Ueda H., Uchigata Y., Miki T., Kumahara Y.;
RT   "A new mitochondrial DNA mutation associated with non-insulin-dependent
RT   diabetes mellitus.";
RL   Biochem. Biophys. Res. Commun. 209:664-668(1995).
RN   [25]
RP   VARIANT CYS-30.
RX   PubMed=21144833; DOI=10.1016/j.bbrc.2010.12.012;
RA   Chamkha I., Mkaouar-Rebai E., Aloulou H., Chabchoub I., Kifagi C.,
RA   Fendri-Kriaa N., Kammoun T., Hachicha M., Fakhfakh F.;
RT   "A novel m.3395A>G missense mutation in the mitochondrial ND1 gene
RT   associated with the new tRNA(Ile) m.4316A>G mutation in a patient with
RT   hypertrophic cardiomyopathy and profound hearing loss.";
RL   Biochem. Biophys. Res. Commun. 404:504-510(2011).
CC   -!- FUNCTION: Core subunit of the mitochondrial membrane respiratory chain
CC       NADH dehydrogenase (Complex I) which catalyzes electron transfer from
CC       NADH through the respiratory chain, using ubiquinone as an electron
CC       acceptor (PubMed:1959619). Essential for the catalytic activity and
CC       assembly of complex I (PubMed:1959619, PubMed:26929434).
CC       {ECO:0000269|PubMed:1959619, ECO:0000269|PubMed:26929434}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4
CC         H(+)(out); Xref=Rhea:RHEA:29091, Rhea:RHEA-COMP:9565, Rhea:RHEA-
CC         COMP:9566, ChEBI:CHEBI:15378, ChEBI:CHEBI:16389, ChEBI:CHEBI:17976,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=7.1.1.2;
CC         Evidence={ECO:0000269|PubMed:1959619};
CC   -!- SUBUNIT: Core subunit of respiratory chain NADH dehydrogenase (Complex
CC       I) which is composed of 45 different subunits.
CC       {ECO:0000269|PubMed:12611891}.
CC   -!- INTERACTION:
CC       P03886; P43490: NAMPT; NbExp=3; IntAct=EBI-1246156, EBI-2829310;
CC   -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC       {ECO:0000250|UniProtKB:P03887}; Multi-pass membrane protein
CC       {ECO:0000255}.
CC   -!- DISEASE: Leber hereditary optic neuropathy (LHON) [MIM:535000]: A
CC       maternally inherited form of Leber hereditary optic neuropathy, a
CC       mitochondrial disease resulting in bilateral painless loss of central
CC       vision due to selective degeneration of the retinal ganglion cells and
CC       their axons. The disorder shows incomplete penetrance and male
CC       predominance. Cardiac conduction defects and neurological defects have
CC       also been described in some LHON patients. LHON results from primary
CC       mitochondrial DNA mutations affecting the respiratory chain complexes.
CC       {ECO:0000269|PubMed:1417830, ECO:0000269|PubMed:1674640,
CC       ECO:0000269|PubMed:1900003, ECO:0000269|PubMed:1928099,
CC       ECO:0000269|PubMed:1959619, ECO:0000269|PubMed:2018041}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Mitochondrial encephalomyopathy with lactic acidosis and
CC       stroke-like episodes syndrome (MELAS) [MIM:540000]: Genetically
CC       heterogeneous disorder, characterized by episodic vomiting, seizures,
CC       and recurrent cerebral insults resembling strokes and causing
CC       hemiparesis, hemianopsia, or cortical blindness.
CC       {ECO:0000269|PubMed:8723687}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Alzheimer disease mitochondrial (AD-MT) [MIM:502500]:
CC       Alzheimer disease is a neurodegenerative disorder characterized by
CC       progressive dementia, loss of cognitive abilities, and deposition of
CC       fibrillar 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. {ECO:0000269|PubMed:8104867}.
CC       Note=Disease susceptibility may be associated with variants affecting
CC       the gene represented in this entry.
CC   -!- DISEASE: Type 2 diabetes mellitus (T2D) [MIM:125853]: A multifactorial
CC       disorder of glucose homeostasis caused by a lack of sensitivity to
CC       insulin. Affected individuals usually have an obese body habitus and
CC       manifestations of a metabolic syndrome characterized by diabetes,
CC       insulin resistance, hypertension and hypertriglyceridemia. The disease
CC       results in long-term complications that affect the eyes, kidneys,
CC       nerves, and blood vessels. {ECO:0000269|PubMed:15265369,
CC       ECO:0000269|PubMed:7733935}. Note=The gene represented in this entry
CC       may be involved in disease pathogenesis.
CC   -!- SIMILARITY: Belongs to the complex I subunit 1 family. {ECO:0000305}.
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DR   EMBL; V00662; CAA24026.1; -; Genomic_DNA.
DR   EMBL; J01415; AAB58943.1; -; Genomic_DNA.
DR   EMBL; D38112; BAA07290.1; -; Genomic_DNA.
DR   EMBL; AY339402; AAP89036.1; -; Genomic_DNA.
DR   EMBL; AY339403; AAP89049.1; -; Genomic_DNA.
DR   EMBL; AY339404; AAP89062.1; -; Genomic_DNA.
DR   EMBL; AY339405; AAP89075.1; -; Genomic_DNA.
DR   EMBL; AY339406; AAP89088.1; -; Genomic_DNA.
DR   EMBL; AY339407; AAP89101.1; -; Genomic_DNA.
DR   EMBL; AY339408; AAP89114.1; -; Genomic_DNA.
DR   EMBL; AY339409; AAP89127.1; -; Genomic_DNA.
DR   EMBL; AY339410; AAP89140.1; -; Genomic_DNA.
DR   EMBL; AY339411; AAP89153.1; -; Genomic_DNA.
DR   EMBL; AY339412; AAP89166.1; -; Genomic_DNA.
DR   EMBL; AY339413; AAP89179.1; -; Genomic_DNA.
DR   EMBL; AY339414; AAP89192.1; -; Genomic_DNA.
DR   EMBL; AY339415; AAP89205.1; -; Genomic_DNA.
DR   EMBL; AY339416; AAP89218.1; -; Genomic_DNA.
DR   EMBL; AY339417; AAP89231.1; -; Genomic_DNA.
DR   EMBL; AY339418; AAP89244.1; -; Genomic_DNA.
DR   EMBL; AY339419; AAP89257.1; -; Genomic_DNA.
DR   EMBL; AY339420; AAP89270.1; -; Genomic_DNA.
DR   EMBL; AY339421; AAP89283.1; -; Genomic_DNA.
DR   EMBL; AY339422; AAP89296.1; -; Genomic_DNA.
DR   EMBL; AY339423; AAP89309.1; -; Genomic_DNA.
DR   EMBL; AY339424; AAP89322.1; -; Genomic_DNA.
DR   EMBL; AY339425; AAP89335.1; -; Genomic_DNA.
DR   EMBL; AY339426; AAP89348.1; -; Genomic_DNA.
DR   EMBL; AY339427; AAP89361.1; -; Genomic_DNA.
DR   EMBL; AY339428; AAP89374.1; -; Genomic_DNA.
DR   EMBL; AY339429; AAP89387.1; -; Genomic_DNA.
DR   EMBL; AY339430; AAP89400.1; -; Genomic_DNA.
DR   EMBL; AY339431; AAP89413.1; -; Genomic_DNA.
DR   EMBL; AY339432; AAP89426.1; -; Genomic_DNA.
DR   EMBL; AY339433; AAP89439.1; -; Genomic_DNA.
DR   EMBL; AY339434; AAP89452.1; -; Genomic_DNA.
DR   EMBL; AY339435; AAP89465.1; -; Genomic_DNA.
DR   EMBL; AY339436; AAP89478.1; -; Genomic_DNA.
DR   EMBL; AY339437; AAP89491.1; -; Genomic_DNA.
DR   EMBL; AY339438; AAP89504.1; -; Genomic_DNA.
DR   EMBL; AY339439; AAP89517.1; -; Genomic_DNA.
DR   EMBL; AY339440; AAP89530.1; -; Genomic_DNA.
DR   EMBL; AY339441; AAP89543.1; -; Genomic_DNA.
DR   EMBL; AY339442; AAP89556.1; -; Genomic_DNA.
DR   EMBL; AY339443; AAP89569.1; -; Genomic_DNA.
DR   EMBL; AY339444; AAP89582.1; -; Genomic_DNA.
DR   EMBL; AY339445; AAP89595.1; -; Genomic_DNA.
DR   EMBL; AY339446; AAP89608.1; -; Genomic_DNA.
DR   EMBL; AY339447; AAP89621.1; -; Genomic_DNA.
DR   EMBL; AY339448; AAP89634.1; -; Genomic_DNA.
DR   EMBL; AY339449; AAP89647.1; -; Genomic_DNA.
DR   EMBL; AY339450; AAP89660.1; -; Genomic_DNA.
DR   EMBL; AY339451; AAP89673.1; -; Genomic_DNA.
DR   EMBL; AY339452; AAP89686.1; -; Genomic_DNA.
DR   EMBL; AY339453; AAP89699.1; -; Genomic_DNA.
DR   EMBL; AY339454; AAP89712.1; -; Genomic_DNA.
DR   EMBL; AY339455; AAP89725.1; -; Genomic_DNA.
DR   EMBL; AY339456; AAP89738.1; -; Genomic_DNA.
DR   EMBL; AY339457; AAP89751.1; -; Genomic_DNA.
DR   EMBL; AY339458; AAP89764.1; -; Genomic_DNA.
DR   EMBL; AY339459; AAP89777.1; -; Genomic_DNA.
DR   EMBL; AY339498; AAP90284.1; -; Genomic_DNA.
DR   EMBL; AY339499; AAP90297.1; -; Genomic_DNA.
DR   EMBL; AY339500; AAP90310.1; -; Genomic_DNA.
DR   EMBL; AY339501; AAP90323.1; -; Genomic_DNA.
DR   EMBL; AY339502; AAP90336.1; -; Genomic_DNA.
DR   EMBL; AY339503; AAP90349.1; -; Genomic_DNA.
DR   EMBL; AY339504; AAP90362.1; -; Genomic_DNA.
DR   EMBL; AY339505; AAP90375.1; -; Genomic_DNA.
DR   EMBL; AY339506; AAP90388.1; -; Genomic_DNA.
DR   EMBL; AY339507; AAP90401.1; -; Genomic_DNA.
DR   EMBL; AY339508; AAP90414.1; -; Genomic_DNA.
DR   EMBL; AY339509; AAP90427.1; -; Genomic_DNA.
DR   EMBL; AY339510; AAP90440.1; -; Genomic_DNA.
DR   EMBL; AY339511; AAP90453.1; -; Genomic_DNA.
DR   EMBL; AY339512; AAP90466.1; -; Genomic_DNA.
DR   EMBL; AY339513; AAP90479.1; -; Genomic_DNA.
DR   EMBL; AY339514; AAP90492.1; -; Genomic_DNA.
DR   EMBL; AY339515; AAP90505.1; -; Genomic_DNA.
DR   EMBL; AY339516; AAP90518.1; -; Genomic_DNA.
DR   EMBL; AY339517; AAP90531.1; -; Genomic_DNA.
DR   EMBL; AY339518; AAP90544.1; -; Genomic_DNA.
DR   EMBL; AY339519; AAP90557.1; -; Genomic_DNA.
DR   EMBL; AY339520; AAP90570.1; -; Genomic_DNA.
DR   EMBL; AY339521; AAP90583.1; -; Genomic_DNA.
DR   EMBL; AY339522; AAP90596.1; -; Genomic_DNA.
DR   EMBL; AY339523; AAP90609.1; -; Genomic_DNA.
DR   EMBL; AY339524; AAP90622.1; -; Genomic_DNA.
DR   EMBL; AY339525; AAP90635.1; -; Genomic_DNA.
DR   EMBL; AY339526; AAP90648.1; -; Genomic_DNA.
DR   EMBL; AY339527; AAP90661.1; -; Genomic_DNA.
DR   EMBL; AY339528; AAP90674.1; -; Genomic_DNA.
DR   EMBL; AY339529; AAP90687.1; -; Genomic_DNA.
DR   EMBL; AY339530; AAP90700.1; -; Genomic_DNA.
DR   EMBL; AY339531; AAP90713.1; -; Genomic_DNA.
DR   EMBL; AY339532; AAP90726.1; -; Genomic_DNA.
DR   EMBL; AY339533; AAP90739.1; -; Genomic_DNA.
DR   EMBL; AY339534; AAP90752.1; -; Genomic_DNA.
DR   EMBL; AY339535; AAP90765.1; -; Genomic_DNA.
DR   EMBL; AY339536; AAP90778.1; -; Genomic_DNA.
DR   EMBL; AY339537; AAP90791.1; -; Genomic_DNA.
DR   EMBL; AY339538; AAP90804.1; -; Genomic_DNA.
DR   EMBL; AY339539; AAP90817.1; -; Genomic_DNA.
DR   EMBL; AY339540; AAP90830.1; -; Genomic_DNA.
DR   EMBL; AY339541; AAP90843.1; -; Genomic_DNA.
DR   EMBL; AY339542; AAP90856.1; -; Genomic_DNA.
DR   EMBL; AY339543; AAP90869.1; -; Genomic_DNA.
DR   EMBL; AY339544; AAP90882.1; -; Genomic_DNA.
DR   EMBL; AY339546; AAP90908.1; -; Genomic_DNA.
DR   EMBL; AY339547; AAP90921.1; -; Genomic_DNA.
DR   EMBL; AY339548; AAP90934.1; -; Genomic_DNA.
DR   EMBL; AY339549; AAP90947.1; -; Genomic_DNA.
DR   EMBL; AY339550; AAP90960.1; -; Genomic_DNA.
DR   EMBL; AY339551; AAP90973.1; -; Genomic_DNA.
DR   EMBL; AY339552; AAP90986.1; -; Genomic_DNA.
DR   EMBL; AY339553; AAP90999.1; -; Genomic_DNA.
DR   EMBL; AY339554; AAP91012.1; -; Genomic_DNA.
DR   EMBL; AY339555; AAP91025.1; -; Genomic_DNA.
DR   EMBL; AY339556; AAP91038.1; -; Genomic_DNA.
DR   EMBL; AY339557; AAP91051.1; -; Genomic_DNA.
DR   EMBL; AY339558; AAP91064.1; -; Genomic_DNA.
DR   EMBL; AY339559; AAP91077.1; -; Genomic_DNA.
DR   EMBL; AY339560; AAP91090.1; -; Genomic_DNA.
DR   EMBL; AY339561; AAP91103.1; -; Genomic_DNA.
DR   EMBL; AY339562; AAP91116.1; -; Genomic_DNA.
DR   EMBL; AY339563; AAP91129.1; -; Genomic_DNA.
DR   EMBL; AY339564; AAP91142.1; -; Genomic_DNA.
DR   EMBL; AY339565; AAP91155.1; -; Genomic_DNA.
DR   EMBL; AF346963; AAK17207.1; -; Genomic_DNA.
DR   EMBL; AF346964; AAK17220.1; -; Genomic_DNA.
DR   EMBL; AF346965; AAK17233.1; -; Genomic_DNA.
DR   EMBL; AF346966; AAK17246.1; -; Genomic_DNA.
DR   EMBL; AF346967; AAK17259.1; -; Genomic_DNA.
DR   EMBL; AF346970; AAK17298.1; -; Genomic_DNA.
DR   EMBL; AF346971; AAK17311.1; -; Genomic_DNA.
DR   EMBL; AF346974; AAK17350.1; -; Genomic_DNA.
DR   EMBL; AF346975; AAK17363.1; -; Genomic_DNA.
DR   EMBL; AF346976; AAK17376.1; -; Genomic_DNA.
DR   EMBL; AF346977; AAK17389.1; -; Genomic_DNA.
DR   EMBL; AF346978; AAK17402.1; -; Genomic_DNA.
DR   EMBL; AF346979; AAK17415.1; -; Genomic_DNA.
DR   EMBL; AF346980; AAK17428.1; -; Genomic_DNA.
DR   EMBL; AF346981; AAK17441.1; -; Genomic_DNA.
DR   EMBL; AF346984; AAK17480.1; -; Genomic_DNA.
DR   EMBL; AF346988; AAK17532.1; -; Genomic_DNA.
DR   EMBL; AF346989; AAK17545.1; -; Genomic_DNA.
DR   EMBL; AF346990; AAK17558.1; -; Genomic_DNA.
DR   EMBL; AF346991; AAK17571.1; -; Genomic_DNA.
DR   EMBL; AF346992; AAK17584.1; -; Genomic_DNA.
DR   EMBL; AF346993; AAK17597.1; -; Genomic_DNA.
DR   EMBL; AF346994; AAK17610.1; -; Genomic_DNA.
DR   EMBL; AF346995; AAK17623.1; -; Genomic_DNA.
DR   EMBL; AF346998; AAK17662.1; -; Genomic_DNA.
DR   EMBL; AF346999; AAK17675.1; -; Genomic_DNA.
DR   EMBL; AF347000; AAK17688.1; -; Genomic_DNA.
DR   EMBL; AF347002; AAK17714.1; -; Genomic_DNA.
DR   EMBL; AF347003; AAK17727.1; -; Genomic_DNA.
DR   EMBL; AF347004; AAK17740.1; -; Genomic_DNA.
DR   EMBL; AF347005; AAK17753.1; -; Genomic_DNA.
DR   EMBL; AF347006; AAK17766.1; -; Genomic_DNA.
DR   EMBL; AF347007; AAK17779.1; -; Genomic_DNA.
DR   EMBL; AF347008; AAK17792.1; -; Genomic_DNA.
DR   EMBL; AF347009; AAK17805.1; -; Genomic_DNA.
DR   EMBL; AF347011; AAK17831.1; -; Genomic_DNA.
DR   EMBL; AF347012; AAK17844.1; -; Genomic_DNA.
DR   EMBL; AF347013; AAK17857.1; -; Genomic_DNA.
DR   EMBL; AF347015; AAK17883.1; -; Genomic_DNA.
DR   EMBL; AY289051; AAP47880.1; -; Genomic_DNA.
DR   EMBL; AY289052; AAP47893.1; -; Genomic_DNA.
DR   EMBL; AY289053; AAP47906.1; -; Genomic_DNA.
DR   EMBL; AY289054; AAP47919.1; -; Genomic_DNA.
DR   EMBL; AY289055; AAP47932.1; -; Genomic_DNA.
DR   EMBL; AY289056; AAP47945.1; -; Genomic_DNA.
DR   EMBL; AY289057; AAP47958.1; -; Genomic_DNA.
DR   EMBL; AY289058; AAP47971.1; -; Genomic_DNA.
DR   EMBL; AY289059; AAP47984.1; -; Genomic_DNA.
DR   EMBL; AY289063; AAP48036.1; -; Genomic_DNA.
DR   EMBL; AY289064; AAP48049.1; -; Genomic_DNA.
DR   EMBL; AY289065; AAP48062.1; -; Genomic_DNA.
DR   EMBL; AY289066; AAP48075.1; -; Genomic_DNA.
DR   EMBL; AY289067; AAP48088.1; -; Genomic_DNA.
DR   EMBL; AY289068; AAP48101.1; -; Genomic_DNA.
DR   EMBL; AY289069; AAP48114.1; -; Genomic_DNA.
DR   EMBL; AY289070; AAP48127.1; -; Genomic_DNA.
DR   EMBL; AY289071; AAP48140.1; -; Genomic_DNA.
DR   EMBL; AY289072; AAP48153.1; -; Genomic_DNA.
DR   EMBL; AY289073; AAP48166.1; -; Genomic_DNA.
DR   EMBL; AY289074; AAP48179.1; -; Genomic_DNA.
DR   EMBL; AY289075; AAP48192.1; -; Genomic_DNA.
DR   EMBL; AY289076; AAP48205.1; -; Genomic_DNA.
DR   EMBL; AY289077; AAP48218.1; -; Genomic_DNA.
DR   EMBL; AY289078; AAP48231.1; -; Genomic_DNA.
DR   EMBL; AY289079; AAP48244.1; -; Genomic_DNA.
DR   EMBL; AY289080; AAP48257.1; -; Genomic_DNA.
DR   EMBL; AY289083; AAP48296.1; -; Genomic_DNA.
DR   EMBL; AY289084; AAP48309.1; -; Genomic_DNA.
DR   EMBL; AY289085; AAP48322.1; -; Genomic_DNA.
DR   EMBL; AY289086; AAP48335.1; -; Genomic_DNA.
DR   EMBL; AY289087; AAP48348.1; -; Genomic_DNA.
DR   EMBL; AY289088; AAP48361.1; -; Genomic_DNA.
DR   EMBL; AY289089; AAP48374.1; -; Genomic_DNA.
DR   EMBL; AY289090; AAP48387.1; -; Genomic_DNA.
DR   EMBL; AY289091; AAP48400.1; -; Genomic_DNA.
DR   EMBL; AY289092; AAP48413.1; -; Genomic_DNA.
DR   EMBL; AY289094; AAP48438.1; -; Genomic_DNA.
DR   EMBL; AY289095; AAP48451.1; -; Genomic_DNA.
DR   EMBL; AY289096; AAP48464.1; -; Genomic_DNA.
DR   EMBL; AY289099; AAP48503.1; -; Genomic_DNA.
DR   EMBL; AY289100; AAP48516.1; -; Genomic_DNA.
DR   EMBL; AY289101; AAP48529.1; -; Genomic_DNA.
DR   EMBL; AY289102; AAP48542.1; -; Genomic_DNA.
DR   EMBL; AY495090; AAR92496.1; -; Genomic_DNA.
DR   EMBL; AY495091; AAR92509.1; -; Genomic_DNA.
DR   EMBL; AY495092; AAR92522.1; -; Genomic_DNA.
DR   EMBL; AY495093; AAR92535.1; -; Genomic_DNA.
DR   EMBL; AY495094; AAR92548.1; -; Genomic_DNA.
DR   EMBL; AY495096; AAR92574.1; -; Genomic_DNA.
DR   EMBL; AY495097; AAR92587.1; -; Genomic_DNA.
DR   EMBL; AY495098; AAR92600.1; -; Genomic_DNA.
DR   EMBL; AY495099; AAR92613.1; -; Genomic_DNA.
DR   EMBL; AY495100; AAR92626.1; -; Genomic_DNA.
DR   EMBL; AY495102; AAR92652.1; -; Genomic_DNA.
DR   EMBL; AY495103; AAR92665.1; -; Genomic_DNA.
DR   EMBL; AY495104; AAR92678.1; -; Genomic_DNA.
DR   EMBL; AY495105; AAR92691.1; -; Genomic_DNA.
DR   EMBL; AY495106; AAR92704.1; -; Genomic_DNA.
DR   EMBL; AY495107; AAR92717.1; -; Genomic_DNA.
DR   EMBL; AY495108; AAR92730.1; -; Genomic_DNA.
DR   EMBL; AY495109; AAR92743.1; -; Genomic_DNA.
DR   EMBL; AY495110; AAR92756.1; -; Genomic_DNA.
DR   EMBL; AY495112; AAR92782.1; -; Genomic_DNA.
DR   EMBL; AY495113; AAR92795.1; -; Genomic_DNA.
DR   EMBL; AY495114; AAR92808.1; -; Genomic_DNA.
DR   EMBL; AY495115; AAR92821.1; -; Genomic_DNA.
DR   EMBL; AY495117; AAR92847.1; -; Genomic_DNA.
DR   EMBL; AY495118; AAR92860.1; -; Genomic_DNA.
DR   EMBL; AY495119; AAR92873.1; -; Genomic_DNA.
DR   EMBL; AY495120; AAR92886.1; -; Genomic_DNA.
DR   EMBL; AY495121; AAR92899.1; -; Genomic_DNA.
DR   EMBL; AY495122; AAR92912.1; -; Genomic_DNA.
DR   EMBL; AY495124; AAR92938.1; -; Genomic_DNA.
DR   EMBL; AY495126; AAR92964.1; -; Genomic_DNA.
DR   EMBL; AY495127; AAR92977.1; -; Genomic_DNA.
DR   EMBL; AY495128; AAR92990.1; -; Genomic_DNA.
DR   EMBL; AY495129; AAR93003.1; -; Genomic_DNA.
DR   EMBL; AY495130; AAR93016.1; -; Genomic_DNA.
DR   EMBL; AY495132; AAR93042.1; -; Genomic_DNA.
DR   EMBL; AY495133; AAR93055.1; -; Genomic_DNA.
DR   EMBL; AY495135; AAR93081.1; -; Genomic_DNA.
DR   EMBL; AY495136; AAR93094.1; -; Genomic_DNA.
DR   EMBL; AY495137; AAR93107.1; -; Genomic_DNA.
DR   EMBL; AY495138; AAR93120.1; -; Genomic_DNA.
DR   EMBL; AY495139; AAR93133.1; -; Genomic_DNA.
DR   EMBL; AY495140; AAR93146.1; -; Genomic_DNA.
DR   EMBL; AY495141; AAR93159.1; -; Genomic_DNA.
DR   EMBL; AY495142; AAR93172.1; -; Genomic_DNA.
DR   EMBL; AY495143; AAR93185.1; -; Genomic_DNA.
DR   EMBL; AY495144; AAR93198.1; -; Genomic_DNA.
DR   EMBL; AY495145; AAR93211.1; -; Genomic_DNA.
DR   EMBL; AY495146; AAR93224.1; -; Genomic_DNA.
DR   EMBL; AY495147; AAR93237.1; -; Genomic_DNA.
DR   EMBL; AY495148; AAR93250.1; -; Genomic_DNA.
DR   EMBL; AY495149; AAR93263.1; -; Genomic_DNA.
DR   EMBL; AY495150; AAR93276.1; -; Genomic_DNA.
DR   EMBL; AY495151; AAR93289.1; -; Genomic_DNA.
DR   EMBL; AY495152; AAR93302.1; -; Genomic_DNA.
DR   EMBL; AY495153; AAR93315.1; -; Genomic_DNA.
DR   EMBL; AY495154; AAR93328.1; -; Genomic_DNA.
DR   EMBL; AY495155; AAR93341.1; -; Genomic_DNA.
DR   EMBL; AY495156; AAR93354.1; -; Genomic_DNA.
DR   EMBL; AY495157; AAR93367.1; -; Genomic_DNA.
DR   EMBL; AY495158; AAR93380.1; -; Genomic_DNA.
DR   EMBL; AY495159; AAR93393.1; -; Genomic_DNA.
DR   EMBL; AY495160; AAR93406.1; -; Genomic_DNA.
DR   EMBL; AY495161; AAR93419.1; -; Genomic_DNA.
DR   EMBL; AY495162; AAR93432.1; -; Genomic_DNA.
DR   EMBL; AY495163; AAR93445.1; -; Genomic_DNA.
DR   EMBL; AY495164; AAR93458.1; -; Genomic_DNA.
DR   EMBL; AY495165; AAR93471.1; -; Genomic_DNA.
DR   EMBL; AY495166; AAR93484.1; -; Genomic_DNA.
DR   EMBL; AY495167; AAR93497.1; -; Genomic_DNA.
DR   EMBL; AY495168; AAR93510.1; -; Genomic_DNA.
DR   EMBL; AY495169; AAR93523.1; -; Genomic_DNA.
DR   EMBL; AY495170; AAR93536.1; -; Genomic_DNA.
DR   EMBL; AY495171; AAR93549.1; -; Genomic_DNA.
DR   EMBL; AY495172; AAR93562.1; -; Genomic_DNA.
DR   EMBL; AY495173; AAR93575.1; -; Genomic_DNA.
DR   EMBL; AY495174; AAR93588.1; -; Genomic_DNA.
DR   EMBL; AY495175; AAR93601.1; -; Genomic_DNA.
DR   EMBL; AY495176; AAR93614.1; -; Genomic_DNA.
DR   EMBL; AY495177; AAR93627.1; -; Genomic_DNA.
DR   EMBL; AY495180; AAR93666.1; -; Genomic_DNA.
DR   EMBL; AY495185; AAR93731.1; -; Genomic_DNA.
DR   EMBL; AY495187; AAR93757.1; -; Genomic_DNA.
DR   EMBL; AY495188; AAR93770.1; -; Genomic_DNA.
DR   EMBL; AY495189; AAR93783.1; -; Genomic_DNA.
DR   EMBL; AY495190; AAR93796.1; -; Genomic_DNA.
DR   EMBL; AY495191; AAR93809.1; -; Genomic_DNA.
DR   EMBL; AY495192; AAR93822.1; -; Genomic_DNA.
DR   EMBL; AY495193; AAR93835.1; -; Genomic_DNA.
DR   EMBL; AY495194; AAR93848.1; -; Genomic_DNA.
DR   EMBL; AY495239; AAR94433.1; -; Genomic_DNA.
DR   EMBL; AY495240; AAR94446.1; -; Genomic_DNA.
DR   EMBL; AY495241; AAR94459.1; -; Genomic_DNA.
DR   EMBL; AY495242; AAR94472.1; -; Genomic_DNA.
DR   EMBL; AY495243; AAR94485.1; -; Genomic_DNA.
DR   EMBL; AY495244; AAR94498.1; -; Genomic_DNA.
DR   EMBL; AY495245; AAR94511.1; -; Genomic_DNA.
DR   EMBL; AY495246; AAR94524.1; -; Genomic_DNA.
DR   EMBL; AY495247; AAR94537.1; -; Genomic_DNA.
DR   EMBL; AY495248; AAR94550.1; -; Genomic_DNA.
DR   EMBL; AY495249; AAR94563.1; -; Genomic_DNA.
DR   EMBL; AY495250; AAR94576.1; -; Genomic_DNA.
DR   EMBL; AY495251; AAR94589.1; -; Genomic_DNA.
DR   EMBL; AY495252; AAR94602.1; -; Genomic_DNA.
DR   EMBL; AY495253; AAR94615.1; -; Genomic_DNA.
DR   EMBL; AY495254; AAR94628.1; -; Genomic_DNA.
DR   EMBL; AY495255; AAR94641.1; -; Genomic_DNA.
DR   EMBL; AY495257; AAR94667.1; -; Genomic_DNA.
DR   EMBL; AY495258; AAR94680.1; -; Genomic_DNA.
DR   EMBL; AY495259; AAR94693.1; -; Genomic_DNA.
DR   EMBL; AY495260; AAR94706.1; -; Genomic_DNA.
DR   EMBL; AY495261; AAR94719.1; -; Genomic_DNA.
DR   EMBL; AY495262; AAR94732.1; -; Genomic_DNA.
DR   EMBL; AY495263; AAR94745.1; -; Genomic_DNA.
DR   EMBL; AY495264; AAR94758.1; -; Genomic_DNA.
DR   EMBL; AY495265; AAR94771.1; -; Genomic_DNA.
DR   EMBL; AY495306; AAR95304.1; -; Genomic_DNA.
DR   EMBL; AY495307; AAR95317.1; -; Genomic_DNA.
DR   EMBL; AY495308; AAR95330.1; -; Genomic_DNA.
DR   EMBL; AY495309; AAR95343.1; -; Genomic_DNA.
DR   EMBL; AY495310; AAR95356.1; -; Genomic_DNA.
DR   EMBL; AY495311; AAR95369.1; -; Genomic_DNA.
DR   EMBL; AY495312; AAR95382.1; -; Genomic_DNA.
DR   EMBL; AY495313; AAR95395.1; -; Genomic_DNA.
DR   EMBL; AY495314; AAR95408.1; -; Genomic_DNA.
DR   EMBL; AY495315; AAR95421.1; -; Genomic_DNA.
DR   EMBL; AY495316; AAR95434.1; -; Genomic_DNA.
DR   EMBL; AY495317; AAR95447.1; -; Genomic_DNA.
DR   EMBL; AY495318; AAR95460.1; -; Genomic_DNA.
DR   EMBL; AY495319; AAR95473.1; -; Genomic_DNA.
DR   EMBL; AY495320; AAR95486.1; -; Genomic_DNA.
DR   EMBL; AY495321; AAR95499.1; -; Genomic_DNA.
DR   EMBL; AY495322; AAR95512.1; -; Genomic_DNA.
DR   EMBL; AY495323; AAR95525.1; -; Genomic_DNA.
DR   EMBL; AY495324; AAR95538.1; -; Genomic_DNA.
DR   EMBL; AY495325; AAR95551.1; -; Genomic_DNA.
DR   EMBL; AY495326; AAR95564.1; -; Genomic_DNA.
DR   EMBL; AY495327; AAR95577.1; -; Genomic_DNA.
DR   EMBL; AY495328; AAR95590.1; -; Genomic_DNA.
DR   EMBL; AY495329; AAR95603.1; -; Genomic_DNA.
DR   EMBL; AY495330; AAR95616.1; -; Genomic_DNA.
DR   EMBL; AY495256; AAR94654.1; -; Genomic_DNA.
DR   EMBL; FJ236980; ACI31490.1; -; Genomic_DNA.
DR   EMBL; M10546; AAA65501.1; -; Genomic_DNA.
DR   PIR; A00407; DNHUN1.
DR   RefSeq; YP_003024026.1; NC_012920.1.
DR   PDB; 5XTC; EM; 3.70 A; s=1-318.
DR   PDB; 5XTD; EM; 3.70 A; s=1-318.
DR   PDB; 9CWT; EM; 3.44 A; s=1-318.
DR   PDBsum; 5XTC; -.
DR   PDBsum; 5XTD; -.
DR   PDBsum; 9CWT; -.
DR   AlphaFoldDB; P03886; -.
DR   EMDB; EMD-45974; -.
DR   SMR; P03886; -.
DR   BioGRID; 110631; 73.
DR   ComplexPortal; CPX-577; Mitochondrial respiratory chain complex I.
DR   CORUM; P03886; -.
DR   FunCoup; P03886; 618.
DR   IntAct; P03886; 58.
DR   MINT; P03886; -.
DR   STRING; 9606.ENSP00000354687; -.
DR   BindingDB; P03886; -.
DR   ChEMBL; CHEMBL2363065; -.
DR   DrugBank; DB01189; Desflurane.
DR   DrugBank; DB01159; Halothane.
DR   DrugBank; DB00753; Isoflurane.
DR   DrugBank; DB01028; Methoxyflurane.
DR   DrugBank; DB04464; N-Formylmethionine.
DR   DrugBank; DB00157; NADH.
DR   DrugBank; DB12695; Phenethyl Isothiocyanate.
DR   DrugBank; DB01236; Sevoflurane.
DR   DrugCentral; P03886; -.
DR   GlyGen; P03886; 1 site, 1 O-linked glycan (1 site).
DR   SwissPalm; P03886; -.
DR   BioMuta; MT-ND1; -.
DR   DMDM; 128641; -.
DR   jPOST; P03886; -.
DR   MassIVE; P03886; -.
DR   PaxDb; 9606-ENSP00000354687; -.
DR   PeptideAtlas; P03886; -.
DR   ProteomicsDB; 51611; -.
DR   Pumba; P03886; -.
DR   Antibodypedia; 35355; 237 antibodies from 29 providers.
DR   DNASU; 4535; -.
DR   Ensembl; ENST00000361390.2; ENSP00000354687.2; ENSG00000198888.2.
DR   GeneID; 4535; -.
DR   KEGG; hsa:4535; -.
DR   AGR; HGNC:7455; -.
DR   ClinPGx; PA31259; -.
DR   CTD; 4535; -.
DR   DisGeNET; 4535; -.
DR   GeneCards; MT-ND1; -.
DR   GeneReviews; MT-ND1; -.
DR   HGNC; HGNC:7455; MT-ND1.
DR   HPA; ENSG00000198888; Tissue enhanced (heart).
DR   MalaCards; MT-ND1; -.
DR   MIM; 125853; phenotype.
DR   MIM; 502500; phenotype.
DR   MIM; 516000; gene.
DR   MIM; 535000; phenotype.
DR   MIM; 540000; phenotype.
DR   OpenTargets; ENSG00000198888; -.
DR   Orphanet; 2609; Isolated complex I deficiency.
DR   Orphanet; 104; Leber hereditary optic neuropathy.
DR   Orphanet; 550; MELAS.
DR   Orphanet; 255210; Mitochondrial DNA-associated Leigh syndrome.
DR   VEuPathDB; HostDB:ENSG00000198888; -.
DR   eggNOG; KOG4770; Eukaryota.
DR   GeneTree; ENSGT00390000006621; -.
DR   HOGENOM; CLU_015134_0_1_1; -.
DR   InParanoid; P03886; -.
DR   OMA; WSGWASN; -.
DR   PAN-GO; P03886; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P03886; -.
DR   BioCyc; MetaCyc:HS00030-MONOMER; -.
DR   PathwayCommons; P03886; -.
DR   Reactome; R-HSA-5419276; Mitochondrial translation termination.
DR   Reactome; R-HSA-611105; Respiratory electron transport.
DR   Reactome; R-HSA-6799198; Complex I biogenesis.
DR   Reactome; R-HSA-9837999; Mitochondrial protein degradation.
DR   SignaLink; P03886; -.
DR   SIGNOR; P03886; -.
DR   Agora; ENSG00000198888; -.
DR   BioGRID-ORCS; 4535; 0 hits in 3 CRISPR screens.
DR   ChiTaRS; ND1; human.
DR   GeneWiki; MT-ND1; -.
DR   GenomeRNAi; 4535; -.
DR   Pharos; P03886; Tclin.
DR   PRO; PR:P03886; -.
DR   Proteomes; UP000005640; Mitochondrion MT.
DR   RNAct; P03886; protein.
DR   Bgee; ENSG00000198888; Expressed in subcutaneous adipose tissue and 96 other cell types or tissues.
DR   ExpressionAtlas; P03886; baseline and differential.
DR   GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IDA:ComplexPortal.
DR   GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; HTP:FlyBase.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0045271; C:respiratory chain complex I; IDA:UniProtKB.
DR   GO; GO:0008137; F:NADH dehydrogenase (ubiquinone) activity; IMP:UniProtKB.
DR   GO; GO:0009060; P:aerobic respiration; IBA:GO_Central.
DR   GO; GO:0006120; P:mitochondrial electron transport, NADH to ubiquinone; IMP:UniProtKB.
DR   GO; GO:0032981; P:mitochondrial respiratory chain complex I assembly; IMP:UniProtKB.
DR   GO; GO:0042776; P:proton motive force-driven mitochondrial ATP synthesis; NAS:ComplexPortal.
DR   GO; GO:0033194; P:response to hydroperoxide; IEA:Ensembl.
DR   GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR   HAMAP; MF_01350; NDH1_NuoH; 1.
DR   InterPro; IPR001694; NADH_UbQ_OxRdtase_su1/FPO.
DR   InterPro; IPR018086; NADH_UbQ_OxRdtase_su1_CS.
DR   PANTHER; PTHR11432; NADH DEHYDROGENASE SUBUNIT 1; 1.
DR   PANTHER; PTHR11432:SF3; NADH-UBIQUINONE OXIDOREDUCTASE CHAIN 1; 1.
DR   Pfam; PF00146; NADHdh; 1.
DR   PROSITE; PS00667; COMPLEX1_ND1_1; 1.
DR   PROSITE; PS00668; COMPLEX1_ND1_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alzheimer disease; Amyloidosis; Diabetes mellitus;
KW   Disease variant; Electron transport; Epilepsy;
KW   Leber hereditary optic neuropathy; MELAS syndrome; Membrane; Mitochondrion;
KW   Mitochondrion inner membrane; NAD; Neurodegeneration;
KW   Primary mitochondrial disease; Proteomics identification;
KW   Reference proteome; Respiratory chain; Translocase; Transmembrane;
KW   Transmembrane helix; Transport; Ubiquinone.
FT   CHAIN           1..318
FT                   /note="NADH-ubiquinone oxidoreductase chain 1"
FT                   /id="PRO_0000117414"
FT   TRANSMEM        2..22
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        68..88
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        100..120
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        146..166
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        171..191
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        231..251
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        253..273
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        294..314
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   VARIANT         4
FT                   /note="A -> T (might contribute to non-insulin dependent
FT                   diabetes mellitus susceptibility in some populations;
FT                   dbSNP:rs2853516)"
FT                   /evidence="ECO:0000269|PubMed:7733935"
FT                   /id="VAR_004747"
FT   VARIANT         30
FT                   /note="Y -> C (in a patient with hypertrophic
FT                   cardiomyopathy and profound hearing loss;
FT                   dbSNP:rs1556422722)"
FT                   /evidence="ECO:0000269|PubMed:21144833"
FT                   /id="VAR_065195"
FT   VARIANT         30
FT                   /note="Y -> H (in LHON; uncertain significance; secondary
FT                   mutation; dbSNP:rs41460449)"
FT                   /evidence="ECO:0000269|PubMed:1417830"
FT                   /id="VAR_004748"
FT   VARIANT         31
FT                   /note="M -> T (in MELAS; dbSNP:rs201212638)"
FT                   /evidence="ECO:0000269|PubMed:8723687"
FT                   /id="VAR_004749"
FT   VARIANT         31
FT                   /note="M -> V (in AD-MT; may be associated with disease
FT                   susceptibility; dbSNP:rs199476120)"
FT                   /evidence="ECO:0000269|PubMed:8104867"
FT                   /id="VAR_004750"
FT   VARIANT         52
FT                   /note="A -> T (in LHON; primary mutation; medium severity;
FT                   some vision recovery; 80% reduction in rotenone-sensitive
FT                   and ubiquinone-dependent electron transfer activity,
FT                   whereas the proximal NADH dehydrogenase activity of the
FT                   complex is unaffected; dbSNP:rs199476118)"
FT                   /evidence="ECO:0000269|PubMed:1674640,
FT                   ECO:0000269|PubMed:1928099, ECO:0000269|PubMed:1959619"
FT                   /id="VAR_004751"
FT   VARIANT         87
FT                   /note="T -> A (in dbSNP:rs2854133)"
FT                   /evidence="ECO:0000269|PubMed:7530363"
FT                   /id="VAR_011346"
FT   VARIANT         168
FT                   /note="T -> A (in dbSNP:rs2854135)"
FT                   /evidence="ECO:0000269|PubMed:7530363"
FT                   /id="VAR_011347"
FT   VARIANT         205
FT                   /note="S -> P"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008587"
FT   VARIANT         214
FT                   /note="E -> K (found in a patient with epileptic
FT                   encephalopathy evolving to Lennox-Gastaut syndrome;
FT                   uncertain significance; dbSNP:rs199476123)"
FT                   /evidence="ECO:0000269|PubMed:24105702"
FT                   /id="VAR_073352"
FT   VARIANT         255
FT                   /note="Y -> C"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008588"
FT   VARIANT         277
FT                   /note="Y -> C (in dbSNP:rs199476121)"
FT                   /evidence="ECO:0000269|PubMed:2018041"
FT                   /id="VAR_004752"
FT   VARIANT         285
FT                   /note="L -> P (in LHON; uncertain significance; secondary
FT                   mutation; dbSNP:rs199476119)"
FT                   /evidence="ECO:0000269|PubMed:2018041"
FT                   /id="VAR_004753"
FT   VARIANT         288
FT                   /note="L -> P"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008589"
FT   VARIANT         304
FT                   /note="Y -> H (in LHON; uncertain significance; secondary
FT                   mutation; dbSNP:rs1599988)"
FT                   /evidence="ECO:0000269|PubMed:1900003"
FT                   /id="VAR_004754"
FT   CONFLICT        287
FT                   /note="H -> R (in Ref. 7; ACI31490)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   318 AA;  35661 MW;  2F771ACB95002591 CRC64;
     MPMANLLLLI VPILIAMAFL MLTERKILGY MQLRKGPNVV GPYGLLQPFA DAMKLFTKEP
     LKPATSTITL YITAPTLALT IALLLWTPLP MPNPLVNLNL GLLFILATSS LAVYSILWSG
     WASNSNYALI GALRAVAQTI SYEVTLAIIL LSTLLMSGSF NLSTLITTQE HLWLLLPSWP
     LAMMWFISTL AETNRTPFDL AEGESELVSG FNIEYAAGPF ALFFMAEYTN IIMMNTLTTT
     IFLGTTYDAL SPELYTTYFV TKTLLLTSLF LWIRTAYPRF RYDQLMHLLW KNFLPLTLAL
     LMWYVSMPIT ISSIPPQT
//
ID   NU2M_HUMAN              Reviewed;         347 AA.
AC   P03891; Q34769; Q9TGI0; Q9TGI1; Q9TGI2; Q9TGI3; Q9TGI4;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-1992, sequence version 2.
DT   28-JAN-2026, entry version 218.
DE   RecName: Full=NADH-ubiquinone oxidoreductase chain 2 {ECO:0000305};
DE            EC=7.1.1.2 {ECO:0000269|PubMed:16996290};
DE   AltName: Full=NADH dehydrogenase subunit 2;
GN   Name=MT-ND2 {ECO:0000312|HGNC:HGNC:7456}; Synonyms=MTND2, NADH2, ND2;
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 [LARGE SCALE GENOMIC DNA].
RX   PubMed=7219534; DOI=10.1038/290457a0;
RA   Anderson S., Bankier A.T., Barrell B.G., de Bruijn M.H.L., Coulson A.R.,
RA   Drouin J., Eperon I.C., Nierlich D.P., Roe B.A., Sanger F., Schreier P.H.,
RA   Smith A.J.H., Staden R., Young I.G.;
RT   "Sequence and organization of the human mitochondrial genome.";
RL   Nature 290:457-465(1981).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=6260957; DOI=10.1016/0022-2836(80)90196-5;
RA   Sanger F., Coulson A.R., Barrell B.G., Smith A.J.H., Roe B.A.;
RT   "Cloning in single-stranded bacteriophage as an aid to rapid DNA
RT   sequencing.";
RL   J. Mol. Biol. 143:161-178(1980).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-69; SER-88; ASP-150;
RP   MET-237; THR-265; VAL-265; THR-278 AND ALA-333.
RX   PubMed=9475751; DOI=10.1093/genetics/148.1.409;
RA   Wise C.A., Sraml M., Easteal S.;
RT   "Departure from neutrality at the mitochondrial NADH dehydrogenase subunit
RT   2 gene in humans, but not in chimpanzees.";
RL   Genetics 148:409-421(1998).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-43; LEU-325 AND
RP   THR-331.
RC   TISSUE=Placenta;
RX   PubMed=7530363; DOI=10.1073/pnas.92.2.532;
RA   Horai S., Hayasaka K., Kondo R., Tsugane K., Takahata N.;
RT   "Recent African origin of modern humans revealed by complete sequences of
RT   hominoid mitochondrial DNAs.";
RL   Proc. Natl. Acad. Sci. U.S.A. 92:532-536(1995).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=12949126; DOI=10.1093/molbev/msg230;
RA   Moilanen J.S., Finnila S., Majamaa K.;
RT   "Lineage-specific selection in human mtDNA: lack of polymorphisms in a
RT   segment of MTND5 gene in haplogroup J.";
RL   Mol. Biol. Evol. 20:2132-2142(2003).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=11130070; DOI=10.1038/35047064;
RA   Ingman M., Kaessmann H., Paeaebo S., Gyllensten U.;
RT   "Mitochondrial genome variation and the origin of modern humans.";
RL   Nature 408:708-713(2000).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=12840039; DOI=10.1101/gr.686603;
RA   Ingman M., Gyllensten U.;
RT   "Mitochondrial genome variation and evolutionary history of Australian and
RT   New Guinean aborigines.";
RL   Genome Res. 13:1600-1606(2003).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=14760490; DOI=10.1007/s00414-004-0427-6;
RA   Coble M.D., Just R.S., O'Callaghan J.E., Letmanyi I.H., Peterson C.T.,
RA   Irwin J.A., Parsons T.J.;
RT   "Single nucleotide polymorphisms over the entire mtDNA genome that increase
RT   the power of forensic testing in Caucasians.";
RL   Int. J. Legal Med. 118:137-146(2004).
RN   [9]
RP   IDENTIFICATION OF PROTEIN.
RX   PubMed=3921850; DOI=10.1038/314592a0;
RA   Chomyn A., Mariottini P., Cleeter M.W.J., Ragan C.I., Matsuno-Yagi A.,
RA   Hatefi Y., Doolittle R.F., Attardi G.;
RT   "Six unidentified reading frames of human mitochondrial DNA encode
RT   components of the respiratory-chain NADH dehydrogenase.";
RL   Nature 314:592-597(1985).
RN   [10]
RP   IDENTIFICATION IN THE NADH-UBIQUINONE OXIDOREDUCTASE COMPLEX, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=12611891; DOI=10.1074/jbc.c300064200;
RA   Murray J., Zhang B., Taylor S.W., Oglesbee D., Fahy E., Marusich M.F.,
RA   Ghosh S.S., Capaldi R.A.;
RT   "The subunit composition of the human NADH dehydrogenase obtained by rapid
RT   one-step immunopurification.";
RL   J. Biol. Chem. 278:13619-13622(2003).
RN   [11]
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   [12]
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   [13]
RP   INTERACTION WITH TMEM242.
RX   PubMed=33753518; DOI=10.1073/pnas.2100558118;
RA   Carroll J., He J., Ding S., Fearnley I.M., Walker J.E.;
RT   "TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase
RT   and interact with assembly factors for complex I.";
RL   Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021).
RN   [14]
RP   VARIANT LHON ASP-150.
RX   PubMed=1900003; DOI=10.1016/0006-291x(91)91567-v;
RA   Johns D.R., Berman J.;
RT   "Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's
RT   hereditary optic neuropathy.";
RL   Biochem. Biophys. Res. Commun. 174:1324-1330(1991).
RN   [15]
RP   VARIANTS LEU-42; ARG-63; ALA-119; PRO-148; SER-150; THR-159 AND ALA-185.
RX   PubMed=1757091; DOI=10.1007/bf00206061;
RA   Marzuki S., Noer A.S., Lertrit P., Thyagarajan D., Kapsa R.,
RA   Utthanaphol P., Byrne E.;
RT   "Normal variants of human mitochondrial DNA and translation products: the
RT   building of a reference data base.";
RL   Hum. Genet. 88:139-145(1991).
RN   [16]
RP   VARIANT LHON SER-259.
RX   PubMed=1732158; DOI=10.1093/genetics/130.1.163;
RA   Brown M.D., Voljavec A.S., Lott M.T., Torroni A., Yang C.C., Wallace D.C.;
RT   "Mitochondrial DNA complex I and III mutations associated with Leber's
RT   hereditary optic neuropathy.";
RL   Genetics 130:163-173(1992).
RN   [17]
RP   VARIANT AD-MT SER-331.
RX   PubMed=1370613; DOI=10.1016/s0006-291x(05)80136-6;
RA   Lin F.-H., Lin R., Wisniewski H.M., Hwang Y.-W., Grundke-Iqbal I.,
RA   Healy-Louie G., Iqbal K.;
RT   "Detection of point mutations in codon 331 of mitochondrial NADH
RT   dehydrogenase subunit 2 in Alzheimer's brains.";
RL   Biochem. Biophys. Res. Commun. 182:238-246(1992).
RN   [18]
RP   VARIANT THR-57.
RX   PubMed=9461455; DOI=10.1093/nar/26.4.967;
RA   Rieder M.J., Taylor S.L., Tobe V.O., Nickerson D.A.;
RT   "Automating the identification of DNA variations using quality-based
RT   fluorescence re-sequencing: analysis of the human mitochondrial genome.";
RL   Nucleic Acids Res. 26:967-973(1998).
RN   [19]
RP   VARIANT LS PRO-71, CHARACTERIZATION OF LS VARIANT PRO-71, FUNCTION, AND
RP   CATALYTIC ACTIVITY.
RX   PubMed=16996290; DOI=10.1016/j.ymgme.2006.08.003;
RA   Ugalde C., Hinttala R., Timal S., Smeets R., Rodenburg R.J., Uusimaa J.,
RA   van Heuvel L.P., Nijtmans L.G., Majamaa K., Smeitink J.A.;
RT   "Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh
RT   syndrome.";
RL   Mol. Genet. Metab. 90:10-14(2007).
CC   -!- FUNCTION: Core subunit of the mitochondrial membrane respiratory chain
CC       NADH dehydrogenase (Complex I) which catalyzes electron transfer from
CC       NADH through the respiratory chain, using ubiquinone as an electron
CC       acceptor (PubMed:16996290). Essential for the catalytic activity and
CC       assembly of complex I (PubMed:16996290). {ECO:0000269|PubMed:16996290}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4
CC         H(+)(out); Xref=Rhea:RHEA:29091, Rhea:RHEA-COMP:9565, Rhea:RHEA-
CC         COMP:9566, ChEBI:CHEBI:15378, ChEBI:CHEBI:16389, ChEBI:CHEBI:17976,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=7.1.1.2;
CC         Evidence={ECO:0000269|PubMed:16996290};
CC   -!- SUBUNIT: Core subunit of respiratory chain NADH dehydrogenase (Complex
CC       I) which is composed of 45 different subunits. Interacts with TMEM242
CC       (PubMed:33753518). {ECO:0000269|PubMed:12611891,
CC       ECO:0000269|PubMed:33753518}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC       {ECO:0000250|UniProtKB:P03892}; Multi-pass membrane protein
CC       {ECO:0000255}.
CC   -!- DISEASE: Leber hereditary optic neuropathy (LHON) [MIM:535000]: A
CC       maternally inherited form of Leber hereditary optic neuropathy, a
CC       mitochondrial disease resulting in bilateral painless loss of central
CC       vision due to selective degeneration of the retinal ganglion cells and
CC       their axons. The disorder shows incomplete penetrance and male
CC       predominance. Cardiac conduction defects and neurological defects have
CC       also been described in some LHON patients. LHON results from primary
CC       mitochondrial DNA mutations affecting the respiratory chain complexes.
CC       {ECO:0000269|PubMed:1732158, ECO:0000269|PubMed:1900003}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Alzheimer disease mitochondrial (AD-MT) [MIM:502500]:
CC       Alzheimer disease is a neurodegenerative disorder characterized by
CC       progressive dementia, loss of cognitive abilities, and deposition of
CC       fibrillar 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. {ECO:0000269|PubMed:1370613}.
CC       Note=Disease susceptibility may be associated with variants affecting
CC       the gene represented in this entry.
CC   -!- DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive
CC       neurodegenerative disorder characterized by the presence of focal,
CC       bilateral lesions in one or more areas of the central nervous system
CC       including the brainstem, thalamus, basal ganglia, cerebellum and spinal
CC       cord. Clinical features depend on which areas of the central nervous
CC       system are involved and include subacute onset of psychomotor
CC       retardation, hypotonia, ataxia, weakness, vision loss, eye movement
CC       abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:16996290}.
CC       Note=Disease susceptibility is associated with variants affecting the
CC       gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the complex I subunit 2 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAA65502.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR   EMBL; J01415; AAB58944.1; -; Genomic_DNA.
DR   EMBL; V00662; CAA24027.1; -; Genomic_DNA.
DR   EMBL; M10546; AAA65502.1; ALT_INIT; Genomic_DNA.
DR   EMBL; D38112; BAA07291.1; -; Genomic_DNA.
DR   EMBL; AF014882; AAC25441.1; -; Genomic_DNA.
DR   EMBL; AF014884; AAC25443.1; -; Genomic_DNA.
DR   EMBL; AF014885; AAC25444.1; -; Genomic_DNA.
DR   EMBL; AF014887; AAC25446.1; -; Genomic_DNA.
DR   EMBL; AF014889; AAC25448.1; -; Genomic_DNA.
DR   EMBL; AF014890; AAC25449.1; -; Genomic_DNA.
DR   EMBL; AF014891; AAC25450.1; -; Genomic_DNA.
DR   EMBL; AF014892; AAC25451.1; -; Genomic_DNA.
DR   EMBL; AF014895; AAC25454.1; -; Genomic_DNA.
DR   EMBL; AF014896; AAC25455.2; -; Genomic_DNA.
DR   EMBL; AF014897; AAC25456.1; -; Genomic_DNA.
DR   EMBL; AF014898; AAC25457.1; -; Genomic_DNA.
DR   EMBL; AF014899; AAC25458.2; -; Genomic_DNA.
DR   EMBL; AF014900; AAC25459.1; -; Genomic_DNA.
DR   EMBL; AF014901; AAC25460.1; -; Genomic_DNA.
DR   EMBL; AY339402; AAP89037.1; -; Genomic_DNA.
DR   EMBL; AY339403; AAP89050.1; -; Genomic_DNA.
DR   EMBL; AY339404; AAP89063.1; -; Genomic_DNA.
DR   EMBL; AY339405; AAP89076.1; -; Genomic_DNA.
DR   EMBL; AY339406; AAP89089.1; -; Genomic_DNA.
DR   EMBL; AY339407; AAP89102.1; -; Genomic_DNA.
DR   EMBL; AY339408; AAP89115.1; -; Genomic_DNA.
DR   EMBL; AY339409; AAP89128.1; -; Genomic_DNA.
DR   EMBL; AY339410; AAP89141.1; -; Genomic_DNA.
DR   EMBL; AY339411; AAP89154.1; -; Genomic_DNA.
DR   EMBL; AY339412; AAP89167.1; -; Genomic_DNA.
DR   EMBL; AY339413; AAP89180.1; -; Genomic_DNA.
DR   EMBL; AY339414; AAP89193.1; -; Genomic_DNA.
DR   EMBL; AY339415; AAP89206.1; -; Genomic_DNA.
DR   EMBL; AY339416; AAP89219.1; -; Genomic_DNA.
DR   EMBL; AY339417; AAP89232.1; -; Genomic_DNA.
DR   EMBL; AY339418; AAP89245.1; -; Genomic_DNA.
DR   EMBL; AY339419; AAP89258.1; -; Genomic_DNA.
DR   EMBL; AY339420; AAP89271.1; -; Genomic_DNA.
DR   EMBL; AY339421; AAP89284.1; -; Genomic_DNA.
DR   EMBL; AY339422; AAP89297.1; -; Genomic_DNA.
DR   EMBL; AY339423; AAP89310.1; -; Genomic_DNA.
DR   EMBL; AY339424; AAP89323.1; -; Genomic_DNA.
DR   EMBL; AY339425; AAP89336.1; -; Genomic_DNA.
DR   EMBL; AY339426; AAP89349.1; -; Genomic_DNA.
DR   EMBL; AY339427; AAP89362.1; -; Genomic_DNA.
DR   EMBL; AY339428; AAP89375.1; -; Genomic_DNA.
DR   EMBL; AY339429; AAP89388.1; -; Genomic_DNA.
DR   EMBL; AY339430; AAP89401.1; -; Genomic_DNA.
DR   EMBL; AY339431; AAP89414.1; -; Genomic_DNA.
DR   EMBL; AY339432; AAP89427.1; -; Genomic_DNA.
DR   EMBL; AY339433; AAP89440.1; -; Genomic_DNA.
DR   EMBL; AY339446; AAP89609.1; -; Genomic_DNA.
DR   EMBL; AY339447; AAP89622.1; -; Genomic_DNA.
DR   EMBL; AY339448; AAP89635.1; -; Genomic_DNA.
DR   EMBL; AY339449; AAP89648.1; -; Genomic_DNA.
DR   EMBL; AY339450; AAP89661.1; -; Genomic_DNA.
DR   EMBL; AY339451; AAP89674.1; -; Genomic_DNA.
DR   EMBL; AY339452; AAP89687.1; -; Genomic_DNA.
DR   EMBL; AY339453; AAP89700.1; -; Genomic_DNA.
DR   EMBL; AY339454; AAP89713.1; -; Genomic_DNA.
DR   EMBL; AY339455; AAP89726.1; -; Genomic_DNA.
DR   EMBL; AY339456; AAP89739.1; -; Genomic_DNA.
DR   EMBL; AY339457; AAP89752.1; -; Genomic_DNA.
DR   EMBL; AY339458; AAP89765.1; -; Genomic_DNA.
DR   EMBL; AY339459; AAP89778.1; -; Genomic_DNA.
DR   EMBL; AY339497; AAP90272.1; -; Genomic_DNA.
DR   EMBL; AY339498; AAP90285.1; -; Genomic_DNA.
DR   EMBL; AY339499; AAP90298.1; -; Genomic_DNA.
DR   EMBL; AY339500; AAP90311.1; -; Genomic_DNA.
DR   EMBL; AY339501; AAP90324.1; -; Genomic_DNA.
DR   EMBL; AY339502; AAP90337.1; -; Genomic_DNA.
DR   EMBL; AY339503; AAP90350.1; -; Genomic_DNA.
DR   EMBL; AY339504; AAP90363.1; -; Genomic_DNA.
DR   EMBL; AY339505; AAP90376.1; -; Genomic_DNA.
DR   EMBL; AY339506; AAP90389.1; -; Genomic_DNA.
DR   EMBL; AY339507; AAP90402.1; -; Genomic_DNA.
DR   EMBL; AY339508; AAP90415.1; -; Genomic_DNA.
DR   EMBL; AY339509; AAP90428.1; -; Genomic_DNA.
DR   EMBL; AY339510; AAP90441.1; -; Genomic_DNA.
DR   EMBL; AY339511; AAP90454.1; -; Genomic_DNA.
DR   EMBL; AY339512; AAP90467.1; -; Genomic_DNA.
DR   EMBL; AY339513; AAP90480.1; -; Genomic_DNA.
DR   EMBL; AY339514; AAP90493.1; -; Genomic_DNA.
DR   EMBL; AY339515; AAP90506.1; -; Genomic_DNA.
DR   EMBL; AY339516; AAP90519.1; -; Genomic_DNA.
DR   EMBL; AY339517; AAP90532.1; -; Genomic_DNA.
DR   EMBL; AY339518; AAP90545.1; -; Genomic_DNA.
DR   EMBL; AY339519; AAP90558.1; -; Genomic_DNA.
DR   EMBL; AY339520; AAP90571.1; -; Genomic_DNA.
DR   EMBL; AY339521; AAP90584.1; -; Genomic_DNA.
DR   EMBL; AY339522; AAP90597.1; -; Genomic_DNA.
DR   EMBL; AY339523; AAP90610.1; -; Genomic_DNA.
DR   EMBL; AY339524; AAP90623.1; -; Genomic_DNA.
DR   EMBL; AY339525; AAP90636.1; -; Genomic_DNA.
DR   EMBL; AY339526; AAP90649.1; -; Genomic_DNA.
DR   EMBL; AY339527; AAP90662.1; -; Genomic_DNA.
DR   EMBL; AY339528; AAP90675.1; -; Genomic_DNA.
DR   EMBL; AY339529; AAP90688.1; -; Genomic_DNA.
DR   EMBL; AY339530; AAP90701.1; -; Genomic_DNA.
DR   EMBL; AY339531; AAP90714.1; -; Genomic_DNA.
DR   EMBL; AY339532; AAP90727.1; -; Genomic_DNA.
DR   EMBL; AY339533; AAP90740.1; -; Genomic_DNA.
DR   EMBL; AY339534; AAP90753.1; -; Genomic_DNA.
DR   EMBL; AY339535; AAP90766.1; -; Genomic_DNA.
DR   EMBL; AY339536; AAP90779.1; -; Genomic_DNA.
DR   EMBL; AY339537; AAP90792.1; -; Genomic_DNA.
DR   EMBL; AY339538; AAP90805.1; -; Genomic_DNA.
DR   EMBL; AY339539; AAP90818.1; -; Genomic_DNA.
DR   EMBL; AY339540; AAP90831.1; -; Genomic_DNA.
DR   EMBL; AY339541; AAP90844.1; -; Genomic_DNA.
DR   EMBL; AY339542; AAP90857.1; -; Genomic_DNA.
DR   EMBL; AY339543; AAP90870.1; -; Genomic_DNA.
DR   EMBL; AY339545; AAP90896.1; -; Genomic_DNA.
DR   EMBL; AY339546; AAP90909.1; -; Genomic_DNA.
DR   EMBL; AY339547; AAP90922.1; -; Genomic_DNA.
DR   EMBL; AY339548; AAP90935.1; -; Genomic_DNA.
DR   EMBL; AY339549; AAP90948.1; -; Genomic_DNA.
DR   EMBL; AY339550; AAP90961.1; -; Genomic_DNA.
DR   EMBL; AY339551; AAP90974.1; -; Genomic_DNA.
DR   EMBL; AY339552; AAP90987.1; -; Genomic_DNA.
DR   EMBL; AY339553; AAP91000.1; -; Genomic_DNA.
DR   EMBL; AY339554; AAP91013.1; -; Genomic_DNA.
DR   EMBL; AY339555; AAP91026.1; -; Genomic_DNA.
DR   EMBL; AY339556; AAP91039.1; -; Genomic_DNA.
DR   EMBL; AY339557; AAP91052.1; -; Genomic_DNA.
DR   EMBL; AY339558; AAP91065.1; -; Genomic_DNA.
DR   EMBL; AY339559; AAP91078.1; -; Genomic_DNA.
DR   EMBL; AY339560; AAP91091.1; -; Genomic_DNA.
DR   EMBL; AY339561; AAP91104.1; -; Genomic_DNA.
DR   EMBL; AY339562; AAP91117.1; -; Genomic_DNA.
DR   EMBL; AY339563; AAP91130.1; -; Genomic_DNA.
DR   EMBL; AY339564; AAP91143.1; -; Genomic_DNA.
DR   EMBL; AY339565; AAP91156.1; -; Genomic_DNA.
DR   EMBL; AY339577; AAP91312.1; -; Genomic_DNA.
DR   EMBL; AY339578; AAP91325.1; -; Genomic_DNA.
DR   EMBL; AY339579; AAP91338.1; -; Genomic_DNA.
DR   EMBL; AY339580; AAP91351.1; -; Genomic_DNA.
DR   EMBL; AY339583; AAP91390.1; -; Genomic_DNA.
DR   EMBL; AY339584; AAP91403.1; -; Genomic_DNA.
DR   EMBL; AY339585; AAP91416.1; -; Genomic_DNA.
DR   EMBL; AY339586; AAP91429.1; -; Genomic_DNA.
DR   EMBL; AY339587; AAP91442.1; -; Genomic_DNA.
DR   EMBL; AY339588; AAP91455.1; -; Genomic_DNA.
DR   EMBL; AY339589; AAP91468.1; -; Genomic_DNA.
DR   EMBL; AY339590; AAP91481.1; -; Genomic_DNA.
DR   EMBL; AY339591; AAP91494.1; -; Genomic_DNA.
DR   EMBL; AY339592; AAP91507.1; -; Genomic_DNA.
DR   EMBL; AY339593; AAP91520.1; -; Genomic_DNA.
DR   EMBL; AF346963; AAK17208.1; -; Genomic_DNA.
DR   EMBL; AF346964; AAK17221.1; -; Genomic_DNA.
DR   EMBL; AF346965; AAK17234.1; -; Genomic_DNA.
DR   EMBL; AF346968; AAK17273.1; -; Genomic_DNA.
DR   EMBL; AF346970; AAK17299.1; -; Genomic_DNA.
DR   EMBL; AF346974; AAK17351.1; -; Genomic_DNA.
DR   EMBL; AF346975; AAK17364.1; -; Genomic_DNA.
DR   EMBL; AF346976; AAK17377.1; -; Genomic_DNA.
DR   EMBL; AF346977; AAK17390.1; -; Genomic_DNA.
DR   EMBL; AF346978; AAK17403.1; -; Genomic_DNA.
DR   EMBL; AF346979; AAK17416.1; -; Genomic_DNA.
DR   EMBL; AF346980; AAK17429.1; -; Genomic_DNA.
DR   EMBL; AF346981; AAK17442.1; -; Genomic_DNA.
DR   EMBL; AF346983; AAK17468.1; -; Genomic_DNA.
DR   EMBL; AF346988; AAK17533.1; -; Genomic_DNA.
DR   EMBL; AF346991; AAK17572.1; -; Genomic_DNA.
DR   EMBL; AF346992; AAK17585.1; -; Genomic_DNA.
DR   EMBL; AF346994; AAK17611.1; -; Genomic_DNA.
DR   EMBL; AF346995; AAK17624.1; -; Genomic_DNA.
DR   EMBL; AF346997; AAK17650.1; -; Genomic_DNA.
DR   EMBL; AF347000; AAK17689.1; -; Genomic_DNA.
DR   EMBL; AF347001; AAK17702.1; -; Genomic_DNA.
DR   EMBL; AF347002; AAK17715.1; -; Genomic_DNA.
DR   EMBL; AF347004; AAK17741.1; -; Genomic_DNA.
DR   EMBL; AF347005; AAK17754.1; -; Genomic_DNA.
DR   EMBL; AF347006; AAK17767.1; -; Genomic_DNA.
DR   EMBL; AF347007; AAK17780.1; -; Genomic_DNA.
DR   EMBL; AF347011; AAK17832.1; -; Genomic_DNA.
DR   EMBL; AF347012; AAK17845.1; -; Genomic_DNA.
DR   EMBL; AF347013; AAK17858.1; -; Genomic_DNA.
DR   EMBL; AF347014; AAK17871.1; -; Genomic_DNA.
DR   EMBL; AF347015; AAK17884.1; -; Genomic_DNA.
DR   EMBL; AY289051; AAP47881.1; -; Genomic_DNA.
DR   EMBL; AY289053; AAP47907.1; -; Genomic_DNA.
DR   EMBL; AY289054; AAP47920.1; -; Genomic_DNA.
DR   EMBL; AY289055; AAP47933.1; -; Genomic_DNA.
DR   EMBL; AY289057; AAP47959.1; -; Genomic_DNA.
DR   EMBL; AY289061; AAP48011.1; -; Genomic_DNA.
DR   EMBL; AY289062; AAP48024.1; -; Genomic_DNA.
DR   EMBL; AY289063; AAP48037.1; -; Genomic_DNA.
DR   EMBL; AY289065; AAP48063.1; -; Genomic_DNA.
DR   EMBL; AY289068; AAP48102.1; -; Genomic_DNA.
DR   EMBL; AY289069; AAP48115.1; -; Genomic_DNA.
DR   EMBL; AY289071; AAP48141.1; -; Genomic_DNA.
DR   EMBL; AY289072; AAP48154.1; -; Genomic_DNA.
DR   EMBL; AY289073; AAP48167.1; -; Genomic_DNA.
DR   EMBL; AY289074; AAP48180.1; -; Genomic_DNA.
DR   EMBL; AY289076; AAP48206.1; -; Genomic_DNA.
DR   EMBL; AY289077; AAP48219.1; -; Genomic_DNA.
DR   EMBL; AY289079; AAP48245.1; -; Genomic_DNA.
DR   EMBL; AY289083; AAP48297.1; -; Genomic_DNA.
DR   EMBL; AY289084; AAP48310.1; -; Genomic_DNA.
DR   EMBL; AY289086; AAP48336.1; -; Genomic_DNA.
DR   EMBL; AY289087; AAP48349.1; -; Genomic_DNA.
DR   EMBL; AY289088; AAP48362.1; -; Genomic_DNA.
DR   EMBL; AY289089; AAP48375.1; -; Genomic_DNA.
DR   EMBL; AY289091; AAP48401.1; -; Genomic_DNA.
DR   EMBL; AY289092; AAP48414.1; -; Genomic_DNA.
DR   EMBL; AY289094; AAP48439.1; -; Genomic_DNA.
DR   EMBL; AY289099; AAP48504.1; -; Genomic_DNA.
DR   EMBL; AY289100; AAP48517.1; -; Genomic_DNA.
DR   EMBL; AY289101; AAP48530.1; -; Genomic_DNA.
DR   EMBL; AY289102; AAP48543.1; -; Genomic_DNA.
DR   EMBL; AY495090; AAR92497.1; -; Genomic_DNA.
DR   EMBL; AY495091; AAR92510.1; -; Genomic_DNA.
DR   EMBL; AY495092; AAR92523.1; -; Genomic_DNA.
DR   EMBL; AY495093; AAR92536.1; -; Genomic_DNA.
DR   EMBL; AY495095; AAR92562.1; -; Genomic_DNA.
DR   EMBL; AY495096; AAR92575.1; -; Genomic_DNA.
DR   EMBL; AY495097; AAR92588.1; -; Genomic_DNA.
DR   EMBL; AY495098; AAR92601.1; -; Genomic_DNA.
DR   EMBL; AY495099; AAR92614.1; -; Genomic_DNA.
DR   EMBL; AY495100; AAR92627.1; -; Genomic_DNA.
DR   EMBL; AY495101; AAR92640.1; -; Genomic_DNA.
DR   EMBL; AY495102; AAR92653.1; -; Genomic_DNA.
DR   EMBL; AY495103; AAR92666.1; -; Genomic_DNA.
DR   EMBL; AY495104; AAR92679.1; -; Genomic_DNA.
DR   EMBL; AY495105; AAR92692.1; -; Genomic_DNA.
DR   EMBL; AY495106; AAR92705.1; -; Genomic_DNA.
DR   EMBL; AY495107; AAR92718.1; -; Genomic_DNA.
DR   EMBL; AY495108; AAR92731.1; -; Genomic_DNA.
DR   EMBL; AY495109; AAR92744.1; -; Genomic_DNA.
DR   EMBL; AY495110; AAR92757.1; -; Genomic_DNA.
DR   EMBL; AY495111; AAR92770.1; -; Genomic_DNA.
DR   EMBL; AY495113; AAR92796.1; -; Genomic_DNA.
DR   EMBL; AY495114; AAR92809.1; -; Genomic_DNA.
DR   EMBL; AY495115; AAR92822.1; -; Genomic_DNA.
DR   EMBL; AY495116; AAR92835.1; -; Genomic_DNA.
DR   EMBL; AY495117; AAR92848.1; -; Genomic_DNA.
DR   EMBL; AY495118; AAR92861.1; -; Genomic_DNA.
DR   EMBL; AY495119; AAR92874.1; -; Genomic_DNA.
DR   EMBL; AY495120; AAR92887.1; -; Genomic_DNA.
DR   EMBL; AY495121; AAR92900.1; -; Genomic_DNA.
DR   EMBL; AY495122; AAR92913.1; -; Genomic_DNA.
DR   EMBL; AY495123; AAR92926.1; -; Genomic_DNA.
DR   EMBL; AY495124; AAR92939.1; -; Genomic_DNA.
DR   EMBL; AY495125; AAR92952.1; -; Genomic_DNA.
DR   EMBL; AY495126; AAR92965.1; -; Genomic_DNA.
DR   EMBL; AY495127; AAR92978.1; -; Genomic_DNA.
DR   EMBL; AY495128; AAR92991.1; -; Genomic_DNA.
DR   EMBL; AY495129; AAR93004.1; -; Genomic_DNA.
DR   EMBL; AY495130; AAR93017.1; -; Genomic_DNA.
DR   EMBL; AY495131; AAR93030.1; -; Genomic_DNA.
DR   EMBL; AY495132; AAR93043.1; -; Genomic_DNA.
DR   EMBL; AY495133; AAR93056.1; -; Genomic_DNA.
DR   EMBL; AY495135; AAR93082.1; -; Genomic_DNA.
DR   EMBL; AY495136; AAR93095.1; -; Genomic_DNA.
DR   EMBL; AY495137; AAR93108.1; -; Genomic_DNA.
DR   EMBL; AY495138; AAR93121.1; -; Genomic_DNA.
DR   EMBL; AY495139; AAR93134.1; -; Genomic_DNA.
DR   EMBL; AY495140; AAR93147.1; -; Genomic_DNA.
DR   EMBL; AY495141; AAR93160.1; -; Genomic_DNA.
DR   EMBL; AY495142; AAR93173.1; -; Genomic_DNA.
DR   EMBL; AY495143; AAR93186.1; -; Genomic_DNA.
DR   EMBL; AY495144; AAR93199.1; -; Genomic_DNA.
DR   EMBL; AY495145; AAR93212.1; -; Genomic_DNA.
DR   EMBL; AY495146; AAR93225.1; -; Genomic_DNA.
DR   EMBL; AY495147; AAR93238.1; -; Genomic_DNA.
DR   EMBL; AY495148; AAR93251.1; -; Genomic_DNA.
DR   EMBL; AY495149; AAR93264.1; -; Genomic_DNA.
DR   EMBL; AY495150; AAR93277.1; -; Genomic_DNA.
DR   EMBL; AY495151; AAR93290.1; -; Genomic_DNA.
DR   EMBL; AY495152; AAR93303.1; -; Genomic_DNA.
DR   EMBL; AY495153; AAR93316.1; -; Genomic_DNA.
DR   EMBL; AY495154; AAR93329.1; -; Genomic_DNA.
DR   EMBL; AY495155; AAR93342.1; -; Genomic_DNA.
DR   EMBL; AY495156; AAR93355.1; -; Genomic_DNA.
DR   EMBL; AY495157; AAR93368.1; -; Genomic_DNA.
DR   EMBL; AY495158; AAR93381.1; -; Genomic_DNA.
DR   EMBL; AY495159; AAR93394.1; -; Genomic_DNA.
DR   EMBL; AY495160; AAR93407.1; -; Genomic_DNA.
DR   EMBL; AY495161; AAR93420.1; -; Genomic_DNA.
DR   EMBL; AY495162; AAR93433.1; -; Genomic_DNA.
DR   EMBL; AY495163; AAR93446.1; -; Genomic_DNA.
DR   EMBL; AY495164; AAR93459.1; -; Genomic_DNA.
DR   EMBL; AY495165; AAR93472.1; -; Genomic_DNA.
DR   EMBL; AY495166; AAR93485.1; -; Genomic_DNA.
DR   EMBL; AY495167; AAR93498.1; -; Genomic_DNA.
DR   EMBL; AY495168; AAR93511.1; -; Genomic_DNA.
DR   EMBL; AY495169; AAR93524.1; -; Genomic_DNA.
DR   EMBL; AY495170; AAR93537.1; -; Genomic_DNA.
DR   EMBL; AY495171; AAR93550.1; -; Genomic_DNA.
DR   EMBL; AY495172; AAR93563.1; -; Genomic_DNA.
DR   EMBL; AY495173; AAR93576.1; -; Genomic_DNA.
DR   EMBL; AY495174; AAR93589.1; -; Genomic_DNA.
DR   EMBL; AY495175; AAR93602.1; -; Genomic_DNA.
DR   EMBL; AY495176; AAR93615.1; -; Genomic_DNA.
DR   EMBL; AY495177; AAR93628.1; -; Genomic_DNA.
DR   EMBL; AY495178; AAR93641.1; -; Genomic_DNA.
DR   EMBL; AY495179; AAR93654.1; -; Genomic_DNA.
DR   EMBL; AY495180; AAR93667.1; -; Genomic_DNA.
DR   EMBL; AY495181; AAR93680.1; -; Genomic_DNA.
DR   EMBL; AY495182; AAR93693.1; -; Genomic_DNA.
DR   EMBL; AY495183; AAR93706.1; -; Genomic_DNA.
DR   EMBL; AY495184; AAR93719.1; -; Genomic_DNA.
DR   EMBL; AY495185; AAR93732.1; -; Genomic_DNA.
DR   EMBL; AY495186; AAR93745.1; -; Genomic_DNA.
DR   EMBL; AY495187; AAR93758.1; -; Genomic_DNA.
DR   EMBL; AY495188; AAR93771.1; -; Genomic_DNA.
DR   EMBL; AY495190; AAR93797.1; -; Genomic_DNA.
DR   EMBL; AY495191; AAR93810.1; -; Genomic_DNA.
DR   EMBL; AY495192; AAR93823.1; -; Genomic_DNA.
DR   EMBL; AY495194; AAR93849.1; -; Genomic_DNA.
DR   EMBL; AY495195; AAR93862.1; -; Genomic_DNA.
DR   EMBL; AY495196; AAR93875.1; -; Genomic_DNA.
DR   EMBL; AY495197; AAR93888.1; -; Genomic_DNA.
DR   EMBL; AY495198; AAR93901.1; -; Genomic_DNA.
DR   EMBL; AY495199; AAR93914.1; -; Genomic_DNA.
DR   EMBL; AY495200; AAR93927.1; -; Genomic_DNA.
DR   EMBL; AY495201; AAR93940.1; -; Genomic_DNA.
DR   EMBL; AY495202; AAR93953.1; -; Genomic_DNA.
DR   EMBL; AY495203; AAR93966.1; -; Genomic_DNA.
DR   EMBL; AY495204; AAR93979.1; -; Genomic_DNA.
DR   EMBL; AY495205; AAR93992.1; -; Genomic_DNA.
DR   EMBL; AY495206; AAR94005.1; -; Genomic_DNA.
DR   EMBL; AY495207; AAR94018.1; -; Genomic_DNA.
DR   EMBL; AY495208; AAR94031.1; -; Genomic_DNA.
DR   EMBL; AY495209; AAR94044.1; -; Genomic_DNA.
DR   EMBL; AY495210; AAR94057.1; -; Genomic_DNA.
DR   EMBL; AY495211; AAR94070.1; -; Genomic_DNA.
DR   EMBL; AY495212; AAR94083.1; -; Genomic_DNA.
DR   EMBL; AY495213; AAR94096.1; -; Genomic_DNA.
DR   EMBL; AY495215; AAR94122.1; -; Genomic_DNA.
DR   EMBL; AY495216; AAR94135.1; -; Genomic_DNA.
DR   EMBL; AY495217; AAR94148.1; -; Genomic_DNA.
DR   EMBL; AY495218; AAR94161.1; -; Genomic_DNA.
DR   EMBL; AY495219; AAR94174.1; -; Genomic_DNA.
DR   EMBL; AY495220; AAR94187.1; -; Genomic_DNA.
DR   EMBL; AY495221; AAR94200.1; -; Genomic_DNA.
DR   EMBL; AY495222; AAR94213.1; -; Genomic_DNA.
DR   EMBL; AY495223; AAR94226.1; -; Genomic_DNA.
DR   EMBL; AY495224; AAR94239.1; -; Genomic_DNA.
DR   EMBL; AY495225; AAR94252.1; -; Genomic_DNA.
DR   EMBL; AY495226; AAR94265.1; -; Genomic_DNA.
DR   EMBL; AY495227; AAR94278.1; -; Genomic_DNA.
DR   EMBL; AY495228; AAR94291.1; -; Genomic_DNA.
DR   EMBL; AY495229; AAR94304.1; -; Genomic_DNA.
DR   EMBL; AY495230; AAR94317.1; -; Genomic_DNA.
DR   EMBL; AY495243; AAR94486.1; -; Genomic_DNA.
DR   EMBL; AY495245; AAR94512.1; -; Genomic_DNA.
DR   EMBL; AY495250; AAR94577.1; -; Genomic_DNA.
DR   EMBL; AY495251; AAR94590.1; -; Genomic_DNA.
DR   EMBL; AY495253; AAR94616.1; -; Genomic_DNA.
DR   EMBL; AY495254; AAR94629.1; -; Genomic_DNA.
DR   EMBL; AY495255; AAR94642.1; -; Genomic_DNA.
DR   EMBL; AY495256; AAR94655.1; -; Genomic_DNA.
DR   EMBL; AY495258; AAR94681.1; -; Genomic_DNA.
DR   EMBL; AY495259; AAR94694.1; -; Genomic_DNA.
DR   EMBL; AY495260; AAR94707.1; -; Genomic_DNA.
DR   EMBL; AY495261; AAR94720.1; -; Genomic_DNA.
DR   EMBL; AY495262; AAR94733.1; -; Genomic_DNA.
DR   EMBL; AY495263; AAR94746.1; -; Genomic_DNA.
DR   EMBL; AY495264; AAR94759.1; -; Genomic_DNA.
DR   EMBL; AY495265; AAR94772.1; -; Genomic_DNA.
DR   EMBL; AY495266; AAR94785.1; -; Genomic_DNA.
DR   EMBL; AY495306; AAR95305.1; -; Genomic_DNA.
DR   EMBL; AY495307; AAR95318.1; -; Genomic_DNA.
DR   EMBL; AY495308; AAR95331.1; -; Genomic_DNA.
DR   EMBL; AY495309; AAR95344.1; -; Genomic_DNA.
DR   EMBL; AY495310; AAR95357.1; -; Genomic_DNA.
DR   EMBL; AY495311; AAR95370.1; -; Genomic_DNA.
DR   EMBL; AY495312; AAR95383.1; -; Genomic_DNA.
DR   EMBL; AY495313; AAR95396.1; -; Genomic_DNA.
DR   EMBL; AY495314; AAR95409.1; -; Genomic_DNA.
DR   EMBL; AY495315; AAR95422.1; -; Genomic_DNA.
DR   EMBL; AY495316; AAR95435.1; -; Genomic_DNA.
DR   EMBL; AY495317; AAR95448.1; -; Genomic_DNA.
DR   EMBL; AY495318; AAR95461.1; -; Genomic_DNA.
DR   EMBL; AY495319; AAR95474.1; -; Genomic_DNA.
DR   EMBL; AY495320; AAR95487.1; -; Genomic_DNA.
DR   EMBL; AY495321; AAR95500.1; -; Genomic_DNA.
DR   EMBL; AY495322; AAR95513.1; -; Genomic_DNA.
DR   EMBL; AY495323; AAR95526.1; -; Genomic_DNA.
DR   EMBL; AY495326; AAR95565.1; -; Genomic_DNA.
DR   EMBL; AY495327; AAR95578.1; -; Genomic_DNA.
DR   EMBL; AY495328; AAR95591.1; -; Genomic_DNA.
DR   EMBL; AY495329; AAR95604.1; -; Genomic_DNA.
DR   EMBL; AY495330; AAR95617.1; -; Genomic_DNA.
DR   EMBL; AY495302; AAR95253.1; -; Genomic_DNA.
DR   PIR; A00414; DNHUN2.
DR   RefSeq; YP_003024027.1; NC_012920.1.
DR   PDB; 5XTC; EM; 3.70 A; i=1-347.
DR   PDB; 5XTD; EM; 3.70 A; i=1-347.
DR   PDB; 5XTH; EM; 3.90 A; i=1-347.
DR   PDB; 5XTI; EM; 17.40 A; Bi/i=1-347.
DR   PDB; 9CWT; EM; 3.44 A; i=1-347.
DR   PDBsum; 5XTC; -.
DR   PDBsum; 5XTD; -.
DR   PDBsum; 5XTH; -.
DR   PDBsum; 5XTI; -.
DR   PDBsum; 9CWT; -.
DR   AlphaFoldDB; P03891; -.
DR   EMDB; EMD-45974; -.
DR   SMR; P03891; -.
DR   BioGRID; 110632; 25.
DR   ComplexPortal; CPX-577; Mitochondrial respiratory chain complex I.
DR   CORUM; P03891; -.
DR   FunCoup; P03891; 260.
DR   IntAct; P03891; 16.
DR   MINT; P03891; -.
DR   STRING; 9606.ENSP00000355046; -.
DR   BindingDB; P03891; -.
DR   ChEMBL; CHEMBL2363065; -.
DR   DrugBank; DB00157; NADH.
DR   DrugCentral; P03891; -.
DR   iPTMnet; P03891; -.
DR   PhosphoSitePlus; P03891; -.
DR   BioMuta; MT-ND2; -.
DR   DMDM; 128676; -.
DR   jPOST; P03891; -.
DR   MassIVE; P03891; -.
DR   PaxDb; 9606-ENSP00000355046; -.
DR   PeptideAtlas; P03891; -.
DR   ProteomicsDB; 51612; -.
DR   Pumba; P03891; -.
DR   Antibodypedia; 47876; 64 antibodies from 19 providers.
DR   DNASU; 4536; -.
DR   Ensembl; ENST00000361453.3; ENSP00000355046.4; ENSG00000198763.3.
DR   GeneID; 4536; -.
DR   KEGG; hsa:4536; -.
DR   AGR; HGNC:7456; -.
DR   ClinPGx; PA31260; -.
DR   CTD; 4536; -.
DR   DisGeNET; 4536; -.
DR   GeneCards; MT-ND2; -.
DR   GeneReviews; MT-ND2; -.
DR   HGNC; HGNC:7456; MT-ND2.
DR   HPA; ENSG00000198763; Tissue enhanced (brain, heart muscle).
DR   MalaCards; MT-ND2; -.
DR   MIM; 256000; phenotype.
DR   MIM; 502500; phenotype.
DR   MIM; 516001; gene.
DR   MIM; 535000; phenotype.
DR   OpenTargets; ENSG00000198763; -.
DR   Orphanet; 2609; Isolated complex I deficiency.
DR   Orphanet; 104; Leber hereditary optic neuropathy.
DR   Orphanet; 255210; Mitochondrial DNA-associated Leigh syndrome.
DR   VEuPathDB; HostDB:ENSG00000198763; -.
DR   eggNOG; KOG4668; Eukaryota.
DR   GeneTree; ENSGT00730000111348; -.
DR   HOGENOM; CLU_007100_1_3_1; -.
DR   InParanoid; P03891; -.
DR   OMA; HFWVPEV; -.
DR   PAN-GO; P03891; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P03891; -.
DR   BioCyc; MetaCyc:HS17772-MONOMER; -.
DR   PathwayCommons; P03891; -.
DR   Reactome; R-HSA-5419276; Mitochondrial translation termination.
DR   Reactome; R-HSA-611105; Respiratory electron transport.
DR   Reactome; R-HSA-6799198; Complex I biogenesis.
DR   Reactome; R-HSA-9837999; Mitochondrial protein degradation.
DR   SignaLink; P03891; -.
DR   SIGNOR; P03891; -.
DR   Agora; ENSG00000198763; -.
DR   BioGRID-ORCS; 4536; 0 hits in 2 CRISPR screens.
DR   ChiTaRS; ND2; human.
DR   GeneWiki; MT-ND2; -.
DR   GenomeRNAi; 4536; -.
DR   Pharos; P03891; Tclin.
DR   PRO; PR:P03891; -.
DR   Proteomes; UP000005640; Mitochondrion MT.
DR   RNAct; P03891; protein.
DR   Bgee; ENSG00000198763; Expressed in subcutaneous adipose tissue and 95 other cell types or tissues.
DR   ExpressionAtlas; P03891; baseline and differential.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IDA:ComplexPortal.
DR   GO; GO:0005739; C:mitochondrion; HTP:FlyBase.
DR   GO; GO:0045271; C:respiratory chain complex I; IDA:UniProtKB.
DR   GO; GO:0035255; F:ionotropic glutamate receptor binding; IEA:Ensembl.
DR   GO; GO:0008137; F:NADH dehydrogenase (ubiquinone) activity; IMP:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR   GO; GO:0009060; P:aerobic respiration; NAS:ComplexPortal.
DR   GO; GO:0006120; P:mitochondrial electron transport, NADH to ubiquinone; IMP:UniProtKB.
DR   GO; GO:0032981; P:mitochondrial respiratory chain complex I assembly; IMP:UniProtKB.
DR   GO; GO:0042776; P:proton motive force-driven mitochondrial ATP synthesis; NAS:ComplexPortal.
DR   GO; GO:0072593; P:reactive oxygen species metabolic process; IEA:Ensembl.
DR   GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR   InterPro; IPR050175; Complex_I_Subunit_2.
DR   InterPro; IPR010933; NADH_DH_su2_C.
DR   InterPro; IPR003917; NADH_UbQ_OxRdtase_chain2.
DR   InterPro; IPR001750; ND/Mrp_TM.
DR   PANTHER; PTHR46552; NADH-UBIQUINONE OXIDOREDUCTASE CHAIN 2; 1.
DR   PANTHER; PTHR46552:SF1; NADH-UBIQUINONE OXIDOREDUCTASE CHAIN 2; 1.
DR   Pfam; PF06444; NADH_dehy_S2_C; 1.
DR   Pfam; PF00361; Proton_antipo_M; 1.
DR   PRINTS; PR01436; NADHDHGNASE2.
PE   1: Evidence at protein level;
KW   3D-structure; Alzheimer disease; Amyloidosis; Disease variant;
KW   Electron transport; Leber hereditary optic neuropathy; Leigh syndrome;
KW   Membrane; Mitochondrion; Mitochondrion inner membrane; NAD;
KW   Neurodegeneration; Primary mitochondrial disease;
KW   Proteomics identification; Reference proteome; Respiratory chain;
KW   Translocase; Transmembrane; Transmembrane helix; Transport; Ubiquinone.
FT   CHAIN           1..347
FT                   /note="NADH-ubiquinone oxidoreductase chain 2"
FT                   /id="PRO_0000117595"
FT   TRANSMEM        13..33
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        56..76
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        96..116
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        123..143
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        149..169
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        178..198
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        201..221
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        247..267
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        274..294
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        326..346
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   VARIANT         42
FT                   /note="P -> L"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008590"
FT   VARIANT         43
FT                   /note="V -> I (in dbSNP:rs1117207)"
FT                   /evidence="ECO:0000269|PubMed:7530363"
FT                   /id="VAR_011348"
FT   VARIANT         57
FT                   /note="I -> T (in dbSNP:rs41510547)"
FT                   /evidence="ECO:0000269|PubMed:9461455"
FT                   /id="VAR_008591"
FT   VARIANT         63
FT                   /note="Q -> R"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008592"
FT   VARIANT         69
FT                   /note="I -> V (in dbSNP:rs1556422884)"
FT                   /evidence="ECO:0000269|PubMed:9475751"
FT                   /id="VAR_011349"
FT   VARIANT         71
FT                   /note="L -> P (in LS; uncertain significance; decrease in
FT                   enzyme activity and impaired assembly of complex I;
FT                   dbSNP:rs267606889)"
FT                   /evidence="ECO:0000269|PubMed:16996290"
FT                   /id="VAR_084383"
FT   VARIANT         88
FT                   /note="N -> S (in dbSNP:rs201854167)"
FT                   /evidence="ECO:0000269|PubMed:9475751"
FT                   /id="VAR_011350"
FT   VARIANT         119
FT                   /note="T -> A (in dbSNP:rs1556422903)"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008593"
FT   VARIANT         148
FT                   /note="S -> P"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008594"
FT   VARIANT         150
FT                   /note="N -> D (in LHON; secondary mutation; does not seem
FT                   to directly cause the disease; dbSNP:rs28357980)"
FT                   /evidence="ECO:0000269|PubMed:1900003,
FT                   ECO:0000269|PubMed:9475751"
FT                   /id="VAR_004755"
FT   VARIANT         150
FT                   /note="N -> S (in dbSNP:rs879058895)"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008595"
FT   VARIANT         159
FT                   /note="I -> T"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008596"
FT   VARIANT         185
FT                   /note="T -> A"
FT                   /evidence="ECO:0000269|PubMed:1757091"
FT                   /id="VAR_008597"
FT   VARIANT         237
FT                   /note="L -> M (in dbSNP:rs28357984)"
FT                   /evidence="ECO:0000269|PubMed:9475751"
FT                   /id="VAR_011351"
FT   VARIANT         259
FT                   /note="G -> S (in LHON; rare primary mutation;
FT                   dbSNP:rs199476115)"
FT                   /evidence="ECO:0000269|PubMed:1732158"
FT                   /id="VAR_004756"
FT   VARIANT         265
FT                   /note="A -> T (in dbSNP:rs1603219855)"
FT                   /evidence="ECO:0000269|PubMed:9475751"
FT                   /id="VAR_011352"
FT   VARIANT         265
FT                   /note="A -> V (in dbSNP:rs41320049)"
FT                   /evidence="ECO:0000269|PubMed:9475751"
FT                   /id="VAR_011353"
FT   VARIANT         278
FT                   /note="I -> T (in dbSNP:rs878853115)"
FT                   /evidence="ECO:0000269|PubMed:9475751"
FT                   /id="VAR_011354"
FT   VARIANT         325
FT                   /note="F -> L (in dbSNP:rs3020601)"
FT                   /evidence="ECO:0000269|PubMed:7530363"
FT                   /id="VAR_011355"
FT   VARIANT         331
FT                   /note="A -> S (in AD-MT)"
FT                   /evidence="ECO:0000269|PubMed:1370613"
FT                   /id="VAR_004758"
FT   VARIANT         331
FT                   /note="A -> T (in dbSNP:rs3021088)"
FT                   /evidence="ECO:0000269|PubMed:7530363"
FT                   /id="VAR_004757"
FT   VARIANT         333
FT                   /note="T -> A (in dbSNP:rs1603219973)"
FT                   /evidence="ECO:0000269|PubMed:9475751"
FT                   /id="VAR_011356"
SQ   SEQUENCE   347 AA;  38961 MW;  C06FD982317C3F2D CRC64;
     MNPLAQPVIY STIFAGTLIT ALSSHWFFTW VGLEMNMLAF IPVLTKKMNP RSTEAAIKYF
     LTQATASMIL LMAILFNNML SGQWTMTNTT NQYSSLMIMM AMAMKLGMAP FHFWVPEVTQ
     GTPLTSGLLL LTWQKLAPIS IMYQISPSLN VSLLLTLSIL SIMAGSWGGL NQTQLRKILA
     YSSITHMGWM MAVLPYNPNM TILNLTIYII LTTTAFLLLN LNSSTTTLLL SRTWNKLTWL
     TPLIPSTLLS LGGLPPLTGF LPKWAIIEEF TKNNSLIIPT IMATITLLNL YFYLRLIYST
     SITLLPMSNN VKMKWQFEHT KPTPFLPTLI ALTTLLLPIS PFMLMIL
//
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   P20D1_HUMAN             Reviewed;         502 AA.
AC   Q6GTS8; Q6P4E3; Q96DM4;
DT   26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   11-JAN-2011, sequence version 3.
DT   28-JAN-2026, entry version 154.
DE   RecName: Full=N-fatty-acyl-amino acid synthase/hydrolase PM20D1 {ECO:0000305|PubMed:27374330};
DE            EC=3.5.1.114 {ECO:0000269|PubMed:27374330};
DE            EC=3.5.1.14 {ECO:0000269|PubMed:27374330};
DE   AltName: Full=Peptidase M20 domain-containing protein 1 {ECO:0000312|HGNC:HGNC:26518};
DE   Flags: Precursor;
GN   Name=PM20D1 {ECO:0000312|HGNC:HGNC:26518};
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] (ISOFORMS 1 AND 2), AND VARIANTS
RP   VAL-149 AND TRP-153.
RC   TISSUE=Kidney, and Spleen;
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=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   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS TYR-33;
RP   VAL-149; TRP-153; THR-237; ARG-346 AND THR-380.
RC   TISSUE=Pancreas, and 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   [4]
RP   FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX   PubMed=27374330; DOI=10.1016/j.cell.2016.05.071;
RA   Long J.Z., Svensson K.J., Bateman L.A., Lin H., Kamenecka T.,
RA   Lokurkar I.A., Lou J., Rao R.R., Chang M.R., Jedrychowski M.P., Paulo J.A.,
RA   Gygi S.P., Griffin P.R., Nomura D.K., Spiegelman B.M.;
RT   "The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of
RT   mitochondria.";
RL   Cell 166:424-435(2016).
RN   [5]
RP   MISCELLANEOUS.
RX   PubMed=29736028; DOI=10.1038/s41591-018-0013-y;
RA   Sanchez-Mut J.V., Heyn H., Silva B.A., Dixsaut L., Garcia-Esparcia P.,
RA   Vidal E., Sayols S., Glauser L., Monteagudo-Sanchez A., Perez-Tur J.,
RA   Ferrer I., Monk D., Schneider B., Esteller M., Graeff J.;
RT   "PM20D1 is a quantitative trait locus associated with Alzheimer's
RT   disease.";
RL   Nat. Med. 24:598-603(2018).
CC   -!- FUNCTION: Secreted enzyme that regulates the endogenous N-fatty acyl
CC       amino acid (NAAs) tissue and circulating levels by functioning as a
CC       bidirectional NAA synthase/hydrolase (PubMed:27374330). It condenses
CC       free fatty acids and free amino acids to generate NAAs and
CC       bidirectionally catalyzes the reverse hydrolysis reaction
CC       (PubMed:27374330). Some of these NAAs stimulate oxidative metabolism
CC       via mitochondrial uncoupling, increasing energy expenditure in a UPC1-
CC       independent manner. Thereby, this secreted protein may indirectly
CC       regulate whole body energy expenditure. PM20D1 circulates in tight
CC       association with both low- and high-density (LDL and HDL,respectively)
CC       lipoprotein particles (By similarity). {ECO:0000250|UniProtKB:Q8C165,
CC       ECO:0000269|PubMed:27374330}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an N-acyl-L-amino acid + H2O = an L-alpha-amino acid + a
CC         carboxylate; Xref=Rhea:RHEA:15565, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:29067, ChEBI:CHEBI:59869, ChEBI:CHEBI:59874; EC=3.5.1.14;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15566;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15567;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an N-acyl-aromatic L-alpha-amino acid + H2O = an aromatic L-
CC         alpha-amino acid + a carboxylate; Xref=Rhea:RHEA:54184,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:29067, ChEBI:CHEBI:84824,
CC         ChEBI:CHEBI:138093; EC=3.5.1.114;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54185;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:54186;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-phenylalanine + (9Z)-octadecenoate = N-(9Z-octadecenoyl)-L-
CC         phenylalanine + H2O; Xref=Rhea:RHEA:51300, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:58095, ChEBI:CHEBI:134020;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51301;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:51302;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-leucine + H2O = L-leucine + (9Z)-
CC         octadecenoate; Xref=Rhea:RHEA:51360, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:57427, ChEBI:CHEBI:134035;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51361;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:51362;
CC         Evidence={ECO:0000269|PubMed:27374330};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-glycine + H2O =
CC         (5Z,8Z,11Z,14Z)-eicosatetraenoate + glycine; Xref=Rhea:RHEA:64108,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:32395, ChEBI:CHEBI:57305,
CC         ChEBI:CHEBI:59002; Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64109;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:64110;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-hexadecanoyl-L-phenylalanine + H2O = hexadecanoate + L-
CC         phenylalanine; Xref=Rhea:RHEA:64124, ChEBI:CHEBI:7896,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:58095, ChEBI:CHEBI:149699;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64125;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-octadecanoyl-L-phenylalanine + H2O = octadecanoate + L-
CC         phenylalanine; Xref=Rhea:RHEA:64128, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:25629, ChEBI:CHEBI:58095, ChEBI:CHEBI:149700;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64129;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-L-phenylalanine +
CC         H2O = (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + L-phenylalanine;
CC         Xref=Rhea:RHEA:64132, ChEBI:CHEBI:15377, ChEBI:CHEBI:58095,
CC         ChEBI:CHEBI:77016, ChEBI:CHEBI:149701;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64133;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-asparagine + H2O = L-asparagine + (9Z)-
CC         octadecenoate; Xref=Rhea:RHEA:64136, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:58048, ChEBI:CHEBI:149730;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64137;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(9Z)-octadecenoate + glycine = N-(9Z-octadecenoyl)glycine +
CC         H2O; Xref=Rhea:RHEA:51316, ChEBI:CHEBI:15377, ChEBI:CHEBI:30823,
CC         ChEBI:CHEBI:57305, ChEBI:CHEBI:133992;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:51318;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-lysine + H2O = L-lysine + (9Z)-
CC         octadecenoate; Xref=Rhea:RHEA:64192, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:32551, ChEBI:CHEBI:149731;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64193;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-methionine + H2O = (9Z)-octadecenoate +
CC         L-methionine; Xref=Rhea:RHEA:64144, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:57844, ChEBI:CHEBI:149732;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64145;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-serine + H2O = L-serine + (9Z)-
CC         octadecenoate; Xref=Rhea:RHEA:51352, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:33384, ChEBI:CHEBI:134031;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51353;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-tryptophan + H2O = L-tryptophan + (9Z)-
CC         octadecenoate; Xref=Rhea:RHEA:64176, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:57912, ChEBI:CHEBI:149733;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64177;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-tyrosine + H2O = L-tyrosine + (9Z)-
CC         octadecenoate; Xref=Rhea:RHEA:64184, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:58315, ChEBI:CHEBI:149734;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64185;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(9Z-octadecenoyl)-L-glutamine + H2O = L-glutamine + (9Z)-
CC         octadecenoate; Xref=Rhea:RHEA:51356, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:58359, ChEBI:CHEBI:134033;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51357;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-L-serine + H2O =
CC         (5Z,8Z,11Z,14Z)-eicosatetraenoate + L-serine; Xref=Rhea:RHEA:64116,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:32395, ChEBI:CHEBI:33384,
CC         ChEBI:CHEBI:149697; Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64117;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:64118;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + L-phenylalanine = N-
CC         (5Z,8Z,11Z,14Z-eicosatetraenoyl)-L-phenylalanine + H2O;
CC         Xref=Rhea:RHEA:51312, ChEBI:CHEBI:15377, ChEBI:CHEBI:32395,
CC         ChEBI:CHEBI:58095, ChEBI:CHEBI:134022;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51313;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:51314;
CC         Evidence={ECO:0000250|UniProtKB:Q8C165};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 2 Zn(2+) ions per subunit. {ECO:0000250};
CC   -!- ACTIVITY REGULATION: Lipoproteins are powerful coactivators of PM20D1
CC       activity in vitro and NAA biosynthesis in vivo.
CC       {ECO:0000250|UniProtKB:Q8C165}.
CC   -!- PATHWAY: Amino-acid metabolism. {ECO:0000269|PubMed:27374330}.
CC   -!- PATHWAY: Energy metabolism. {ECO:0000269|PubMed:27374330}.
CC   -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC       {ECO:0000269|PubMed:27374330}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q8C165}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q6GTS8-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q6GTS8-2; Sequence=VSP_031826, VSP_031827;
CC   -!- MISCELLANEOUS: Genetically increasing or decreasing the expression of
CC       PM20D1 reduces and aggravates Alzheimer's disease (AD) related
CC       pathologies, respectively. These findings suggest that in a particular
CC       genetic background, PM20D1 contributes to neuroprotection against AD.
CC       {ECO:0000269|PubMed:29736028}.
CC   -!- SIMILARITY: Belongs to the peptidase M20A family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Protein Spotlight; Note=A touch of warmth - Issue
CC       195 of September 2017;
CC       URL="https://www.proteinspotlight.org/back_issues/195/";
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DR   EMBL; AK057131; BAB71368.1; -; mRNA.
DR   EMBL; AK290786; BAF83475.1; -; mRNA.
DR   EMBL; AC119673; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC039170; AAH39170.1; -; mRNA.
DR   EMBL; BC063477; AAH63477.1; -; mRNA.
DR   CCDS; CCDS1460.1; -. [Q6GTS8-1]
DR   RefSeq; NP_689704.4; NM_152491.4. [Q6GTS8-1]
DR   AlphaFoldDB; Q6GTS8; -.
DR   SMR; Q6GTS8; -.
DR   BioGRID; 127171; 23.
DR   FunCoup; Q6GTS8; 68.
DR   IntAct; Q6GTS8; 10.
DR   STRING; 9606.ENSP00000356104; -.
DR   SwissLipids; SLP:000001665; -.
DR   MEROPS; M20.011; -.
DR   GlyCosmos; Q6GTS8; 1 site, No reported glycans.
DR   GlyGen; Q6GTS8; 4 sites, 1 N-linked glycan (1 site).
DR   iPTMnet; Q6GTS8; -.
DR   PhosphoSitePlus; Q6GTS8; -.
DR   BioMuta; PM20D1; -.
DR   DMDM; 317373406; -.
DR   MassIVE; Q6GTS8; -.
DR   PaxDb; 9606-ENSP00000356104; -.
DR   PeptideAtlas; Q6GTS8; -.
DR   ProteomicsDB; 66320; -. [Q6GTS8-1]
DR   ProteomicsDB; 66321; -. [Q6GTS8-2]
DR   Antibodypedia; 2556; 26 antibodies from 12 providers.
DR   DNASU; 148811; -.
DR   Ensembl; ENST00000367136.5; ENSP00000356104.4; ENSG00000162877.13. [Q6GTS8-1]
DR   GeneID; 148811; -.
DR   KEGG; hsa:148811; -.
DR   MANE-Select; ENST00000367136.5; ENSP00000356104.4; NM_152491.5; NP_689704.4.
DR   UCSC; uc001hdj.4; human. [Q6GTS8-1]
DR   AGR; HGNC:26518; -.
DR   ClinPGx; PA162399772; -.
DR   CTD; 148811; -.
DR   DisGeNET; 148811; -.
DR   GeneCards; PM20D1; -.
DR   HGNC; HGNC:26518; PM20D1.
DR   HPA; ENSG00000162877; Group enriched (pancreas, skin).
DR   MIM; 617124; gene.
DR   OpenTargets; ENSG00000162877; -.
DR   VEuPathDB; HostDB:ENSG00000162877; -.
DR   eggNOG; KOG2275; Eukaryota.
DR   GeneTree; ENSGT00940000156659; -.
DR   HOGENOM; CLU_021802_11_1_1; -.
DR   InParanoid; Q6GTS8; -.
DR   OMA; DWTHHPF; -.
DR   OrthoDB; 3064516at2759; -.
DR   PAN-GO; Q6GTS8; 5 GO annotations based on evolutionary models.
DR   PhylomeDB; Q6GTS8; -.
DR   PathwayCommons; Q6GTS8; -.
DR   Reactome; R-HSA-9673163; Oleoyl-phe metabolism.
DR   SignaLink; Q6GTS8; -.
DR   UniPathway; UPA00199; -.
DR   Agora; ENSG00000162877; -.
DR   BioGRID-ORCS; 148811; 11 hits in 1142 CRISPR screens.
DR   ChiTaRS; PM20D1; human.
DR   GenomeRNAi; 148811; -.
DR   Pharos; Q6GTS8; Tdark.
DR   PRO; PR:Q6GTS8; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; Q6GTS8; protein.
DR   Bgee; ENSG00000162877; Expressed in upper leg skin and 95 other cell types or tissues.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0004046; F:aminoacylase activity; IEA:UniProtKB-EC.
DR   GO; GO:0016811; F:hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides; EXP:Reactome.
DR   GO; GO:0016829; F:lyase activity; IEA:UniProtKB-KW.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:1990845; P:adaptive thermogenesis; TAS:Reactome.
DR   GO; GO:0043604; P:amide biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0043605; P:amide catabolic process; IDA:UniProtKB.
DR   GO; GO:0006520; P:amino acid metabolic process; IDA:UniProtKB.
DR   GO; GO:0097009; P:energy homeostasis; IEA:Ensembl.
DR   GO; GO:0006631; P:fatty acid metabolic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0006629; P:lipid metabolic process; IDA:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   CDD; cd05674; M20_yscS; 1.
DR   FunFam; 1.10.150.900:FF:000003; N-fatty-acyl-amino acid synthase/hydrolase PM20D1; 1.
DR   FunFam; 3.40.630.10:FF:000027; N-fatty-acyl-amino acid synthase/hydrolase PM20D1; 1.
DR   Gene3D; 1.10.150.900; -; 1.
DR   Gene3D; 3.30.70.360; -; 1.
DR   Gene3D; 3.40.630.10; Zn peptidases; 1.
DR   InterPro; IPR036264; Bact_exopeptidase_dim_dom.
DR   InterPro; IPR047177; Pept_M20A.
DR   InterPro; IPR002933; Peptidase_M20.
DR   InterPro; IPR011650; Peptidase_M20_dimer.
DR   PANTHER; PTHR45962; N-FATTY-ACYL-AMINO ACID SYNTHASE/HYDROLASE PM20D1; 1.
DR   PANTHER; PTHR45962:SF1; N-FATTY-ACYL-AMINO ACID SYNTHASE_HYDROLASE PM20D1; 1.
DR   Pfam; PF07687; M20_dimer; 1.
DR   Pfam; PF01546; Peptidase_M20; 1.
DR   SUPFAM; SSF55031; Bacterial exopeptidase dimerisation domain; 1.
DR   SUPFAM; SSF53187; Zn-dependent exopeptidases; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Glycoprotein; Hydrolase; Lipid metabolism; Lyase;
KW   Metal-binding; Protease; Proteomics identification; Reference proteome;
KW   Secreted; Signal; Zinc.
FT   SIGNAL          1..25
FT                   /evidence="ECO:0000255"
FT   CHAIN           26..502
FT                   /note="N-fatty-acyl-amino acid synthase/hydrolase PM20D1"
FT                   /id="PRO_0000321928"
FT   ACT_SITE        127
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        191
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250"
FT   BINDING         125
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         157
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         157
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         192
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         217
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         464
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        252
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         302..361
FT                   /note="FPFPVNIILSNPWLFEPLISRFMERNPLTNAIIRTTTALTIFKAGVKFNVIP
FT                   PVAQATVN -> VYGEKSLNQCNNQDHHGTHHIQSRGQVQCHPPSGPGHSQLPDSPWTD
FT                   SPRGPRTHEEHCG (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_031826"
FT   VAR_SEQ         362..502
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_031827"
FT   VARIANT         33
FT                   /note="H -> Y (in dbSNP:rs11540014)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_039380"
FT   VARIANT         149
FT                   /note="I -> V (in dbSNP:rs1891460)"
FT                   /evidence="ECO:0000269|PubMed:14702039,
FT                   ECO:0000269|PubMed:15489334"
FT                   /id="VAR_039381"
FT   VARIANT         153
FT                   /note="R -> W (in dbSNP:rs1104899)"
FT                   /evidence="ECO:0000269|PubMed:14702039,
FT                   ECO:0000269|PubMed:15489334"
FT                   /id="VAR_039382"
FT   VARIANT         237
FT                   /note="I -> T (in dbSNP:rs7518979)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_039383"
FT   VARIANT         258
FT                   /note="S -> C (in dbSNP:rs11581214)"
FT                   /id="VAR_039384"
FT   VARIANT         346
FT                   /note="G -> R (in dbSNP:rs11240573)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_039385"
FT   VARIANT         380
FT                   /note="I -> T (in dbSNP:rs1361754)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_039386"
FT   CONFLICT        84
FT                   /note="H -> R (in Ref. 3; AAH39170)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   502 AA;  55741 MW;  0CC2C45E1A7ADEA8 CRC64;
     MAQRCVCVLA LVAMLLLVFP TVSRSMGPRS GEHQRASRIP SQFSKEERVA MKEALKGAIQ
     IPTVTFSSEK SNTTALAEFG KYIHKVFPTV VSTSFIQHEV VEEYSHLFTI QGSDPSLQPY
     LLMAHFDVVP APEEGWEVPP FSGLERDGII YGRGTLDDKN SVMALLQALE LLLIRKYIPR
     RSFFISLGHD EESSGTGAQR ISALLQSRGV QLAFIVDEGG FILDDFIPNF KKPIALIAVS
     EKGSMNLMLQ VNMTSGHSSA PPKETSIGIL AAAVSRLEQT PMPIIFGSGT VVTVLQQLAN
     EFPFPVNIIL SNPWLFEPLI SRFMERNPLT NAIIRTTTAL TIFKAGVKFN VIPPVAQATV
     NFRIHPGQTV QEVLELTKNI VADNRVQFHV LSAFDPLPVS PSDDKALGYQ LLRQTVQSVF
     PEVNITAPVT SIGNTDSRFF TNLTTGIYRF YPIYIQPEDF KRIHGVNEKI SVQAYETQVK
     FIFELIQNAD TDQEPVSHLH KL
//
ID   PLD3_HUMAN              Reviewed;         490 AA.
AC   Q8IV08; Q92853; Q9BW87;
DT   20-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2003, sequence version 1.
DT   28-JAN-2026, entry version 176.
DE   RecName: Full=5'-3' exonuclease PLD3 {ECO:0000305};
DE            EC=3.1.16.1 {ECO:0000269|PubMed:30111894, ECO:0000269|PubMed:30312375};
DE   AltName: Full=(S,S)-bis(monoacylglycero)phosphate synthase PLD3 {ECO:0000305|PubMed:39423811};
DE            EC=3.1.4.- {ECO:0000269|PubMed:39423811};
DE   AltName: Full=HindIII K4L homolog;
DE   AltName: Full=Hu-K4 {ECO:0000303|PubMed:15794758};
DE   AltName: Full=Phospholipase D3;
GN   Name=PLD3 {ECO:0000303|PubMed:26411346, ECO:0000312|HGNC:HGNC:17158};
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=Mammary gland;
RX   PubMed=9140189; DOI=10.1016/s0168-1702(96)01422-0;
RA   Cao J.X., Koop B.F., Upton C.;
RT   "A human homolog of the vaccinia virus HindIII K4L gene is a member of the
RT   phospholipase D superfamily.";
RL   Virus Res. 48:11-18(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, Colon, 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   [3]
RP   SUBCELLULAR LOCATION, TOPOLOGY, TISSUE SPECIFICITY, AND GLYCOSYLATION.
RX   PubMed=15794758; DOI=10.1111/j.1742-4658.2005.04601.x;
RA   Munck A., Boehm C., Seibel N.M., Hashemol Hosseini Z., Hampe W.;
RT   "Hu-K4 is a ubiquitously expressed type 2 transmembrane protein associated
RT   with the endoplasmic reticulum.";
RL   FEBS J. 272:1718-1726(2005).
RN   [4]
RP   GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-97 AND ASN-132.
RC   TISSUE=Liver;
RX   PubMed=19159218; DOI=10.1021/pr8008012;
RA   Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT   "Glycoproteomics analysis of human liver tissue by combination of multiple
RT   enzyme digestion and hydrazide chemistry.";
RL   J. Proteome Res. 8:651-661(2009).
RN   [5]
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   [6]
RP   SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-418, AND FUNCTION.
RX   PubMed=22428023; DOI=10.1371/journal.pone.0033341;
RA   Osisami M., Ali W., Frohman M.A.;
RT   "A role for phospholipase D3 in myotube formation.";
RL   PLoS ONE 7:E33341-E33341(2012).
RN   [7]
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   [8]
RP   FUNCTION, POSSIBLE INVOLVEMENT IN ALZHEIMER DISEASE, VARIANT MET-232,
RP   TISSUE SPECIFICITY, AND INTERACTION WITH APP.
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   [9]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANTS SER-63; ALA-76;
RP   MET-159; CYS-162; SER-173; GLY-175; CYS-188; HIS-222; MET-232; GLN-242;
RP   GLY-249; CYS-272; SER-284; VAL-293; LEU-297; TYR-300; PRO-308; ILE-358;
RP   ALA-426 AND ARG-429.
RX   PubMed=26411346; DOI=10.1002/humu.22908;
RG   Belgium Neurology (BELNEU) Consortium and the European Early-Onset Dementia (EU EOD) Consortium;
RA   Cacace R., Van den Bossche T., Engelborghs S., Geerts N., Laureys A.,
RA   Dillen L., Graff C., Thonberg H., Chiang H.H., Pastor P., Ortega-Cubero S.,
RA   Pastor M.A., Diehl-Schmid J., Alexopoulos P., Benussi L., Ghidoni R.,
RA   Binetti G., Nacmias B., Sorbi S., Sanchez-Valle R., Llado A., Gelpi E.,
RA   Almeida M.R., Santana I., Tsolaki M., Koutroumani M., Clarimon J., Lleo A.,
RA   Fortea J., de Mendonca A., Martins M., Borroni B., Padovani A., Matej R.,
RA   Rohan Z., Vandenbulcke M., Vandenberghe R., De Deyn P.P., Cras P.,
RA   van der Zee J., Sleegers K., Van Broeckhoven C.;
RT   "Rare variants in PLD3 do not affect risk for early-onset Alzheimer disease
RT   in a European consortium cohort.";
RL   Hum. Mutat. 36:1226-1235(2015).
RN   [10]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX   PubMed=25832408; DOI=10.1038/nature14036;
RA   Lambert J.C., Grenier-Boley B., Bellenguez C., Pasquier F., Campion D.,
RA   Dartigues J.F., Berr C., Tzourio C., Amouyel P.;
RT   "PLD3 and sporadic Alzheimer's disease risk.";
RL   Nature 520:E1-E1(2015).
RN   [11]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX   PubMed=25832410; DOI=10.1038/nature14038;
RA   van der Lee S.J., Holstege H., Wong T.H., Jakobsdottir J., Bis J.C.,
RA   Chouraki V., van Rooij J.G., Grove M.L., Smith A.V., Amin N., Choi S.H.,
RA   Beiser A.S., Garcia M.E., van Ijcken W.F., Pijnenburg Y.A.,
RA   Louwersheimer E., Brouwer R.W., van den Hout M.C., Oole E.,
RA   Eirkisdottir G., Levy D., Rotter J.I., Emilsson V., O'Donnell C.J.,
RA   Aspelund T., Uitterlinden A.G., Launer L.J., Hofman A., Boerwinkle E.,
RA   Psaty B.M., DeStefano A.L., Scheltens P., Seshadri S., van Swieten J.C.,
RA   Gudnason V., van der Flier W.M., Ikram M.A., van Duijn C.M.;
RT   "PLD3 variants in population studies.";
RL   Nature 520:E2-E3(2015).
RN   [12]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX   PubMed=25832411; DOI=10.1038/nature14039;
RA   Heilmann S., Drichel D., Clarimon J., Fernandez V., Lacour A., Wagner H.,
RA   Thelen M., Hernandez I., Fortea J., Alegret M., Blesa R., Mauleon A.,
RA   Roca M.R., Kornhuber J., Peters O., Heun R., Froelich L., Huell M.,
RA   Heneka M.T., Ruether E., Riedel-Heller S., Scherer M., Wiltfang J.,
RA   Jessen F., Becker T., Tarraga L., Boada M., Maier W., Lleo A., Ruiz A.,
RA   Noethen M.M., Ramirez A.;
RT   "PLD3 in non-familial Alzheimer's disease.";
RL   Nature 520:E3-E5(2015).
RN   [13]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX   PubMed=25832413; DOI=10.1038/nature14040;
RA   Hooli B.V., Lill C.M., Mullin K., Qiao D., Lange C., Bertram L.,
RA   Tanzi R.E.;
RT   "PLD3 gene variants and Alzheimer's disease.";
RL   Nature 520:E7-E8(2015).
RN   [14]
RP   POSSIBLE INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX   PubMed=25832409; DOI=10.1038/nature14041;
RA   Cruchaga C., Goate A.M.;
RT   "Cruchaga & Goate reply.";
RL   Nature 520:E10-E10(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).
RN   [16]
RP   INVOLVEMENT IN SCA46, VARIANT SCA46 PRO-308, AND GLYCOSYLATION.
RX   PubMed=29053796; DOI=10.1093/brain/awx251;
RA   Nibbeling E.A.R., Duarri A., Verschuuren-Bemelmans C.C., Fokkens M.R.,
RA   Karjalainen J.M., Smeets C.J.L.M., de Boer-Bergsma J.J., van der Vries G.,
RA   Dooijes D., Bampi G.B., van Diemen C., Brunt E., Ippel E., Kremer B.,
RA   Vlak M., Adir N., Wijmenga C., van de Warrenburg B.P.C., Franke L.,
RA   Sinke R.J., Verbeek D.S.;
RT   "Exome sequencing and network analysis identifies shared mechanisms
RT   underlying spinocerebellar ataxia.";
RL   Brain 140:2860-2878(2017).
RN   [17]
RP   LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, TISSUE SPECIFICITY,
RP   CHARACTERIZATION OF VARIANTS MET-232, FUNCTION, AND MUTAGENESIS OF LYS-418.
RX   PubMed=28128235; DOI=10.1038/nature21030;
RA   Fazzari P., Horre K., Arranz A.M., Frigerio C.S., Saito T., Saido T.C.,
RA   De Strooper B.;
RT   "PLD3 gene and processing of APP.";
RL   Nature 541:E1-E2(2017).
RN   [18]
RP   CHARACTERIZATION OF VARIANT SCA46 PRO-308, FUNCTION, CATALYTIC ACTIVITY,
RP   AND SUBCELLULAR LOCATION.
RX   PubMed=30312375; DOI=10.1093/brain/awy258;
RA   Gonzalez A.C., Stroobants S., Reisdorf P., Gavin A.L., Nemazee D.,
RA   Schwudke D., D'Hooge R., Saftig P., Damme M.;
RT   "PLD3 and spinocerebellar ataxia.";
RL   Brain 141:E78-E78(2018).
RN   [19]
RP   FUNCTION, SUBCELLULAR LOCATION, AND TOPOLOGY.
RX   PubMed=29368044; DOI=10.1007/s00018-018-2752-9;
RA   Mukadam A.S., Breusegem S.Y., Seaman M.N.J.;
RT   "Analysis of novel endosome-to-Golgi retrieval genes reveals a role for
RT   PLD3 in regulating endosomal protein sorting and amyloid precursor protein
RT   processing.";
RL   Cell. Mol. Life Sci. 75:2613-2625(2018).
RN   [20]
RP   SUBCELLULAR LOCATION, GLYCOSYLATION, AND MUTAGENESIS OF TYR-7.
RX   PubMed=29386126; DOI=10.1016/j.celrep.2017.12.100;
RA   Gonzalez A.C., Schweizer M., Jagdmann S., Bernreuther C., Reinheckel T.,
RA   Saftig P., Damme M.;
RT   "Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes.";
RL   Cell Rep. 22:1040-1053(2018).
RN   [21]
RP   FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=30111894; DOI=10.1038/s41590-018-0179-y;
RA   Gavin A.L., Huang D., Huber C., Maartensson A., Tardif V., Skog P.D.,
RA   Blane T.R., Thinnes T.C., Osborn K., Chong H.S., Kargaran F., Kimm P.,
RA   Zeitjian A., Sielski R.L., Briggs M., Schulz S.R., Zarpellon A.,
RA   Cravatt B., Pang E.S., Teijaro J., de la Torre J.C., O'Keeffe M.,
RA   Hochrein H., Damme M., Teyton L., Lawson B.R., Nemazee D.;
RT   "PLD3 and PLD4 are single-stranded acid exonucleases that regulate
RT   endosomal nucleic-acid sensing.";
RL   Nat. Immunol. 19:942-953(2018).
RN   [22]
RP   FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=34620855; DOI=10.1038/s41467-021-26150-w;
RA   Gavin A.L., Huang D., Blane T.R., Thinnes T.C., Murakami Y., Fukui R.,
RA   Miyake K., Nemazee D.;
RT   "Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory
RT   triggering by multiple sensors.";
RL   Nat. Commun. 12:5874-5874(2021).
RN   [23]
RP   FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS MET-232; SER-284
RP   AND ALA-426, AND MUTAGENESIS OF MET-6; LYS-228 AND ASN-236.
RX   PubMed=37225734; DOI=10.1038/s41467-023-38501-w;
RA   Van Acker Z.P., Perdok A., Hellemans R., North K., Vorsters I., Cappel C.,
RA   Dehairs J., Swinnen J.V., Sannerud R., Bretou M., Damme M., Annaert W.;
RT   "Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide
RT   signaling and APP metabolism.";
RL   Nat. Commun. 14:2847-2847(2023).
RN   [24]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF HIS-201;
RP   LYS-203; ASP-208; HIS-416; LYS-418 AND GLU-423, CHARACTERIZATION OF VARIANT
RP   MET-232, AND CHARACTERIZATION OF VARIANT SCA46 PRO-308.
RX   PubMed=39423811; DOI=10.1016/j.cell.2024.09.036;
RA   Singh S., Dransfeld U.E., Ambaw Y.A., Lopez-Scarim J., Farese R.V. Jr.,
RA   Walther T.C.;
RT   "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid
RT   degradation in lysosomes.";
RL   Cell 0:0-0(2024).
RN   [25]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP   PROPERTIES, CHARACTERIZATION OF VARIANT SCA46 PRO-308, VARIANT MET-232, AND
RP   MUTAGENESIS OF ILE-163; ARG-356 AND PRO-410.
RX   PubMed=38537643; DOI=10.1016/j.str.2024.02.019;
RA   Yuan M., Peng L., Huang D., Gavin A., Luan F., Tran J., Feng Z., Zhu X.,
RA   Matteson J., Wilson I.A., Nemazee D.;
RT   "Structural and mechanistic insights into disease-associated endolysosomal
RT   exonucleases PLD3 and PLD4.";
RL   Structure 32:766-779.e7(2024).
RN   [26] {ECO:0007744|PDB:8S86}
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.80 ANGSTROMS) OF 60-490, FUNCTION,
RP   CATALYTIC ACTIVITY, TISSUE SPECIFICITY, SUBUNIT, DOMAIN, MUTAGENESIS OF
RP   HIS-201; HIS-337; HIS-339; ARG-340; HIS-388; HIS-390; TYR-411 AND HIS-416,
RP   CHARACTERIZATION OF VARIANT SCA46 PRO-308, AND CHARACTERIZATION OF VARIANT
RP   MET-232.
RX   PubMed=38697119; DOI=10.1016/j.immuni.2024.04.010;
RA   Berouti M., Lammens K., Heiss M., Hansbauer L., Bauernfried S., Stoeckl J.,
RA   Pinci F., Piseddu I., Greulich W., Wang M., Jung C., Froehlich T.,
RA   Carell T., Hopfner K.P., Hornung V.;
RT   "Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively
RT   generate RNA ligands for TLR7 activation.";
RL   Immunity 57:1482-1496.e8(2024).
RN   [27] {ECO:0007744|PDB:8Q1K, ECO:0007744|PDB:8Q1X}
RP   X-RAY CRYSTALLOGRAPHY (1.51 ANGSTROMS) OF 72-490 IN COMPLEX WITH MG(2+),
RP   SUBUNIT, DOMAIN, GLYCOSYLATION AT ASN-97; ASN-132; ASN-236; ASN-284 AND
RP   ASN-387, PROTEOLYTIC CLEAVAGE, FUNCTION, AND MUTAGENESIS OF CYS-300;
RP   ARG-350; TYR-354; PHE-377; SER-380; LYS-418; GLU-423 AND ASN-432.
RX   PubMed=37994783; DOI=10.1093/nar/gkad1114;
RA   Roske Y., Cappel C., Cremer N., Hoffmann P., Koudelka T., Tholey A.,
RA   Heinemann U., Daumke O., Damme M.;
RT   "Structural analysis of PLD3 reveals insights into the mechanism of
RT   lysosomal 5' exonuclease-mediated nucleic acid degradation.";
RL   Nucleic Acids Res. 52:370-384(2024).
CC   -!- FUNCTION: 5'->3' exonuclease that hydrolyzes the phosphodiester bond of
CC       single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3'-
CC       monophosphates and 5'-end 5'-hydroxy deoxyribonucleotide/ribonucleotide
CC       fragments (PubMed:30111894, PubMed:30312375, PubMed:34620855,
CC       PubMed:37225734, PubMed:37994783, PubMed:38537643, PubMed:38697119).
CC       Partially redundant with PLD4, can cleave all four nucleotides
CC       displaying higher efficiency for ssDNA and RNA fragments initiated with
CC       uridine and guanosine residues and lower efficiency for cytidine-
CC       initiated substrates (PubMed:30111894, PubMed:30312375,
CC       PubMed:34620855, PubMed:37225734, PubMed:37994783, PubMed:38537643,
CC       PubMed:38697119). As a result, it does not always degrade
CC       polynucleotides to the single nucleotide level, it can stall at
CC       specific sites sparing certain fragments from exonucleolytic
CC       degradation (PubMed:30111894, PubMed:30312375, PubMed:34620855,
CC       PubMed:37225734, PubMed:37994783, PubMed:38537643, PubMed:38697119).
CC       Processes self and pathogenic ssDNA and RNA molecules that reach the
CC       endolysosomal compartment via phagocytosis or autophagy and may serve
CC       as 'danger' signals for recognition by innate immune receptors such as
CC       toll-like receptors (TLRs) (PubMed:34620855, PubMed:37225734,
CC       PubMed:38697119). Degrades mitochondrial CpG-rich ssDNA fragments to
CC       prevent TLR9 activation and autoinflammatory response, but it can
CC       cleave viral RNA to generate ligands for TLR7 activation and initiate
CC       antiviral immune responses (PubMed:34620855, PubMed:37225734,
CC       PubMed:38697119). In plasmacytoid dendritic cells, it cooperates with
CC       endonuclease RNASET2 to release 2',3'-cyclic guanosine monophosphate
CC       (2',3'-cGMP), a potent stimulatory ligand for TLR7 (PubMed:34620855,
CC       PubMed:37225734, PubMed:38697119). Produces 2',3'-cGMPs and cytidine-
CC       rich RNA fragments that occupy TLR7 ligand-binding pockets and trigger
CC       a signaling-competent state (PubMed:34620855, PubMed:37225734,
CC       PubMed:38697119). Can exert polynucleotide phosphatase activity toward
CC       5'-phosphorylated ssDNA substrates although at a slow rate
CC       (PubMed:38537643). Transphosphatidylase that catalyzes the exchange
CC       with R to S stereo-inversion of the glycerol moiety between (S,R)-
CC       lysophosphatidylglycerol (LPG) and monoacylglycerol (MAG) substrates to
CC       yield (S,S)-bis(monoacylglycero)phosphate (BMP) (PubMed:39423811). Can
CC       synthesize a variety of (S,S)-BMPs representing the main phospholipid
CC       constituent of lysosomal intralumenal vesicle (ILV) membranes that bind
CC       acid hydrolases for lipid degradation (PubMed:39423811). Regulates the
CC       homeostasis and interorganellar communication of the endolysosomal
CC       system with an overall impact on cellular removal of dysfunctional
CC       organelles via autophagy as well as proper protein and lipid turnover
CC       (PubMed:28128235, PubMed:29368044, PubMed:37225734). May play a role in
CC       myotube formation in response to ER stress (PubMed:22428023).
CC       {ECO:0000269|PubMed:22428023, ECO:0000269|PubMed:28128235,
CC       ECO:0000269|PubMed:29368044, ECO:0000269|PubMed:30111894,
CC       ECO:0000269|PubMed:30312375, ECO:0000269|PubMed:34620855,
CC       ECO:0000269|PubMed:37225734, ECO:0000269|PubMed:37994783,
CC       ECO:0000269|PubMed:38537643, ECO:0000269|PubMed:38697119,
CC       ECO:0000269|PubMed:39423811}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Exonucleolytic cleavage in the 5'- to 3'-direction to yield
CC         nucleoside 3'-phosphates.; EC=3.1.16.1;
CC         Evidence={ECO:0000269|PubMed:30111894, ECO:0000269|PubMed:30312375,
CC         ECO:0000269|PubMed:34620855, ECO:0000269|PubMed:37225734,
CC         ECO:0000269|PubMed:38537643};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end 5'-dephospho-ribonucleotidyl-ribonucleotide-RNA + H2O
CC         = a ribonucleoside 3'-phosphate + a 5'-end dephospho-ribonucleoside-
CC         RNA + H(+); Xref=Rhea:RHEA:81375, Rhea:RHEA-COMP:13936, Rhea:RHEA-
CC         COMP:19670, ChEBI:CHEBI:13197, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:138284, ChEBI:CHEBI:231871;
CC         Evidence={ECO:0000269|PubMed:34620855};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:81376;
CC         Evidence={ECO:0000305|PubMed:34620855};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ribonucleoside 3'-phosphate-2'-3'-cyclophospho-GMP + H2O = a
CC         ribonucleoside 3'-phosphate + 2',3'-cyclophospho-GMP + H(+);
CC         Xref=Rhea:RHEA:81319, ChEBI:CHEBI:13197, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:60837, ChEBI:CHEBI:231870;
CC         Evidence={ECO:0000269|PubMed:38697119};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:81320;
CC         Evidence={ECO:0000269|PubMed:38697119};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end 5'-dephospho-2'-deoxyribonucleotidyl-2'-
CC         deoxyribonucleotide in single-stranded DNA + H2O = a 5'-end
CC         dephospho-2'-deoxyribonucleoside in single-stranded DNA + a 2'-
CC         deoxyribonucleoside 3'-phosphate + H(+); Xref=Rhea:RHEA:81379,
CC         Rhea:RHEA-COMP:19701, Rhea:RHEA-COMP:19702, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:131705, ChEBI:CHEBI:136416,
CC         ChEBI:CHEBI:231873; Evidence={ECO:0000269|PubMed:30111894,
CC         ECO:0000269|PubMed:37225734, ECO:0000269|PubMed:38537643};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:81380;
CC         Evidence={ECO:0000305|PubMed:30111894, ECO:0000305|PubMed:37225734,
CC         ECO:0000305|PubMed:38537643};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end 5'-phospho-2'-deoxyribonucleotide in single-stranded
CC         DNA + H2O = a 5'-end 5'-dephospho-2'-deoxyribonucleotide in single-
CC         stranded DNA + phosphate; Xref=Rhea:RHEA:82335, Rhea:RHEA-COMP:19868,
CC         Rhea:RHEA-COMP:19869, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474,
CC         ChEBI:CHEBI:136412, ChEBI:CHEBI:136416;
CC         Evidence={ECO:0000269|PubMed:38537643};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:82336;
CC         Evidence={ECO:0000305|PubMed:38537643};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an (R,S)-glycero-3-phospho-(3'-acyl-1'-glycerol) + a 1-acyl-
CC         sn-glycerol = a 3-acyl-sn-glycero-1-phospho-(3'-acyl-1'-sn-glycerol)
CC         + glycerol; Xref=Rhea:RHEA:82563, ChEBI:CHEBI:17754,
CC         ChEBI:CHEBI:64683, ChEBI:CHEBI:77717, ChEBI:CHEBI:232393;
CC         Evidence={ECO:0000269|PubMed:39423811};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:82564;
CC         Evidence={ECO:0000305|PubMed:39423811};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3-lyso-sn-glycero-1-phospho-(3'-(9Z-octadecenoyl)-1'-sn-
CC         glycerol) + 1-(9Z-octadecenoyl)-sn-glycerol = 3-(9Z-octadecenoyl)-sn-
CC         glycero-1-phospho-(3'-(9Z-octadecenoyl)-1'-sn-glycerol) + glycerol;
CC         Xref=Rhea:RHEA:82567, ChEBI:CHEBI:17754, ChEBI:CHEBI:75757,
CC         ChEBI:CHEBI:139150, ChEBI:CHEBI:232394;
CC         Evidence={ECO:0000269|PubMed:39423811};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:82568;
CC         Evidence={ECO:0000305|PubMed:39423811};
CC   -!- ACTIVITY REGULATION: The exonuclease activity toward ssDNA substrate is
CC       Ca(2+) and Mg(2+)-independent, but it is inhibited by Fe(2+), Cu(2+)
CC       and to a lesser extent Zn(2+) ions. {ECO:0000269|PubMed:38537643}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=18 uM for 5'-OH ApA diribonucleotide
CC         {ECO:0000269|PubMed:34620855};
CC         KM=72 uM for 5'-OH CpA diribonucleotide
CC         {ECO:0000269|PubMed:34620855};
CC         KM=84 uM for 5'-OH UpA diribonucleotide
CC         {ECO:0000269|PubMed:34620855};
CC         KM=93 uM for 5'-OH GpA diribonucleotide
CC         {ECO:0000269|PubMed:34620855};
CC       pH dependence:
CC         Active at acidic pHs. {ECO:0000269|PubMed:30111894,
CC         ECO:0000269|PubMed:34620855, ECO:0000269|PubMed:38537643};
CC   -!- SUBUNIT: Homodimer (PubMed:37994783, PubMed:38697119). Interacts with
CC       APP. {ECO:0000269|PubMed:24336208, ECO:0000269|PubMed:37994783,
CC       ECO:0000269|PubMed:38697119}.
CC   -!- INTERACTION:
CC       Q8IV08; Q8TBE1: CNIH3; NbExp=3; IntAct=EBI-2689908, EBI-12208021;
CC       Q8IV08; P19838: NFKB1; NbExp=2; IntAct=EBI-2689908, EBI-300010;
CC       Q8IV08; P35372-10: OPRM1; NbExp=3; IntAct=EBI-2689908, EBI-12807478;
CC       Q8IV08; Q9NRQ5: SMCO4; NbExp=3; IntAct=EBI-2689908, EBI-8640191;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}; Single-pass
CC       type II membrane protein {ECO:0000269|PubMed:15794758,
CC       ECO:0000269|PubMed:22428023}. Lysosome lumen
CC       {ECO:0000269|PubMed:29386126, ECO:0000269|PubMed:30312375,
CC       ECO:0000305|PubMed:39423811}. Early endosome membrane
CC       {ECO:0000269|PubMed:29386126}; Single-pass type II membrane protein
CC       {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}. Late
CC       endosome membrane {ECO:0000269|PubMed:29386126}; Single-pass type II
CC       membrane protein {ECO:0000269|PubMed:15794758,
CC       ECO:0000269|PubMed:22428023}. Golgi apparatus membrane
CC       {ECO:0000269|PubMed:29368044}; Single-pass type II membrane protein
CC       {ECO:0000269|PubMed:29368044}. Endosome membrane
CC       {ECO:0000269|PubMed:29368044}; Single-pass type II membrane protein
CC       {ECO:0000269|PubMed:29368044}. Note=Localizes to ER-associated vesicles
CC       in differentiating myotubes (PubMed:22428023). Sorted into intralumenal
CC       vesicles (ILVs) in lysosomes. The soluble form in lysosome arises by
CC       proteolytic processing of the membrane-bound form (PubMed:29386126).
CC       Colocalizes with APP in endosomes (PubMed:29368044).
CC       {ECO:0000269|PubMed:22428023, ECO:0000269|PubMed:29368044,
CC       ECO:0000269|PubMed:29386126}.
CC   -!- TISSUE SPECIFICITY: Widely expressed. In the brain, high levels of
CC       expression are detected in the frontal, temporal and occipital cortices
CC       and hippocampus. Expressed at low level in corpus callosum. Expressed
CC       in plasmacytoid dendritic cells and monocytes (at protein level).
CC       {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:24336208,
CC       ECO:0000269|PubMed:38697119}.
CC   -!- DOMAIN: The catalytic domain contains two conserved PLD
CC       phosphodiesterase HxK(x4)D(E) motifs that accomodate the phosphate
CC       group of the nucleic acid substrates, with one nucleophile histidine
CC       residue forming a phosphohistidine intermediate and the other histidine
CC       protonating the leaving 5'-OH ssDNA/RNA fragment, resulting in the
CC       cleavage of the phosphodiester bond. The homodimer has two independent
CC       catalytic domains arranged at the dimer interface.
CC       {ECO:0000269|PubMed:37994783, ECO:0000269|PubMed:38697119}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:15794758,
CC       ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:29053796,
CC       ECO:0000269|PubMed:29386126, ECO:0000269|PubMed:37994783}.
CC   -!- PTM: Proteolytically processed to a soluble active form that is stable
CC       within endosomes and lysosomes. During transport through the secretory
CC       pathway becomes proteolysed by cysteine proteases, thereby releasing a
CC       stable soluble lysosomal lumenal polypeptide, whereas the
CC       transmembrane-bound fragment is rapidly degraded. Its transport route
CC       to lysosomes involves ubiquitination and the ESCRT complex.
CC       {ECO:0000269|PubMed:29386126, ECO:0000269|PubMed:37994783}.
CC   -!- PTM: Ubiquitinated at N-terminus. Ubiquitination mediates sorting into
CC       lysosomes. {ECO:0000269|PubMed:29386126}.
CC   -!- DISEASE: Spinocerebellar ataxia 46 (SCA46) [MIM:617770]: A form of
CC       spinocerebellar ataxia, a clinically and genetically heterogeneous
CC       group of cerebellar disorders. Patients show progressive incoordination
CC       of gait and often poor coordination of hands, speech and eye movements,
CC       due to degeneration of the cerebellum with variable involvement of the
CC       brainstem and spinal cord. SCA46 is a slowly progressive, autosomal
CC       dominant form with onset in adulthood. {ECO:0000269|PubMed:29053796,
CC       ECO:0000269|PubMed:30312375, ECO:0000269|PubMed:38537643,
CC       ECO:0000269|PubMed:38697119, ECO:0000269|PubMed:39423811}. Note=The
CC       disease may be caused by variants affecting the gene represented in
CC       this entry. There is limited evidences for implication of PLD3 in
CC       SCA46. Knockout mice do not present signs of cerebellar degeneration or
CC       spinocerebellar ataxia at 9 months of age, challenging the
CC       interpretation of the suggested loss-of-function mechanism for PLD3 as
CC       the SCA46-causative gene. {ECO:0000269|PubMed:30312375}.
CC   -!- DISEASE: Note=Genetic variants in PLD3 have been suggested to be
CC       associated with an increased risk for Alzheimer disease
CC       (PubMed:24336208, PubMed:25832409). Further studies, however, did not
CC       support PLD3 involvement in this disease (PubMed:25832408,
CC       PubMed:25832410, PubMed:25832411, PubMed:25832413, PubMed:26411346).
CC       Futhermore, it is controversial whether PLD3 plays a role in amyloid
CC       precursor protein processing (APP) or not (PubMed:24336208). In a
CC       relevant Alzheimer's disease mouse model PLD3 deficiency does not
CC       affect APP metabolism or amyloid plaque burden (PubMed:28128235).
CC       However one study shown that PLD3 influences APP processing
CC       (PubMed:24336208). {ECO:0000269|PubMed:24336208,
CC       ECO:0000269|PubMed:25832408, ECO:0000269|PubMed:25832409,
CC       ECO:0000269|PubMed:25832410, ECO:0000269|PubMed:25832411,
CC       ECO:0000269|PubMed:25832413, ECO:0000269|PubMed:26411346,
CC       ECO:0000269|PubMed:28128235}.
CC   -!- SIMILARITY: Belongs to the phospholipase D family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAB16799.1; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; U60644; AAB16799.1; ALT_FRAME; mRNA.
DR   EMBL; BC000553; AAH00553.2; -; mRNA.
DR   EMBL; BC036327; AAH36327.1; -; mRNA.
DR   EMBL; BC096820; AAH96820.1; -; mRNA.
DR   CCDS; CCDS33027.1; -.
DR   RefSeq; NP_001026866.1; NM_001031696.4.
DR   RefSeq; NP_001278240.1; NM_001291311.2.
DR   RefSeq; NP_036400.2; NM_012268.4.
DR   PDB; 8Q1K; X-ray; 1.51 A; A/B=72-490.
DR   PDB; 8Q1X; X-ray; 1.85 A; A/B=61-490.
DR   PDB; 8S86; EM; 2.80 A; A/B=60-490.
DR   PDB; 8V5T; X-ray; 2.30 A; A/B=1-490.
DR   PDBsum; 8Q1K; -.
DR   PDBsum; 8Q1X; -.
DR   PDBsum; 8S86; -.
DR   PDBsum; 8V5T; -.
DR   AlphaFoldDB; Q8IV08; -.
DR   EMDB; EMD-19798; -.
DR   SMR; Q8IV08; -.
DR   BioGRID; 117173; 282.
DR   FunCoup; Q8IV08; 863.
DR   IntAct; Q8IV08; 80.
DR   MINT; Q8IV08; -.
DR   STRING; 9606.ENSP00000387050; -.
DR   BindingDB; Q8IV08; -.
DR   ChEMBL; CHEMBL2769; -.
DR   GlyConnect; 1604; 14 N-Linked glycans (3 sites).
DR   GlyCosmos; Q8IV08; 5 sites, 14 glycans.
DR   GlyGen; Q8IV08; 7 sites, 37 N-linked glycans (4 sites), 3 N-linked;o-linked glycans (1 site), 1 O-linked glycan (1 site).
DR   iPTMnet; Q8IV08; -.
DR   PhosphoSitePlus; Q8IV08; -.
DR   SwissPalm; Q8IV08; -.
DR   BioMuta; PLD3; -.
DR   DMDM; 74750647; -.
DR   jPOST; Q8IV08; -.
DR   MassIVE; Q8IV08; -.
DR   PaxDb; 9606-ENSP00000387050; -.
DR   PeptideAtlas; Q8IV08; -.
DR   ProteomicsDB; 70639; -.
DR   Pumba; Q8IV08; -.
DR   TopDownProteomics; Q8IV08; -.
DR   Antibodypedia; 2295; 133 antibodies from 24 providers.
DR   DNASU; 23646; -.
DR   Ensembl; ENST00000356508.9; ENSP00000348901.5; ENSG00000105223.22.
DR   Ensembl; ENST00000409281.5; ENSP00000387022.1; ENSG00000105223.22.
DR   Ensembl; ENST00000409419.5; ENSP00000386293.1; ENSG00000105223.22.
DR   Ensembl; ENST00000409587.5; ENSP00000387050.1; ENSG00000105223.22.
DR   Ensembl; ENST00000409735.9; ENSP00000386938.3; ENSG00000105223.22.
DR   Ensembl; ENST00000700616.1; ENSP00000515107.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700619.1; ENSP00000515110.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700620.1; ENSP00000515111.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700621.1; ENSP00000515112.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700623.1; ENSP00000515113.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700625.1; ENSP00000515115.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700626.1; ENSP00000515116.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700628.1; ENSP00000515117.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700630.1; ENSP00000515118.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700631.1; ENSP00000515119.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700632.1; ENSP00000515120.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700633.1; ENSP00000515121.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700634.1; ENSP00000515122.1; ENSG00000105223.22.
DR   Ensembl; ENST00000700637.1; ENSP00000515123.1; ENSG00000105223.22.
DR   GeneID; 23646; -.
DR   KEGG; hsa:23646; -.
DR   MANE-Select; ENST00000409735.9; ENSP00000386938.3; NM_012268.4; NP_036400.2.
DR   UCSC; uc002onj.5; human.
DR   AGR; HGNC:17158; -.
DR   ClinPGx; PA134887482; -.
DR   CTD; 23646; -.
DR   DisGeNET; 23646; -.
DR   GeneCards; PLD3; -.
DR   HGNC; HGNC:17158; PLD3.
DR   HPA; ENSG00000105223; Tissue enhanced (pituitary).
DR   MalaCards; PLD3; -.
DR   MIM; 615698; gene.
DR   MIM; 617770; phenotype.
DR   OpenTargets; ENSG00000105223; -.
DR   Orphanet; 589522; Spinocerebellar ataxia type 46.
DR   VEuPathDB; HostDB:ENSG00000105223; -.
DR   eggNOG; KOG3603; Eukaryota.
DR   GeneTree; ENSGT00950000183059; -.
DR   HOGENOM; CLU_027021_0_0_1; -.
DR   InParanoid; Q8IV08; -.
DR   OMA; RDNHTHF; -.
DR   OrthoDB; 1923775at2759; -.
DR   PAN-GO; Q8IV08; 0 GO annotations based on evolutionary models.
DR   PhylomeDB; Q8IV08; -.
DR   PathwayCommons; Q8IV08; -.
DR   Reactome; R-HSA-1483148; Synthesis of PG.
DR   Reactome; R-HSA-2029485; Role of phospholipids in phagocytosis.
DR   SignaLink; Q8IV08; -.
DR   SIGNOR; Q8IV08; -.
DR   Agora; ENSG00000105223; -.
DR   BioGRID-ORCS; 23646; 16 hits in 1172 CRISPR screens.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; PLD3; human.
DR   GenomeRNAi; 23646; -.
DR   Pharos; Q8IV08; Tbio.
DR   PRO; PR:Q8IV08; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; Q8IV08; protein.
DR   Bgee; ENSG00000105223; Expressed in adenohypophysis and 197 other cell types or tissues.
DR   ExpressionAtlas; Q8IV08; baseline and differential.
DR   GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB.
DR   GO; GO:0012505; C:endomembrane system; IBA:GO_Central.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR   GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB.
DR   GO; GO:0043202; C:lysosomal lumen; IDA:UniProtKB.
DR   GO; GO:0005765; C:lysosomal membrane; IEA:Ensembl.
DR   GO; GO:0004630; F:phospholipase D activity; TAS:ProtInc.
DR   GO; GO:0045145; F:single-stranded DNA 5'-3' DNA exonuclease activity; IDA:UniProtKB.
DR   GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR   GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR   GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0014902; P:myotube differentiation; IDA:UniProtKB.
DR   GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR   CDD; cd09144; PLDc_vPLD3_1; 1.
DR   CDD; cd09147; PLDc_vPLD3_2; 1.
DR   FunFam; 3.30.870.10:FF:000013; phospholipase D3 isoform X1; 1.
DR   FunFam; 3.30.870.10:FF:000019; phospholipase D3 isoform X1; 1.
DR   Gene3D; 3.30.870.10; Endonuclease Chain A; 2.
DR   InterPro; IPR050874; Diverse_PLD-related.
DR   InterPro; IPR032803; PLDc_3.
DR   InterPro; IPR001736; PLipase_D/transphosphatidylase.
DR   PANTHER; PTHR10185:SF16; 5'-3' EXONUCLEASE PLD3; 1.
DR   PANTHER; PTHR10185; PHOSPHOLIPASE D - RELATED; 1.
DR   Pfam; PF13918; PLDc_3; 1.
DR   SMART; SM00155; PLDc; 2.
DR   SUPFAM; SSF56024; Phospholipase D/nuclease; 2.
DR   PROSITE; PS50035; PLD; 2.
PE   1: Evidence at protein level;
KW   3D-structure; Disease variant; Disulfide bond; Endoplasmic reticulum;
KW   Endosome; Exonuclease; Glycoprotein; Golgi apparatus; Hydrolase; Immunity;
KW   Inflammatory response; Lipid metabolism; Lysosome; Membrane;
KW   Neurodegeneration; Nuclease; Phospholipid metabolism;
KW   Proteomics identification; Reference proteome; Repeat; Signal-anchor;
KW   Spinocerebellar ataxia; Transmembrane; Transmembrane helix;
KW   Ubl conjugation.
FT   CHAIN           1..490
FT                   /note="5'-3' exonuclease PLD3"
FT                   /id="PRO_0000280326"
FT   TOPO_DOM        1..38
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305|PubMed:22428023"
FT   TRANSMEM        39..59
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000269|PubMed:22428023"
FT   TOPO_DOM        60..490
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000305|PubMed:22428023"
FT   DOMAIN          196..223
FT                   /note="PLD phosphodiesterase 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT   DOMAIN          411..437
FT                   /note="PLD phosphodiesterase 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT   ACT_SITE        201
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT   ACT_SITE        201
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT   ACT_SITE        203
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT   ACT_SITE        208
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT   ACT_SITE        416
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   BINDING         201
FT                   /ligand="phosphate"
FT                   /ligand_id="ChEBI:CHEBI:43474"
FT                   /ligand_part="5'-phosphate 2'-deoxynucleoside residue"
FT                   /ligand_part_id="ChEBI:CHEBI:136412"
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   BINDING         203
FT                   /ligand="phosphate"
FT                   /ligand_id="ChEBI:CHEBI:43474"
FT                   /ligand_part="5'-phosphate 2'-deoxynucleoside residue"
FT                   /ligand_part_id="ChEBI:CHEBI:136412"
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   BINDING         218
FT                   /ligand="phosphate"
FT                   /ligand_id="ChEBI:CHEBI:43474"
FT                   /ligand_part="5'-phosphate 2'-deoxynucleoside residue"
FT                   /ligand_part_id="ChEBI:CHEBI:136412"
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   BINDING         416
FT                   /ligand="phosphate"
FT                   /ligand_id="ChEBI:CHEBI:43474"
FT                   /ligand_part="5'-phosphate 2'-deoxynucleoside residue"
FT                   /ligand_part_id="ChEBI:CHEBI:136412"
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   BINDING         438
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000269|PubMed:37994783,
FT                   ECO:0007744|PDB:8Q1X"
FT   SITE            71..72
FT                   /note="Cleavage; by lysosomal cysteine proteases"
FT                   /evidence="ECO:0000305|PubMed:29386126,
FT                   ECO:0000305|PubMed:37994783"
FT   CARBOHYD        97
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19159218,
FT                   ECO:0000269|PubMed:37994783"
FT   CARBOHYD        132
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19159218,
FT                   ECO:0000269|PubMed:37994783"
FT   CARBOHYD        236
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   CARBOHYD        284
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   CARBOHYD        387
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   DISULFID        77..239
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   DISULFID        81..237
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   DISULFID        366..487
FT                   /evidence="ECO:0000250|UniProtKB:O35405"
FT   VARIANT         63
FT                   /note="G -> S (in dbSNP:rs142070038)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075905"
FT   VARIANT         76
FT                   /note="P -> A (in dbSNP:rs138674695)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075906"
FT   VARIANT         159
FT                   /note="V -> M (in dbSNP:rs374184677)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075907"
FT   VARIANT         162
FT                   /note="R -> C"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075908"
FT   VARIANT         173
FT                   /note="P -> S (in dbSNP:rs866850284)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075909"
FT   VARIANT         175
FT                   /note="A -> G (in dbSNP:rs780604999)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075910"
FT   VARIANT         188
FT                   /note="R -> C (in dbSNP:rs1326374111)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075911"
FT   VARIANT         222
FT                   /note="R -> H (in dbSNP:rs765630414)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075912"
FT   VARIANT         232
FT                   /note="V -> M (found in patients with Alzheimer disease;
FT                   uncertain significance; does not reduce either amyloid-beta
FT                   levels or APP expression; no effect on protein maturation
FT                   or trafficking to lysosomes; partial loss of dimer
FT                   formation; decreased or complete loss of exonuclease
FT                   activity toward mitochondrial CpG-rich ssDNA fragments
FT                   resulting in DNA build-up in the endolysosomal compartment,
FT                   increased TLR9 pro-inflammatory signaling and increased
FT                   mitophagy; decreased exonuclease activity toward RNA
FT                   substrate; decreased (S,S)- BMP synthase activity;
FT                   dbSNP:rs145999145)"
FT                   /evidence="ECO:0000269|PubMed:24336208,
FT                   ECO:0000269|PubMed:25832408, ECO:0000269|PubMed:25832409,
FT                   ECO:0000269|PubMed:25832410, ECO:0000269|PubMed:25832411,
FT                   ECO:0000269|PubMed:25832413, ECO:0000269|PubMed:26411346,
FT                   ECO:0000269|PubMed:28128235, ECO:0000269|PubMed:37225734,
FT                   ECO:0000269|PubMed:38537643, ECO:0000269|PubMed:38697119,
FT                   ECO:0000269|PubMed:39423811"
FT                   /id="VAR_071186"
FT   VARIANT         242
FT                   /note="R -> Q (in dbSNP:rs757965784)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075913"
FT   VARIANT         249
FT                   /note="E -> G (in dbSNP:rs746715924)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075914"
FT   VARIANT         272
FT                   /note="R -> C (in dbSNP:rs144312764)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075915"
FT   VARIANT         284
FT                   /note="N -> S (no effect on protein maturation or
FT                   trafficking to lysosomes; displays differential exonuclease
FT                   activity depending on ssDNA sequence, showing increased
FT                   activity toward ATP6 CpG-rich ssDNA and normal activity
FT                   toward ND4L CpG-rich ssDNA; increases mitophagy rate;
FT                   dbSNP:rs200274020)"
FT                   /evidence="ECO:0000269|PubMed:26411346,
FT                   ECO:0000269|PubMed:37225734"
FT                   /id="VAR_075916"
FT   VARIANT         293
FT                   /note="A -> V (in dbSNP:rs368737000)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075917"
FT   VARIANT         297
FT                   /note="P -> L"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075918"
FT   VARIANT         300
FT                   /note="C -> Y (in dbSNP:rs146083475)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075919"
FT   VARIANT         308
FT                   /note="L -> P (in SCA46; uncertain significance; induces
FT                   retention in the ER; reduced lysosomal localization;
FT                   reduced proteolytic cleavage; loss of dimerization; loss of
FT                   exonuclease activity toward ssDNA and RNA substrates; loss
FT                   of (S,S)-BMP synthase activity; dbSNP:rs537053537)"
FT                   /evidence="ECO:0000269|PubMed:26411346,
FT                   ECO:0000269|PubMed:29053796, ECO:0000269|PubMed:30312375,
FT                   ECO:0000269|PubMed:38537643, ECO:0000269|PubMed:38697119,
FT                   ECO:0000269|PubMed:39423811"
FT                   /id="VAR_075920"
FT   VARIANT         358
FT                   /note="V -> I (in dbSNP:rs370488565)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075921"
FT   VARIANT         426
FT                   /note="T -> A (no effect on protein maturation or
FT                   trafficking to lysosomes; displays differential exonuclease
FT                   activity depending on ssDNA sequence, showing increased
FT                   activity toward ATP6 CpG-rich ssDNA sequence and normal
FT                   activity toward ND4L CpG-rich ssDNA sequence; increases
FT                   mitophagy rate; dbSNP:rs745463234)"
FT                   /evidence="ECO:0000269|PubMed:26411346,
FT                   ECO:0000269|PubMed:37225734"
FT                   /id="VAR_075922"
FT   VARIANT         429
FT                   /note="G -> R (in dbSNP:rs986006936)"
FT                   /evidence="ECO:0000269|PubMed:26411346"
FT                   /id="VAR_075923"
FT   MUTAGEN         6
FT                   /note="M->R: No effect on protein maturation or trafficking
FT                   to lysosomes. Decreases exonuclease activity toward
FT                   mitochondrial CpG-rich ssDNA fragments resulting in
FT                   mitochondrial DNA build-up in the endolysosomal compartment
FT                   and increased mitophagy rate associated with accumulation
FT                   of amyloid precursor protein-derived C-terminal fragments
FT                   (APP-CTFs) in autophagosomes/autolysosomes."
FT                   /evidence="ECO:0000269|PubMed:37225734"
FT   MUTAGEN         7
FT                   /note="Y->A: Slightly increases plasma membrane
FT                   localization, does not affect delivery to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:29386126"
FT   MUTAGEN         163
FT                   /note="I->M: Tends to form aggregates. Decreases
FT                   exonuclease activity toward ssDNA."
FT                   /evidence="ECO:0000269|PubMed:38537643"
FT   MUTAGEN         201
FT                   /note="H->A: Loss of (S,S)-BMP synthase activity. No effect
FT                   on protein expression or localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:39423811"
FT   MUTAGEN         201
FT                   /note="H->N: Decreases RNA binding; when associated with D-
FT                   337 and N-416. Almost complete loss of RNA binding; when
FT                   associated with D-340 and N-416."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         203
FT                   /note="K->A: Loss of (S,S)-BMP synthase activity. No effect
FT                   on protein expression or localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:39423811"
FT   MUTAGEN         208
FT                   /note="D->A: Loss of (S,S)-BMP synthase activity. No effect
FT                   on protein expression or localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:39423811"
FT   MUTAGEN         228
FT                   /note="K->R: Decreases exonuclease activity toward CpG-free
FT                   or CpG-rich ssDNA substrates. Increases mitophagy rate. No
FT                   effect on protein maturation or trafficking to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:37225734"
FT   MUTAGEN         236
FT                   /note="N->S: Increases exonuclease activity toward CpG-free
FT                   ssDNA substrates. Slightly decreases exonuclease activity
FT                   toward a CpG-rich ATP6 ssDNA sequence. Loss of exonuclease
FT                   activity toward a CpG-rich ND4L ssDNA sequence. Increases
FT                   mitophagy rate. No effect on protein maturation or
FT                   trafficking to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:37225734"
FT   MUTAGEN         300
FT                   /note="C->S: No effect on proteolytical processing or
FT                   localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   MUTAGEN         337
FT                   /note="H->D: Decreases exonuclease activity toward RNA.
FT                   Decreases RNA binding; when associated with N-201 and N-
FT                   416. Results in a 10-fold reduction of exonuclease activity
FT                   toward RNA; when associated with N-339."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         339
FT                   /note="H->D: Results in a 10-fold reduction of exonuclease
FT                   activity toward RNA; when associated with N-337."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         340
FT                   /note="R->D: Prevents dimerization resulting in decreased
FT                   exonuclease activity toward RNA and CpG ssDNA substrates.
FT                   Almost complete loss of RNA binding; when associated with
FT                   N-201 and N-416."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         350
FT                   /note="R->A: Retained in the endoplasmic reticulum. Loss of
FT                   exonuclease activity toward ssDNA; when associated with A-
FT                   354; A-377 and A-380."
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   MUTAGEN         354
FT                   /note="Y->A: Retained in the endoplasmic reticulum. Loss of
FT                   exonuclease activity toward ssDNA; when associated with A-
FT                   350, A-377 and A-380."
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   MUTAGEN         356
FT                   /note="R->H: No effect on exonuclease activity toward
FT                   ssDNA."
FT                   /evidence="ECO:0000269|PubMed:38537643"
FT   MUTAGEN         377
FT                   /note="F->A: Retained in the endoplasmic reticulum. Loss of
FT                   exonuclease activity toward ssDNA; when associated with A-
FT                   350; A-354 and A-380."
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   MUTAGEN         380
FT                   /note="S->A: Retained in the endoplasmic reticulum. Loss of
FT                   exonuclease activity toward ssDNA; when associated with A-
FT                   350; A-354 and A-377."
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   MUTAGEN         388
FT                   /note="H->D: No effect on exonuclease activity toward RNA
FT                   and CpG ssDNA."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         390
FT                   /note="H->D: No effect on exonuclease activity toward RNA
FT                   and CpG ssDNA."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         410
FT                   /note="P->S: No effect on exonuclease activity toward
FT                   ssDNA."
FT                   /evidence="ECO:0000269|PubMed:38537643"
FT   MUTAGEN         411
FT                   /note="Y->A: Decreases exonuclease activity toward RNA and
FT                   ssDNA."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         416
FT                   /note="H->A: Loss of (S,S)-BMP synthase activity. No effect
FT                   on protein expression or localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:39423811"
FT   MUTAGEN         416
FT                   /note="H->N: Decreases RNA binding; when associated with N-
FT                   201 and D-337. Almost complete loss of RNA binding; when
FT                   associated with N-201 and D-340."
FT                   /evidence="ECO:0000269|PubMed:38697119"
FT   MUTAGEN         418
FT                   /note="K->A: Loss of (S,S)-BMP synthase activity. Loss of
FT                   exonuclease activity toward ssDNA. No effect on protein
FT                   expression or localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:39423811"
FT   MUTAGEN         418
FT                   /note="K->R: Impairs myotube formation. Loss of exonuclease
FT                   activity toward ssDNA. No effect on localization to
FT                   lysosomes."
FT                   /evidence="ECO:0000269|PubMed:22428023,
FT                   ECO:0000269|PubMed:28128235, ECO:0000269|PubMed:37994783"
FT   MUTAGEN         423
FT                   /note="E->A: Loss of (S,S)-BMP synthase activity. No effect
FT                   on protein expression or localization to lysosomes. Loss of
FT                   exonuclease activity toward ssDNA."
FT                   /evidence="ECO:0000269|PubMed:37994783,
FT                   ECO:0000269|PubMed:39423811"
FT   MUTAGEN         423
FT                   /note="E->D: No effect on (S,S)-BMP synthase activity,
FT                   protein expression or localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:39423811"
FT   MUTAGEN         432
FT                   /note="N->A: Loss of exonuclease activity toward ssDNA. No
FT                   effect on protein localization to lysosomes."
FT                   /evidence="ECO:0000269|PubMed:37994783"
FT   CONFLICT        473
FT                   /note="S -> I (in Ref. 1; AAB16799)"
FT                   /evidence="ECO:0000305"
FT   STRAND          79..88
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           105..115
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          117..125
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           131..134
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           139..141
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           142..151
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   TURN            152..154
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           155..157
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          160..166
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           175..183
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          186..190
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           192..196
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          204..207
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   TURN            208..210
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          211..216
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           222..225
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          227..236
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           238..254
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           267..269
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          274..277
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          279..283
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          286..295
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           297..299
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           307..317
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          319..327
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          331..333
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           344..356
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          359..365
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           374..382
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   TURN            387..390
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          391..398
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           404..407
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          413..415
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          418..424
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          426..431
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           436..439
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          441..449
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          451..455
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   HELIX           456..469
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          473..475
FT                   /evidence="ECO:0007829|PDB:8S86"
FT   HELIX           480..482
FT                   /evidence="ECO:0007829|PDB:8Q1K"
FT   STRAND          483..485
FT                   /evidence="ECO:0007829|PDB:8Q1K"
SQ   SEQUENCE   490 AA;  54705 MW;  444EC4D02F5610F1 CRC64;
     MKPKLMYQEL KVPAEEPANE LPMNEIEAWK AAEKKARWVL LVLILAVVGF GALMTQLFLW
     EYGDLHLFGP NQRPAPCYDP CEAVLVESIP EGLDFPNAST GNPSTSQAWL GLLAGAHSSL
     DIASFYWTLT NNDTHTQEPS AQQGEEVLRQ LQTLAPKGVN VRIAVSKPSG PQPQADLQAL
     LQSGAQVRMV DMQKLTHGVL HTKFWVVDQT HFYLGSANMD WRSLTQVKEL GVVMYNCSCL
     ARDLTKIFEA YWFLGQAGSS IPSTWPRFYD TRYNQETPME ICLNGTPALA YLASAPPPLC
     PSGRTPDLKA LLNVVDNARS FIYVAVMNYL PTLEFSHPHR FWPAIDDGLR RATYERGVKV
     RLLISCWGHS EPSMRAFLLS LAALRDNHTH SDIQVKLFVV PADEAQARIP YARVNHNKYM
     VTERATYIGT SNWSGNYFTE TAGTSLLVTQ NGRGGLRSQL EAIFLRDWDS PYSHDLDTSA
     DSVGNACRLL
//
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   PSN2_HUMAN              Reviewed;         448 AA.
AC   P49810; A8K8D4; B1AP21; Q96P32;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 1.
DT   28-JAN-2026, entry version 243.
DE   RecName: Full=Presenilin-2 {ECO:0000303|PubMed:10497236};
DE            Short=PS-2;
DE            EC=3.4.23.- {ECO:0000269|PubMed:10497236};
DE   AltName: Full=AD3LP;
DE   AltName: Full=AD5;
DE   AltName: Full=E5-1;
DE   AltName: Full=STM-2;
DE   Contains:
DE     RecName: Full=Presenilin-2 NTF subunit {ECO:0000305|PubMed:10652302};
DE   Contains:
DE     RecName: Full=Presenilin-2 CTF subunit {ECO:0000305|PubMed:10497236, ECO:0000305|PubMed:10652302};
GN   Name=PSEN2 {ECO:0000312|HGNC:HGNC:9509};
GN   Synonyms=AD4, PS2, PSNL2, STM2 {ECO:0000303|PubMed:8661049};
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], AND VARIANT AD4 ILE-141.
RX   PubMed=7638622; DOI=10.1126/science.7638622;
RA   Levy-Lahad E., Wasco W., Poorkaj P., Romano D.M., Oshima J.,
RA   Pettingell W.H. Jr., Yu C.-E., Jondro P.D., Schmidt S.D., Wang K.,
RA   Crowley A.C., Fu Y.-H., Guenette S.Y., Galas D., Nemens E., Wijsman E.M.,
RA   Bird T.D., Schellenberg G.D., Tanzi R.E.;
RT   "Candidate gene for the chromosome 1 familial Alzheimer's disease locus.";
RL   Science 269:973-977(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS AD4 ILE-141 AND VAL-239.
RC   TISSUE=Brain, and Colon;
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   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=8661049; DOI=10.1006/geno.1996.0266;
RA   Levy-Lahad E., Poorkaj P., Wang K., Fu Y.H., Oshima J., Mulligan J.,
RA   Schellenberg G.D.;
RT   "Genomic structure and expression of STM2, the chromosome 1 familial
RT   Alzheimer disease gene.";
RL   Genomics 34:198-204(1996).
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 MRNA] (ISOFORM 3).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Muscle;
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 1-361.
RX   PubMed=8618867; DOI=10.1073/pnas.92.26.12180;
RA   Li J., Ma J., Potter H.;
RT   "Identification and expression analysis of a potential familial Alzheimer
RT   disease gene on chromosome 1 related to AD3.";
RL   Proc. Natl. Acad. Sci. U.S.A. 92:12180-12184(1995).
RN   [10]
RP   NUCLEOTIDE SEQUENCE OF 1-390.
RA   Xu Y., Hu X., Zhou Y., Peng X., Yuan J., Qiang B.;
RL   Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN   [11]
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   [12]
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   [13]
RP   FUNCTION, PROTEOLYTIC CLEAVAGE, ACTIVE SITE ASP-366, AND MUTAGENESIS OF
RP   ASP-366.
RX   PubMed=10497236; DOI=10.1074/jbc.274.40.28669;
RA   Steiner H., Duff K., Capell A., Romig H., Grim M.G., Lincoln S., Hardy J.,
RA   Yu X., Picciano M., Fechteler K., Citron M., Kopan R., Pesold B., Keck S.,
RA   Baader M., Tomita T., Iwatsubo T., Baumeister R., Haass C.;
RT   "A loss of function mutation of presenilin-2 interferes with amyloid beta-
RT   peptide production and notch signaling.";
RL   J. Biol. Chem. 274:28669-28673(1999).
RN   [14]
RP   FUNCTION, PROTEOLYTIC CLEAVAGE, ACTIVE SITES ASP-263 AND ASP-366, AND
RP   MUTAGENESIS OF ASP-263 AND ASP-366.
RX   PubMed=10652302; DOI=10.1074/jbc.275.5.3173;
RA   Kimberly W.T., Xia W., Rahmati T., Wolfe M.S., Selkoe D.J.;
RT   "The transmembrane aspartates in presenilin 1 and 2 are obligatory for
RT   gamma-secretase activity and amyloid beta-protein generation.";
RL   J. Biol. Chem. 275:3173-3178(2000).
RN   [15]
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   [16]
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   [17]
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   [18]
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   [19]
RP   SUBUNIT, AND PROTEOLYTIC CLEAVAGE.
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   [20]
RP   FUNCTION, AND CHARACTERIZATION OF VARIANT AD4 ILE-141.
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   [21]
RP   FUNCTION, AND CHARACTERIZATION OF VARIANT AD4 ILE-141.
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   [22]
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   [23]
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   [24]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22 AND SER-25, 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   [25]
RP   FUNCTION, CHARACTERIZATION OF VARIANTS AD4 ARG-122 AND ILE-141, AND
RP   MUTAGENESIS OF ASP-366.
RX   PubMed=21285369; DOI=10.1073/pnas.1100735108;
RA   Zampese E., Fasolato C., Kipanyula M.J., Bortolozzi M., Pozzan T.,
RA   Pizzo P.;
RT   "Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria
RT   interactions and Ca2+ cross-talk.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:2777-2782(2011).
RN   [26]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22 AND SER-25, 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   [27]
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   [28]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH AP1G1, MUTAGENESIS OF
RP   SER-7; SER-9; 16-GLU--MET-21 AND SER-19, PHOSPHORYLATION AT SER-19, TISSUE
RP   SPECIFICITY, VARIANTS AD4 PRO-122; ILE-141; VAL-239 AND ILE-239, AND
RP   CHARACTERIZATION OF VARIANTS AD4 PRO-122; ILE-141; VAL-239 AND ILE-239.
RX   PubMed=27293189; DOI=10.1016/j.cell.2016.05.020;
RA   Sannerud R., Esselens C., Ejsmont P., Mattera R., Rochin L.,
RA   Tharkeshwar A.K., De Baets G., De Wever V., Habets R., Baert V.,
RA   Vermeire W., Michiels C., Groot A.J., Wouters R., Dillen K., Vints K.,
RA   Baatsen P., Munck S., Derua R., Waelkens E., Basi G.S., Mercken M.,
RA   Vooijs M., Bollen M., Schymkowitz J., Rousseau F., Bonifacino J.S.,
RA   Van Niel G., De Strooper B., Annaert W.;
RT   "Restricted Location of PSEN2/gamma-Secretase Determines Substrate
RT   Specificity and Generates an Intracellular Abeta Pool.";
RL   Cell 166:193-208(2016).
RN   [29] {ECO:0007744|PDB:7Y5X, ECO:0007744|PDB:7Y5Z}
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.00 ANGSTROMS) IN COMPLEX WITH NCSTN;
RP   APH1A AND PSENEN, IDENTIFICATION OF GAMMA SECRETASE COMPLEX, AND FUNCTION.
RX   PubMed=36272978; DOI=10.1038/s41467-022-33817-5;
RA   Guo X., Wang Y., Zhou J., Jin C., Wang J., Jia B., Jing D., Yan C., Lei J.,
RA   Zhou R., Shi Y.;
RT   "Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-
RT   560.";
RL   Nat. Commun. 13:6299-6299(2022).
RN   [30]
RP   VARIANT AD4 HIS-62.
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   [31]
RP   VARIANT AD4 ILE-148.
RX   PubMed=10732806; DOI=10.1007/s100480050044;
RA   Lao J.I., Beyer K., Fernandez-Novoa L., Cacabelos R.;
RT   "A novel mutation in the predicted TM2 domain of the presenilin 2 gene in
RT   Spanish patient with late-onset Alzheimer's disease.";
RL   Neurogenetics 1:293-296(1998).
RN   [32]
RP   VARIANTS AD4 PRO-122 AND ILE-239.
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   [33]
RP   VARIANT AD4 ARG-122.
RX   PubMed=14681895; DOI=10.1002/ana.10760;
RA   Binetti G., Signorini S., Squitti R., Alberici A., Benussi L., Cassetta E.,
RA   Frisoni G.B., Barbiero L., Feudatari E., Nicosia F., Testa C., Zanetti O.,
RA   Gennarelli M., Perani D., Anchisi D., Ghidoni R., Rossini P.M.;
RT   "Atypical dementia associated with a novel presenilin-2 mutation.";
RL   Ann. Neurol. 54:832-836(2003).
RN   [34]
RP   VARIANT CMD1V LEU-130.
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   [35]
RP   VARIANT AD4 TRP-71.
RX   PubMed=21544564; DOI=10.1007/s00415-011-6066-1;
RA   Piscopo P., Talarico G., Malvezzi-Campeggi L., Crestini A., Rivabene R.,
RA   Gasparini M., Tosto G., Vanacore N., Lenzi G.L., Bruno G., Confaloni A.;
RT   "Presenilin 2 mutation R71W in an Italian early-onset sporadic Alzheimer's
RT   disease case.";
RL   J. Neurol. 258:2043-2047(2011).
RN   [36]
RP   VARIANTS AD4 HIS-62; TRP-71 AND LEU-130.
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   [37]
RP   VARIANT AD4 LYS-126.
RX   PubMed=24844686; DOI=10.3233/jad-140399;
RA   Mueller U., Winter P., Bolender C., Nolte D.;
RT   "Previously unrecognized missense mutation E126K of PSEN2 segregates with
RT   early onset Alzheimer's disease in a family.";
RL   J. Alzheimers Dis. 42:109-113(2014).
RN   [38]
RP   VARIANT AD4 TYR-141.
RX   PubMed=24838186; DOI=10.1016/j.neurobiolaging.2014.04.011;
RA   Niu F., Yu S., Zhang Z., Yi X., Ye L., Tang W., Qiu C., Wen H., Sun Y.,
RA   Gao J., Guo Y.;
RT   "Novel mutation in the PSEN2 gene (N141Y) associated with early-onset
RT   autosomal dominant Alzheimer's disease in a Chinese Han family.";
RL   Neurobiol. Aging 35:E1-E5(2014).
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:10497236, PubMed:10652302,
CC       PubMed:16752394, PubMed:27293189, PubMed:36272978). Selectively cleaves
CC       late endosomal/lysosomal localized substrates and generates the
CC       prominent pool of intracellular amyloid beta that contains longer
CC       amyloid beta (PubMed:27293189). The holoprotein functions as a calcium-
CC       leak channel that allows the passive movement of calcium from
CC       endoplasmic reticulum to cytosol and is involved in calcium homeostasis
CC       (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic
CC       reticulum membrane tethering and modulates calcium ions shuttling
CC       between ER and mitochondria (PubMed:21285369).
CC       {ECO:0000269|PubMed:10497236, ECO:0000269|PubMed:10652302,
CC       ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:16959576,
CC       ECO:0000269|PubMed:21285369, ECO:0000269|PubMed:27293189,
CC       ECO:0000269|PubMed:36272978}.
CC   -!- SUBUNIT: Homodimer; predominantly heterodimer of a N-terminal (NTF) and
CC       a C-terminal (CTF) endoproteolytical fragment (PubMed:15274632).
CC       Component of the gamma-secretase complex, a complex composed of a
CC       presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A
CC       or APH1B) and PSENEN (PubMed:36272978). Such minimal complex is
CC       sufficient for secretase activity, although other components may exist
CC       (By similarity). Interacts with DOCK3 (PubMed:10854253). Interacts with
CC       HERPUD1, FLNA, FLNB and PARL (PubMed:11799129, PubMed:12214059,
CC       PubMed:9437013). Interacts with AP1G1; this interaction is
CC       phosphorylation dependent and directs PSEN2 via early endosome to late
CC       endosome/lysosome (PubMed:27293189). {ECO:0000250|UniProtKB:P49768,
CC       ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129,
CC       ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:15274632,
CC       ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:36272978,
CC       ECO:0000269|PubMed:9437013}.
CC   -!- INTERACTION:
CC       P49810; P54819: AK2; NbExp=3; IntAct=EBI-2010251, EBI-1056291;
CC       P49810; P05067: APP; NbExp=4; IntAct=EBI-2010251, EBI-77613;
CC       P49810; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-2010251, EBI-10186132;
CC       P49810; Q16611: BAK1; NbExp=3; IntAct=EBI-2010251, EBI-519866;
CC       P49810; Q07817: BCL2L1; NbExp=3; IntAct=EBI-2010251, EBI-78035;
CC       P49810; P29466-3: CASP1; NbExp=3; IntAct=EBI-2010251, EBI-12248206;
CC       P49810; Q99828: CIB1; NbExp=3; IntAct=EBI-2010251, EBI-372594;
CC       P49810; Q86WV2: COX4I1; NbExp=3; IntAct=EBI-2010251, EBI-10260134;
CC       P49810; Q14204: DYNC1H1; NbExp=3; IntAct=EBI-2010251, EBI-356015;
CC       P49810; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-2010251, EBI-712452;
CC       P49810; O00472: ELL2; NbExp=3; IntAct=EBI-2010251, EBI-395274;
CC       P49810; Q14192: FHL2; NbExp=3; IntAct=EBI-2010251, EBI-701903;
CC       P49810; P21333: FLNA; NbExp=2; IntAct=EBI-2010251, EBI-350432;
CC       P49810; O75369: FLNB; NbExp=2; IntAct=EBI-2010251, EBI-352089;
CC       P49810; Q3SYB3: FOXD4L6; NbExp=3; IntAct=EBI-2010251, EBI-6425864;
CC       P49810; P02792: FTL; NbExp=3; IntAct=EBI-2010251, EBI-713279;
CC       P49810; P68431: H3C12; NbExp=3; IntAct=EBI-2010251, EBI-79722;
CC       P49810; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-2010251, EBI-25845242;
CC       P49810; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-2010251, EBI-4397720;
CC       P49810; O94851: MICAL2; NbExp=3; IntAct=EBI-2010251, EBI-2804835;
CC       P49810; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-2010251, EBI-21250407;
CC       P49810; P41218: MNDA; NbExp=3; IntAct=EBI-2010251, EBI-2829677;
CC       P49810; Q96HT8: MRFAP1L1; NbExp=3; IntAct=EBI-2010251, EBI-748896;
CC       P49810; O76041: NEBL; NbExp=3; IntAct=EBI-2010251, EBI-2880203;
CC       P49810; Q53EL6: PDCD4; NbExp=3; IntAct=EBI-2010251, EBI-935824;
CC       P49810; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-2010251, EBI-716063;
CC       P49810; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-2010251, EBI-9090282;
CC       P49810; Q99496: RNF2; NbExp=3; IntAct=EBI-2010251, EBI-722416;
CC       P49810; Q8N488: RYBP; NbExp=3; IntAct=EBI-2010251, EBI-752324;
CC       P49810; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-2010251, EBI-10182463;
CC       P49810; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-2010251, EBI-358545;
CC       P49810; Q9NSD5-3: SLC6A13; NbExp=3; IntAct=EBI-2010251, EBI-25831241;
CC       P49810; O95416: SOX14; NbExp=3; IntAct=EBI-2010251, EBI-9087806;
CC       P49810; Q3SY56: SP6; NbExp=3; IntAct=EBI-2010251, EBI-11175533;
CC       P49810; P30626: SRI; NbExp=2; IntAct=EBI-2010251, EBI-750459;
CC       P49810; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-2010251, EBI-749370;
CC       P49810; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-2010251, EBI-741480;
CC       P49810; Q96NC0: ZMAT2; NbExp=3; IntAct=EBI-2010251, EBI-2682299;
CC       P49810; Q8N895: ZNF366; NbExp=3; IntAct=EBI-2010251, EBI-2813661;
CC       P49810; Q8NBB4-2: ZSCAN1; NbExp=3; IntAct=EBI-2010251, EBI-12021938;
CC       P49810; Q2QGD7: ZXDC; NbExp=3; IntAct=EBI-2010251, EBI-1538838;
CC       P49810; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-2010251, EBI-7030357;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:8574969}; Multi-pass membrane protein
CC       {ECO:0000255}. Golgi apparatus membrane {ECO:0000269|PubMed:8574969};
CC       Multi-pass membrane protein {ECO:0000255}. Late endosome membrane
CC       {ECO:0000269|PubMed:27293189}. Lysosome membrane
CC       {ECO:0000269|PubMed:27293189}. Note=Late endosome/lysosome localization
CC       is dependent of the phosphorylation-mediated interaction with the AP1G1
CC       (PubMed:27293189). Also highly enriched in mitochondria-associated
CC       endoplasmic reticulum membrane contact site (By similarity).
CC       {ECO:0000250|UniProtKB:Q61144, ECO:0000269|PubMed:27293189}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=P49810-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P49810-2; Sequence=VSP_005194;
CC       Name=3;
CC         IsoId=P49810-3; Sequence=VSP_043648;
CC   -!- TISSUE SPECIFICITY: [Isoform 1]: Expressed in the placenta, skeletal
CC       muscle and heart (PubMed:8574969). Expressed in the somatodendritic
CC       compartment of hippocampal neurons (PubMed:27293189).
CC       {ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:8574969}.
CC   -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in the heart, brain,
CC       placenta, liver, skeletal muscle and kidney.
CC       {ECO:0000269|PubMed:8574969}.
CC   -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC       {ECO:0000250|UniProtKB:P49768}.
CC   -!- PTM: Heterogeneous proteolytic processing generates N-terminal and C-
CC       terminal fragments. {ECO:0000269|PubMed:10497236,
CC       ECO:0000269|PubMed:10652302, ECO:0000269|PubMed:36272978}.
CC   -!- PTM: Phosphorylated on serine residues (PubMed:27293189).
CC       Phosphorylation at Ser-19 affects PSEN2 sorting (PubMed:27293189).
CC       {ECO:0000269|PubMed:27293189}.
CC   -!- DISEASE: Alzheimer disease 4 (AD4) [MIM:606889]: 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:10631141, ECO:0000269|PubMed:10732806,
CC       ECO:0000269|PubMed:14681895, ECO:0000269|PubMed:16752394,
CC       ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:21285369,
CC       ECO:0000269|PubMed:21544564, ECO:0000269|PubMed:22503161,
CC       ECO:0000269|PubMed:24838186, ECO:0000269|PubMed:24844686,
CC       ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:7638622,
CC       ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9384602}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Cardiomyopathy, dilated, 1V (CMD1V) [MIM:613697]: 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}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAC50290.1; Type=Frameshift; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins
CC       mutations;
CC       URL="https://www.alzforum.org/mutations/psen-2";
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/41883/PSEN2";
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DR   EMBL; L43964; AAB59557.1; -; mRNA.
DR   EMBL; L44577; AAC42012.1; -; mRNA.
DR   EMBL; U50871; AAB50054.1; -; Genomic_DNA.
DR   EMBL; BT006984; AAP35630.1; -; mRNA.
DR   EMBL; AK292299; BAF84988.1; -; mRNA.
DR   EMBL; AL391628; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471098; EAW69798.1; -; Genomic_DNA.
DR   EMBL; CH471098; EAW69800.1; -; Genomic_DNA.
DR   EMBL; BC006365; AAH06365.1; -; mRNA.
DR   EMBL; U34349; AAC50290.1; ALT_FRAME; mRNA.
DR   EMBL; AF416718; AAL16812.1; -; mRNA.
DR   CCDS; CCDS1556.1; -. [P49810-1]
DR   CCDS; CCDS44324.1; -. [P49810-3]
DR   PIR; A56993; A56993.
DR   PIR; I39174; I39174.
DR   RefSeq; NP_000438.2; NM_000447.3. [P49810-1]
DR   RefSeq; NP_001424466.1; NM_001437537.1. [P49810-1]
DR   RefSeq; NP_036618.2; NM_012486.3. [P49810-3]
DR   RefSeq; XP_016857324.1; XM_017001835.2. [P49810-1]
DR   RefSeq; XP_016857325.1; XM_017001836.2. [P49810-3]
DR   RefSeq; XP_047281552.1; XM_047425596.1. [P49810-1]
DR   RefSeq; XP_047281553.1; XM_047425597.1. [P49810-3]
DR   RefSeq; XP_047281557.1; XM_047425601.1. [P49810-3]
DR   RefSeq; XP_054193714.1; XM_054337739.1. [P49810-1]
DR   RefSeq; XP_054193715.1; XM_054337740.1. [P49810-3]
DR   RefSeq; XP_054193716.1; XM_054337741.1. [P49810-3]
DR   PDB; 7Y5X; EM; 3.00 A; B=1-448.
DR   PDB; 7Y5Z; EM; 3.40 A; B=1-448.
DR   PDBsum; 7Y5X; -.
DR   PDBsum; 7Y5Z; -.
DR   AlphaFoldDB; P49810; -.
DR   EMDB; EMD-33628; -.
DR   EMDB; EMD-33629; -.
DR   PCDDB; P49810; -.
DR   SMR; P49810; -.
DR   BioGRID; 111643; 82.
DR   ComplexPortal; CPX-4231; Gamma-secretase complex, APH1A-PSEN2 variant.
DR   ComplexPortal; CPX-4232; Gamma-secretase complex, APH1B-PSEN2 variant.
DR   CORUM; P49810; -.
DR   FunCoup; P49810; 386.
DR   IntAct; P49810; 76.
DR   MINT; P49810; -.
DR   STRING; 9606.ENSP00000355747; -.
DR   BindingDB; P49810; -.
DR   ChEMBL; CHEMBL3708; -.
DR   DrugBank; DB16159; Esflurbiprofen.
DR   DrugBank; DB12005; Nirogacestat.
DR   DrugBank; DB05289; Tarenflurbil.
DR   MEROPS; A22.002; -.
DR   TCDB; 1.A.54.1.2; the presenilin er ca(2+) leak channel (presenilin) family.
DR   GlyGen; P49810; 1 site.
DR   iPTMnet; P49810; -.
DR   PhosphoSitePlus; P49810; -.
DR   SwissPalm; P49810; -.
DR   BioMuta; PSEN2; -.
DR   DMDM; 1709858; -.
DR   jPOST; P49810; -.
DR   MassIVE; P49810; -.
DR   PaxDb; 9606-ENSP00000355747; -.
DR   PeptideAtlas; P49810; -.
DR   ProteomicsDB; 56139; -. [P49810-1]
DR   ProteomicsDB; 56140; -. [P49810-2]
DR   ProteomicsDB; 56141; -. [P49810-3]
DR   Pumba; P49810; -.
DR   Antibodypedia; 4424; 455 antibodies from 42 providers.
DR   DNASU; 5664; -.
DR   Ensembl; ENST00000366782.6; ENSP00000355746.2; ENSG00000143801.19. [P49810-1]
DR   Ensembl; ENST00000366783.8; ENSP00000355747.3; ENSG00000143801.19. [P49810-1]
DR   Ensembl; ENST00000422240.6; ENSP00000403737.2; ENSG00000143801.19. [P49810-3]
DR   Ensembl; ENST00000524196.6; ENSP00000429036.2; ENSG00000143801.19. [P49810-1]
DR   Ensembl; ENST00000626989.3; ENSP00000486498.2; ENSG00000143801.19. [P49810-1]
DR   Ensembl; ENST00000677414.1; ENSP00000503116.1; ENSG00000143801.19. [P49810-1]
DR   Ensembl; ENST00000678233.1; ENSP00000504728.1; ENSG00000143801.19. [P49810-1]
DR   Ensembl; ENST00000679088.1; ENSP00000504727.1; ENSG00000143801.19. [P49810-1]
DR   Ensembl; ENST00000679098.1; ENSP00000504303.1; ENSG00000143801.19. [P49810-1]
DR   GeneID; 5664; -.
DR   KEGG; hsa:5664; -.
DR   MANE-Select; ENST00000366783.8; ENSP00000355747.3; NM_000447.3; NP_000438.2.
DR   UCSC; uc009xeo.2; human. [P49810-1]
DR   AGR; HGNC:9509; -.
DR   ClinPGx; PA33856; -.
DR   CTD; 5664; -.
DR   DisGeNET; 5664; -.
DR   GeneCards; PSEN2; -.
DR   GeneReviews; PSEN2; -.
DR   HGNC; HGNC:9509; PSEN2.
DR   HPA; ENSG00000143801; Low tissue specificity.
DR   MalaCards; PSEN2; -.
DR   MIM; 600759; gene.
DR   MIM; 606889; phenotype.
DR   MIM; 613697; phenotype.
DR   OpenTargets; ENSG00000143801; -.
DR   Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR   Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR   VEuPathDB; HostDB:ENSG00000143801; -.
DR   eggNOG; KOG2736; Eukaryota.
DR   GeneTree; ENSGT00940000157923; -.
DR   HOGENOM; CLU_022975_3_1_1; -.
DR   InParanoid; P49810; -.
DR   OMA; WTTITFC; -.
DR   OrthoDB; 20287at2759; -.
DR   PAN-GO; P49810; 22 GO annotations based on evolutionary models.
DR   PhylomeDB; P49810; -.
DR   PathwayCommons; P49810; -.
DR   Reactome; R-HSA-1251985; Nuclear signaling by ERBB4.
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-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; P49810; -.
DR   SIGNOR; P49810; -.
DR   Agora; ENSG00000143801; -.
DR   BioGRID-ORCS; 5664; 11 hits in 1154 CRISPR screens.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   ChiTaRS; PSEN2; human.
DR   GeneWiki; PSEN2; -.
DR   GenomeRNAi; 5664; -.
DR   Pharos; P49810; Tchem.
DR   PRO; PR:P49810; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; P49810; protein.
DR   Bgee; ENSG00000143801; Expressed in body of pancreas and 98 other cell types or tissues.
DR   ExpressionAtlas; P49810; baseline and differential.
DR   GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR   GO; GO:0005769; C:early endosome; IEA:Ensembl.
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:ARUK-UCL.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:HGNC-UCL.
DR   GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0000776; C:kinetochore; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0005637; C:nuclear inner membrane; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HGNC-UCL.
DR   GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl.
DR   GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR   GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR   GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IBA:GO_Central.
DR   GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL.
DR   GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL.
DR   GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central.
DR   GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR   GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL.
DR   GO; GO:1990456; P:mitochondrion-endoplasmic reticulum membrane tethering; IMP:UniProtKB.
DR   GO; GO:0007220; P:Notch receptor processing; TAS:HGNC-UCL.
DR   GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central.
DR   GO; GO:0016485; P:protein processing; IDA:HGNC-UCL.
DR   GO; GO:0110097; P:regulation of calcium import into the mitochondrion; IMP:UniProtKB.
DR   GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR   FunFam; 1.10.472.100:FF:000001; Presenilin; 1.
DR   Gene3D; 1.10.472.100; Presenilin; 1.
DR   InterPro; IPR001493; Pept_A22A_PS2.
DR   InterPro; IPR001108; Peptidase_A22A.
DR   InterPro; IPR006639; Preselin/SPP.
DR   InterPro; IPR042524; Presenilin_C.
DR   PANTHER; PTHR10202; PRESENILIN; 1.
DR   PANTHER; PTHR10202:SF24; PRESENILIN-2; 1.
DR   Pfam; PF01080; Presenilin; 2.
DR   PRINTS; PR01072; PRESENILIN.
DR   PRINTS; PR01074; PRESENILIN2.
DR   SMART; SM00730; PSN; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis;
KW   Cardiomyopathy; Disease variant; Endoplasmic reticulum; Endosome;
KW   Golgi apparatus; Hydrolase; Lysosome; Membrane; Neurodegeneration;
KW   Notch signaling pathway; Phosphoprotein; Protease;
KW   Proteomics identification; Reference proteome; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..297
FT                   /note="Presenilin-2 NTF subunit"
FT                   /evidence="ECO:0000305|PubMed:10652302,
FT                   ECO:0000305|PubMed:15274632"
FT                   /id="PRO_0000025603"
FT   CHAIN           298..448
FT                   /note="Presenilin-2 CTF subunit"
FT                   /evidence="ECO:0000305|PubMed:10497236,
FT                   ECO:0000305|PubMed:10652302, ECO:0000305|PubMed:15274632"
FT                   /id="PRO_0000025604"
FT   TOPO_DOM        1..87
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        88..108
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        109..138
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        139..159
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        160..166
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        167..187
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        188..200
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        201..221
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        222..223
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        224..244
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        245..249
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        250..270
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        271..361
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        362..382
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        383..388
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        389..409
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        410..413
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   INTRAMEM        414..434
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        435..448
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          1..70
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           16..21
FT                   /note="Involved in late endosome/lysosome localization"
FT                   /evidence="ECO:0000269|PubMed:27293189"
FT   MOTIF           414..416
FT                   /note="PAL"
FT   COMPBIAS        19..30
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        263
FT                   /evidence="ECO:0000305|PubMed:10652302"
FT   ACT_SITE        366
FT                   /evidence="ECO:0000305|PubMed:10497236,
FT                   ECO:0000305|PubMed:10652302"
FT   MOD_RES         19
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000305|PubMed:27293189"
FT   MOD_RES         22
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         25
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         30
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61144"
FT   VAR_SEQ         263..296
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_005194"
FT   VAR_SEQ         324
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_043648"
FT   VARIANT         62
FT                   /note="R -> H (in AD4; likely benign; dbSNP:rs58973334)"
FT                   /evidence="ECO:0000269|PubMed:22503161,
FT                   ECO:0000269|PubMed:9384602"
FT                   /id="VAR_006461"
FT   VARIANT         71
FT                   /note="R -> W (in AD4; uncertain significance;
FT                   dbSNP:rs140501902)"
FT                   /evidence="ECO:0000269|PubMed:21544564,
FT                   ECO:0000269|PubMed:22503161"
FT                   /id="VAR_070027"
FT   VARIANT         122
FT                   /note="T -> P (in AD4; does not affect localization at late
FT                   endosome/lysosome; strongly decreased N-cadherin- and Notch
FT                   receptor processing; ligand-dependent; does not affect
FT                   amyloid-beta formation; dbSNP:rs63749851)"
FT                   /evidence="ECO:0000269|PubMed:10631141,
FT                   ECO:0000269|PubMed:27293189"
FT                   /id="VAR_009214"
FT   VARIANT         122
FT                   /note="T -> R (in AD4; increased mitochondrion-endoplasmic
FT                   reticulum membrane tethering resulting in increased calcium
FT                   transfer to mitochondria; dbSNP:rs28936380)"
FT                   /evidence="ECO:0000269|PubMed:14681895,
FT                   ECO:0000269|PubMed:21285369"
FT                   /id="VAR_081261"
FT   VARIANT         126
FT                   /note="E -> K (in AD4; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:24844686"
FT                   /id="VAR_081262"
FT   VARIANT         130
FT                   /note="S -> L (in CMD1V and AD4; uncertain significance;
FT                   dbSNP:rs63750197)"
FT                   /evidence="ECO:0000269|PubMed:17186461,
FT                   ECO:0000269|PubMed:22503161"
FT                   /id="VAR_064903"
FT   VARIANT         141
FT                   /note="N -> I (in AD4; results in altered amyloid-beta
FT                   production and increased amyloid-beta 42/amyloid-beta 40
FT                   ratio; loss of function as calcium-leak channel; results in
FT                   calcium overload in the endoplasmic reticulum; increased
FT                   mitochondrion-endoplasmic reticulum membrane tethering
FT                   resulting in increased calcium transfer to mitochondria;
FT                   does not affect localization at late endosome/lysosome;
FT                   strongly decreased N-cadherin- and Notch receptor
FT                   processing; ligand-dependent; does not affect amyloid-beta
FT                   formation; dbSNP:rs63750215)"
FT                   /evidence="ECO:0000269|PubMed:16752394,
FT                   ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:21285369,
FT                   ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:7638622,
FT                   ECO:0000269|PubMed:7651536"
FT                   /id="VAR_006462"
FT   VARIANT         141
FT                   /note="N -> Y (in AD4; dbSNP:rs61761208)"
FT                   /evidence="ECO:0000269|PubMed:24838186"
FT                   /id="VAR_081263"
FT   VARIANT         148
FT                   /note="V -> I (in AD4; late-onset Alzheimer disease;
FT                   dbSNP:rs63750812)"
FT                   /evidence="ECO:0000269|PubMed:10732806"
FT                   /id="VAR_007958"
FT   VARIANT         239
FT                   /note="M -> I (in AD4; Does not affect localization at late
FT                   endosome/lysosome.Affects amyloid-beta formation.;
FT                   dbSNP:rs63749884)"
FT                   /evidence="ECO:0000269|PubMed:10631141,
FT                   ECO:0000269|PubMed:27293189"
FT                   /id="VAR_009215"
FT   VARIANT         239
FT                   /note="M -> V (in AD4; oes not affect localization at late
FT                   endosome/lysosome; affects amyloid-beta formation;
FT                   dbSNP:rs28936379)"
FT                   /evidence="ECO:0000269|PubMed:27293189,
FT                   ECO:0000269|PubMed:7651536"
FT                   /id="VAR_006463"
FT   MUTAGEN         16..21
FT                   /note="ERTSLM->ARTSAA: Impairs AP1G1 interaction. Does not
FT                   affect aspartic endopeptidase activity, intramembrane
FT                   cleaving. Does not affect gamma-secretase complex assemlby.
FT                   Significantly decreases localization at late
FT                   endosome/lysosome."
FT                   /evidence="ECO:0000269|PubMed:27293189"
FT   MUTAGEN         19
FT                   /note="S->A: Does not affect AP1G1 interaction. Does not
FT                   affect aspartic endopeptidase activity, intramembrane
FT                   cleaving. Does not affect gamma-secretase complex assemlby.
FT                   Does not affect localization at late endosome/lysosome."
FT                   /evidence="ECO:0000269|PubMed:27293189"
FT   MUTAGEN         19
FT                   /note="S->D: Impairs AP1G1 interaction. Does not affect
FT                   aspartic endopeptidase activity, intramembrane cleaving.
FT                   Does not affect gamma-secretase complex assembly. Decreases
FT                   localization at late endosome/lysosome."
FT                   /evidence="ECO:0000269|PubMed:27293189"
FT   MUTAGEN         263
FT                   /note="D->A: Reduces production of amyloid-beta in APP
FT                   processing."
FT                   /evidence="ECO:0000269|PubMed:10652302"
FT   MUTAGEN         366
FT                   /note="D->A: Reduces production of amyloid-beta in APP
FT                   processing and of NICD in NOTCH1 processing. Increased
FT                   mitochondrion-endoplasmic reticulum membrane tethering
FT                   resulting in increased calcium transfer to mitochondria."
FT                   /evidence="ECO:0000269|PubMed:10497236,
FT                   ECO:0000269|PubMed:10652302, ECO:0000269|PubMed:21285369"
FT   CONFLICT        123
FT                   /note="P -> T (in Ref. 1; AAB59557 and 10; AAL16812)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        295
FT                   /note="S -> L (in Ref. 10; AAL16812)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        325
FT                   /note="Missing (in Ref. 9; AAC50290)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        358..361
FT                   /note="RGVK -> SKGA (in Ref. 9; AAC50290)"
FT                   /evidence="ECO:0000305"
FT   HELIX           86..106
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   TURN            107..109
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   TURN            170..173
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           174..180
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   TURN            181..183
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           184..195
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           201..219
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           225..245
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   TURN            249..251
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           252..261
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           364..377
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   STRAND          380..383
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           385..409
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           416..430
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   TURN            431..434
FT                   /evidence="ECO:0007829|PDB:7Y5X"
FT   HELIX           435..443
FT                   /evidence="ECO:0007829|PDB:7Y5X"
SQ   SEQUENCE   448 AA;  50140 MW;  A927EEC623468116 CRC64;
     MLTFMASDSE EEVCDERTSL MSAESPTPRS CQEGRQGPED GENTAQWRSQ ENEEDGEEDP
     DRYVCSGVPG RPPGLEEELT LKYGAKHVIM LFVPVTLCMI VVVATIKSVR FYTEKNGQLI
     YTPFTEDTPS VGQRLLNSVL NTLIMISVIV VMTIFLVVLY KYRCYKFIHG WLIMSSLMLL
     FLFTYIYLGE VLKTYNVAMD YPTLLLTVWN FGAVGMVCIH WKGPLVLQQA YLIMISALMA
     LVFIKYLPEW SAWVILGAIS VYDLVAVLCP KGPLRMLVET AQERNEPIFP ALIYSSAMVW
     TVGMAKLDPS SQGALQLPYD PEMEEDSYDS FGEPSYPEVF EPPLTGYPGE ELEEEEERGV
     KLGLGDFIFY SVLVGKAAAT GSGDWNTTLA CFVAILIGLC LTLLLLAVFK KALPALPISI
     TFGLIFYFST DNLVRPFMDT LASHQLYI
//
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   SHMOS_HUMAN             Reviewed;          58 AA.
AC   C0HM83;
DT   08-NOV-2023, integrated into UniProtKB/Swiss-Prot.
DT   08-NOV-2023, sequence version 1.
DT   09-APR-2025, entry version 6.
DE   RecName: Full=Protein SHMOOSE {ECO:0000303|PubMed:36127429};
DE   AltName: Full=Small human mitochondrial ORF over serine tRNA {ECO:0000303|PubMed:36127429};
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] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=7219534; DOI=10.1038/290457a0;
RA   Anderson S., Bankier A.T., Barrell B.G., de Bruijn M.H.L., Coulson A.R.,
RA   Drouin J., Eperon I.C., Nierlich D.P., Roe B.A., Sanger F., Schreier P.H.,
RA   Smith A.J.H., Staden R., Young I.G.;
RT   "Sequence and organization of the human mitochondrial genome.";
RL   Nature 290:457-465(1981).
RN   [2] {ECO:0000305}
RP   PROTEIN SEQUENCE OF 15-25 AND 42-58, FUNCTION, INTERACTION WITH IMMT,
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, VARIANT ASN-47, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=36127429; DOI=10.1038/s41380-022-01769-3;
RG   Alzheimer's Disease Neuroimaging Initiative;
RA   Miller B., Kim S.J., Mehta H.H., Cao K., Kumagai H., Thumaty N.,
RA   Leelaprachakul N., Braniff R.G., Jiao H., Vaughan J., Diedrich J.,
RA   Saghatelian A., Arpawong T.E., Crimmins E.M., Ertekin-Taner N., Tubi M.A.,
RA   Hare E.T., Braskie M.N., Decarie-Spain L., Kanoski S.E., Grodstein F.,
RA   Bennett D.A., Zhao L., Toga A.W., Wan J., Yen K., Cohen P.;
RT   "Mitochondrial DNA variation in Alzheimer's disease reveals a unique
RT   microprotein called SHMOOSE.";
RL   Mol. Psychiatry 28:1813-1826(2023).
RN   [3] {ECO:0000305}
RP   ERRATUM OF PUBMED:36127429.
RX   PubMed=36658336; DOI=10.1038/s41380-023-01956-w;
RG   Alzheimer's Disease Neuroimaging Initiative;
RA   Miller B., Kim S.J., Mehta H.H., Cao K., Kumagai H., Thumaty N.,
RA   Leelaprachakul N., Braniff R.G., Jiao H., Vaughan J., Diedrich J.,
RA   Saghatelian A., Arpawong T.E., Crimmins E.M., Ertekin-Taner N., Tubi M.A.,
RA   Hare E.T., Braskie M.N., Decarie-Spain L., Kanoski S.E., Grodstein F.,
RA   Bennett D.A., Zhao L., Toga A.W., Wan J., Yen K., Cohen P.;
RL   Mol. Psychiatry 28:1827-1827(2023).
CC   -!- FUNCTION: Increases neural cell metabolic activity and mitochondrial
CC       oxygen consumption rate. {ECO:0000269|PubMed:36127429}.
CC   -!- SUBUNIT: Interacts with IMMT/mitofilin. {ECO:0000269|PubMed:36127429}.
CC   -!- INTERACTION:
CC       C0HM83; Q16891: IMMT; NbExp=5; IntAct=EBI-46442350, EBI-473801;
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:36127429}.
CC       Nucleus {ECO:0000269|PubMed:36127429}. Note=Detected in neuronal
CC       mitochondria and nuclei. {ECO:0000269|PubMed:36127429}.
CC   -!- TISSUE SPECIFICITY: Detected in cerebrospinal fluid (at protein level).
CC       {ECO:0000269|PubMed:36127429}.
CC   -!- MISCELLANEOUS: Shows elevated expression in Alzheimer disease patient
CC       brains and protects against cell death in vitro in neuronal cells
CC       stressed with oligomerized amyloid-beta protein 42.
CC       {ECO:0000269|PubMed:36127429}.
CC   -!- MISCELLANEOUS: Intracerebroventricular administration to the rat brain
CC       for 24 hours results in significant alterations to the hypothalamus
CC       transcriptome and, to a lesser extent, the hippocampus transcriptome.
CC       {ECO:0000269|PubMed:36127429}.
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DR   EMBL; J01415; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   IntAct; C0HM83; 1.
DR   Proteomes; UP000005640; Mitochondrion MT.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   Pfam; PF23661; SHMOOSE; 1.
PE   1: Evidence at protein level;
KW   Direct protein sequencing; Mitochondrion; Nucleus; Reference proteome.
FT   CHAIN           1..58
FT                   /note="Protein SHMOOSE"
FT                   /id="PRO_0000458864"
FT   REGION          27..58
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        35..45
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        46..58
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VARIANT         47
FT                   /note="D -> N (risk factor for Alzheimer disease; protein
FT                   does not protect against cell death in vitro in neuronal
FT                   cells stressed with oligomerized amyloid-beta protein 42;
FT                   dbSNP:rs2853499)"
FT                   /evidence="ECO:0000269|PubMed:36127429"
FT                   /id="VAR_088368"
SQ   SEQUENCE   58 AA;  6637 MW;  961C5C3F9CF34204 CRC64;
     MPPCLTTWLS QLLKDNSYPL VLGPKNFGAT PNKSNNHAHY YNHPNPDFPN SPHPYHPR
//
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   TEFF2_HUMAN             Reviewed;         374 AA.
AC   Q9UIK5; Q2FA44; Q4ZFW4; Q53H90; Q53RE1; Q8N2R5; Q9NR15; Q9NSS5; Q9P2Y9;
AC   Q9UK65;
DT   19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   28-JAN-2026, entry version 188.
DE   RecName: Full=Tomoregulin-2;
DE            Short=TR-2;
DE   AltName: Full=Hyperplastic polyposis protein 1;
DE   AltName: Full=Transmembrane protein with EGF-like and two follistatin-like domains;
DE   Flags: Precursor;
GN   Name=TMEFF2; Synonyms=HPP1, TENB2, TPEF; ORFNames=UNQ178/PRO204;
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=10903839; DOI=10.1006/geno.2000.6228;
RA   Horie M., Mitsumoto Y., Kyushiki H., Kanemoto N., Watanabe A.,
RA   Taniguchi Y., Nishino N., Okamoto T., Kondo M., Mori T., Noguchi K.,
RA   Nakamura Y., Takahashi E., Tanigami A.;
RT   "Identification and characterization of TMEFF2, a novel survival factor for
RT   hippocampal and mesencephalic neurons.";
RL   Genomics 67:146-152(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [GENOMIC DNA]
RP   OF 1-57, INDUCTION, AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=10987305;
RA   Liang G., Robertson K.D., Talmadge C., Sumegi J., Jones P.A.;
RT   "The gene for a novel transmembrane protein containing epidermal growth
RT   factor and follistatin domains is frequently hypermethylated in human tumor
RT   cells.";
RL   Cancer Res. 60:4907-4912(2000).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, AND TISSUE
RP   SPECIFICITY.
RC   TISSUE=Prostatic carcinoma;
RX   PubMed=11668495; DOI=10.1002/ijc.1450;
RA   Glynne-Jones E., Harper M.E., Seery L.T., James R., Anglin I., Morgan H.E.,
RA   Taylor K.M., Gee J.M., Nicholson R.I.;
RT   "TENB2, a proteoglycan identified in prostate cancer that is associated
RT   with disease progression and androgen independence.";
RL   Int. J. Cancer 94:178-184(2001).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND TISSUE SPECIFICITY.
RX   PubMed=16439095; DOI=10.1016/j.ygeno.2005.12.004;
RA   Quayle S.N., Sadar M.D.;
RT   "A truncated isoform of TMEFF2 encodes a secreted protein in prostate
RT   cancer cells.";
RL   Genomics 87:633-637(2006).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=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   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RA   Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA   Tanaka A., Yokoyama S.;
RL   Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=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   [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 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   [12]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 1-360.
RX   PubMed=10600548; DOI=10.1006/bbrc.1999.1873;
RA   Uchida T., Wada K., Akamatsu T., Yonezawa M., Noguchi H., Mizoguchi A.,
RA   Kasuga M., Sakamoto C.;
RT   "A novel epidermal growth factor-like molecule containing two follistatin
RT   modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric
RT   cancer cells.";
RL   Biochem. Biophys. Res. Commun. 266:593-602(1999).
RN   [13]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-57, TISSUE SPECIFICITY, AND
RP   INDUCTION.
RC   TISSUE=Colon;
RX   PubMed=11120884; DOI=10.1073/pnas.98.1.265;
RA   Young J., Biden K.G., Simms L.A., Huggard P., Karamatic R., Eyre H.J.,
RA   Sutherland G.R., Herath N., Barker M., Anderson G.J., Fitzpatrick D.R.,
RA   Ramm G.A., Jass J.R., Leggett B.A.;
RT   "HPP1: a transmembrane protein-encoding gene commonly methylated in
RT   colorectal polyps and cancers.";
RL   Proc. Natl. Acad. Sci. U.S.A. 98:265-270(2001).
RN   [14]
RP   PROTEIN SEQUENCE OF 41-55.
RX   PubMed=15340161; DOI=10.1110/ps.04682504;
RA   Zhang Z., Henzel W.J.;
RT   "Signal peptide prediction based on analysis of experimentally verified
RT   cleavage sites.";
RL   Protein Sci. 13:2819-2824(2004).
RN   [15]
RP   TISSUE SPECIFICITY.
RX   PubMed=16805794; DOI=10.1111/j.1471-4159.2006.03801.x;
RA   Siegel D.A., Davies P., Dobrenis K., Huang M.;
RT   "Tomoregulin-2 is found extensively in plaques in Alzheimer's disease
RT   brain.";
RL   J. Neurochem. 98:34-44(2006).
RN   [16]
RP   CLEAVAGE, AND FUNCTION.
RX   PubMed=17942404; DOI=10.1074/jbc.m702170200;
RA   Ali N., Knaeuper V.;
RT   "Phorbol ester-induced shedding of the prostate cancer marker transmembrane
RT   protein with epidermal growth factor and two follistatin motifs 2 is
RT   mediated by the disintegrin and metalloproteinase-17.";
RL   J. Biol. Chem. 282:37378-37388(2007).
RN   [17]
RP   GLYCOSYLATION AT ASN-204.
RX   PubMed=19139490; DOI=10.1074/mcp.m800504-mcp200;
RA   Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F., Zheng Z.B.,
RA   Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y., Zhang Y.K., Deng Y.L.,
RA   Ying W.T., He S.M., Qian X.H.;
RT   "A strategy for precise and large scale identification of core fucosylated
RT   glycoproteins.";
RL   Mol. Cell. Proteomics 8:913-923(2009).
CC   -!- FUNCTION: May be a survival factor for hippocampal and mesencephalic
CC       neurons. The shedded form up-regulates cancer cell proliferation,
CC       probably by promoting ERK1/2 phosphorylation.
CC       {ECO:0000269|PubMed:10903839, ECO:0000269|PubMed:17942404}.
CC   -!- INTERACTION:
CC       Q9UIK5; PRO_0000000090 [P05067]: APP; NbExp=3; IntAct=EBI-11423693, EBI-21194918;
CC       Q9UIK5; O75031: HSF2BP; NbExp=3; IntAct=EBI-11423693, EBI-7116203;
CC       Q9UIK5; P0DPK4: NOTCH2NLC; NbExp=3; IntAct=EBI-11423693, EBI-22310682;
CC       Q9UIK5; Q7Z5B4-5: RIC3; NbExp=3; IntAct=EBI-11423693, EBI-12375429;
CC       Q9UIK5; Q96Q45-2: TMEM237; NbExp=3; IntAct=EBI-11423693, EBI-10982110;
CC       Q9UIK5; P34981: TRHR; NbExp=3; IntAct=EBI-11423693, EBI-18055230;
CC       Q9UIK5; Q9Y5Z9: UBIAD1; NbExp=3; IntAct=EBI-11423693, EBI-2819725;
CC       Q9UIK5; Q96MV8: ZDHHC15; NbExp=3; IntAct=EBI-11423693, EBI-12837904;
CC       Q9UIK5-2; P55212: CASP6; NbExp=3; IntAct=EBI-25835153, EBI-718729;
CC       Q9UIK5-2; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-25835153, EBI-5280197;
CC       Q9UIK5-2; P62826: RAN; NbExp=3; IntAct=EBI-25835153, EBI-286642;
CC   -!- SUBCELLULAR LOCATION: [Isoform 1]: Membrane {ECO:0000305}; Single-pass
CC       type I membrane protein {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 2]: Membrane {ECO:0000305}; Single-pass
CC       type I membrane protein {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q9UIK5-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q9UIK5-2; Sequence=VSP_014312, VSP_014313;
CC       Name=3; Synonyms=TMEFF2-S;
CC         IsoId=Q9UIK5-3; Sequence=VSP_024973, VSP_024974;
CC   -!- TISSUE SPECIFICITY: Highly expressed in adult and fetal brain, spinal
CC       cord and prostate. Expressed in all brain regions except the pituitary
CC       gland, with highest levels in amygdala and corpus callosum. Expressed
CC       in the pericryptal myofibroblasts and other stromal cells of normal
CC       colonic mucosa. Expressed in prostate carcinoma. Down-regulated in
CC       colorectal cancer. Present in Alzheimer disease plaques (at protein
CC       level). Isoform 3 is expressed weakly in testis and at high levels in
CC       normal and cancerous prostate. {ECO:0000269|PubMed:10903839,
CC       ECO:0000269|PubMed:10987305, ECO:0000269|PubMed:11120884,
CC       ECO:0000269|PubMed:11668495, ECO:0000269|PubMed:16439095,
CC       ECO:0000269|PubMed:16805794}.
CC   -!- INDUCTION: Down-regulated in tumor cell lines in response to a high
CC       level of methylation in the 5' region. The CpG island methylation
CC       correlates with TMEFF2 silencing in tumor cell lines.
CC       {ECO:0000269|PubMed:10987305, ECO:0000269|PubMed:11120884}.
CC   -!- PTM: O-glycosylated; contains chondroitin sulfate glycosaminoglycans.
CC       {ECO:0000269|PubMed:11668495}.
CC   -!- PTM: A soluble form (TMEFF2-ECD) is produced by proteolytic shedding.
CC       This shedding can be induced by phorbol ester or pro-inflammatory
CC       cytokines such as TNFalpha, and is mediated by ADAM17.
CC   -!- SIMILARITY: Belongs to the tomoregulin family.
CC       {ECO:0000269|PubMed:17942404}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA90820.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Mitochondrial contamination starting in position 361.; Evidence={ECO:0000305};
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DR   EMBL; AB017269; BAA87897.1; -; mRNA.
DR   EMBL; AF242221; AAG49451.1; -; Genomic_DNA.
DR   EMBL; AF242222; AAG49452.1; -; mRNA.
DR   EMBL; AF179274; AAD55776.2; -; mRNA.
DR   EMBL; DQ133599; AAZ43216.1; -; mRNA.
DR   EMBL; AY358907; AAQ89266.1; -; mRNA.
DR   EMBL; AK074507; BAC11030.1; -; mRNA.
DR   EMBL; CR457390; CAG33671.1; -; mRNA.
DR   EMBL; AK222691; BAD96411.1; -; mRNA.
DR   EMBL; AL157430; CAB75654.1; -; mRNA.
DR   EMBL; AC092644; AAY14874.1; -; Genomic_DNA.
DR   EMBL; AC098617; AAX88893.1; -; Genomic_DNA.
DR   EMBL; BC008973; AAH08973.1; -; mRNA.
DR   EMBL; AB004064; BAA90820.1; ALT_TERM; mRNA.
DR   EMBL; AF264150; AAF91397.1; -; Genomic_DNA.
DR   CCDS; CCDS2314.1; -. [Q9UIK5-1]
DR   CCDS; CCDS82547.1; -. [Q9UIK5-3]
DR   CCDS; CCDS82548.1; -. [Q9UIK5-2]
DR   PIR; T46914; T46914.
DR   RefSeq; NP_001292063.1; NM_001305134.2. [Q9UIK5-2]
DR   RefSeq; NP_001292074.1; NM_001305145.1. [Q9UIK5-3]
DR   RefSeq; NP_057276.2; NM_016192.3. [Q9UIK5-1]
DR   AlphaFoldDB; Q9UIK5; -.
DR   SMR; Q9UIK5; -.
DR   BioGRID; 117189; 12.
DR   FunCoup; Q9UIK5; 376.
DR   IntAct; Q9UIK5; 16.
DR   MINT; Q9UIK5; -.
DR   STRING; 9606.ENSP00000272771; -.
DR   MEROPS; I01.969; -.
DR   MEROPS; I01.978; -.
DR   GlyCosmos; Q9UIK5; 3 sites, No reported glycans.
DR   GlyGen; Q9UIK5; 2 sites.
DR   iPTMnet; Q9UIK5; -.
DR   PhosphoSitePlus; Q9UIK5; -.
DR   SwissPalm; Q9UIK5; -.
DR   BioMuta; TMEFF2; -.
DR   DMDM; 71153590; -.
DR   jPOST; Q9UIK5; -.
DR   MassIVE; Q9UIK5; -.
DR   PaxDb; 9606-ENSP00000272771; -.
DR   PeptideAtlas; Q9UIK5; -.
DR   ProteomicsDB; 84539; -. [Q9UIK5-1]
DR   ProteomicsDB; 84540; -. [Q9UIK5-2]
DR   ProteomicsDB; 84541; -. [Q9UIK5-3]
DR   Antibodypedia; 2895; 391 antibodies from 32 providers.
DR   DNASU; 23671; -.
DR   Ensembl; ENST00000272771.10; ENSP00000272771.5; ENSG00000144339.13. [Q9UIK5-1]
DR   Ensembl; ENST00000392314.5; ENSP00000376128.1; ENSG00000144339.13. [Q9UIK5-2]
DR   Ensembl; ENST00000409056.3; ENSP00000386871.3; ENSG00000144339.13. [Q9UIK5-3]
DR   GeneID; 23671; -.
DR   KEGG; hsa:23671; -.
DR   MANE-Select; ENST00000272771.10; ENSP00000272771.5; NM_016192.4; NP_057276.2.
DR   UCSC; uc002utc.4; human. [Q9UIK5-1]
DR   AGR; HGNC:11867; -.
DR   ClinPGx; PA36568; -.
DR   CTD; 23671; -.
DR   DisGeNET; 23671; -.
DR   GeneCards; TMEFF2; -.
DR   HGNC; HGNC:11867; TMEFF2.
DR   HPA; ENSG00000144339; Tissue enhanced (brain, prostate, seminal vesicle).
DR   MIM; 605734; gene.
DR   OpenTargets; ENSG00000144339; -.
DR   VEuPathDB; HostDB:ENSG00000144339; -.
DR   eggNOG; KOG3649; Eukaryota.
DR   GeneTree; ENSGT00940000156056; -.
DR   HOGENOM; CLU_048579_1_0_1; -.
DR   InParanoid; Q9UIK5; -.
DR   OMA; HCQGQTL; -.
DR   OrthoDB; 328123at2759; -.
DR   PAN-GO; Q9UIK5; 6 GO annotations based on evolutionary models.
DR   PhylomeDB; Q9UIK5; -.
DR   PathwayCommons; Q9UIK5; -.
DR   SignaLink; Q9UIK5; -.
DR   Agora; ENSG00000144339; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 23671; 7 hits in 1065 CRISPR screens.
DR   ChiTaRS; TMEFF2; human.
DR   GeneWiki; TMEFF2; -.
DR   GenomeRNAi; 23671; -.
DR   Pharos; Q9UIK5; Tbio.
DR   PRO; PR:Q9UIK5; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q9UIK5; protein.
DR   Bgee; ENSG00000144339; Expressed in middle temporal gyrus and 148 other cell types or tissues.
DR   GO; GO:0005576; C:extracellular region; IBA:GO_Central.
DR   GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR   GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR   GO; GO:0030336; P:negative regulation of cell migration; IDA:MGI.
DR   GO; GO:0045720; P:negative regulation of integrin biosynthetic process; IMP:MGI.
DR   GO; GO:0051497; P:negative regulation of stress fiber assembly; IDA:MGI.
DR   GO; GO:0044319; P:wound healing, spreading of cells; IDA:MGI.
DR   CDD; cd00104; KAZAL_FS; 2.
DR   FunFam; 2.10.25.10:FF:000234; tomoregulin-2 isoform X1; 1.
DR   FunFam; 3.30.60.30:FF:000002; tomoregulin-2 isoform X1; 1.
DR   FunFam; 3.30.60.30:FF:000020; tomoregulin-2 isoform X2; 1.
DR   Gene3D; 3.30.60.30; -; 2.
DR   Gene3D; 2.10.25.10; Laminin; 1.
DR   InterPro; IPR000742; EGF.
DR   InterPro; IPR002350; Kazal_dom.
DR   InterPro; IPR036058; Kazal_dom_sf.
DR   PANTHER; PTHR21632; REGULATORY PROTEIN ZESTE; 1.
DR   PANTHER; PTHR21632:SF5; TOMOREGULIN-2 ISOFORM X1; 1.
DR   Pfam; PF07648; Kazal_2; 2.
DR   SMART; SM00280; KAZAL; 2.
DR   SUPFAM; SSF57196; EGF/Laminin; 1.
DR   SUPFAM; SSF100895; Kazal-type serine protease inhibitors; 2.
DR   PROSITE; PS00022; EGF_1; 1.
DR   PROSITE; PS01186; EGF_2; 1.
DR   PROSITE; PS50026; EGF_3; 1.
DR   PROSITE; PS51465; KAZAL_2; 2.
PE   1: Evidence at protein level;
KW   Alternative splicing; Direct protein sequencing; Disulfide bond;
KW   EGF-like domain; Glycoprotein; Membrane; Proteoglycan;
KW   Proteomics identification; Reference proteome; Repeat; Secreted; Signal;
KW   Transmembrane; Transmembrane helix.
FT   SIGNAL          1..40
FT                   /evidence="ECO:0000269|PubMed:15340161"
FT   CHAIN           41..374
FT                   /note="Tomoregulin-2"
FT                   /id="PRO_0000016587"
FT   TOPO_DOM        41..320
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        321..341
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        342..374
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          90..137
FT                   /note="Kazal-like 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DOMAIN          181..229
FT                   /note="Kazal-like 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DOMAIN          261..301
FT                   /note="EGF-like"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   REGION          303..320
FT                   /note="Required for shedding"
FT                   /evidence="ECO:0000269|PubMed:17942404"
FT   REGION          353..374
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        356..374
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            97..98
FT                   /note="Reactive bond"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   SITE            188..189
FT                   /note="Reactive bond"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   CARBOHYD        204
FT                   /note="N-linked (GlcNAc...) (complex) asparagine; atypical"
FT                   /evidence="ECO:0000269|PubMed:19139490"
FT   CARBOHYD        230
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        91..121
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DISULFID        95..114
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DISULFID        103..135
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DISULFID        182..213
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DISULFID        186..206
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DISULFID        195..227
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT   DISULFID        265..278
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   DISULFID        273..289
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   DISULFID        291..300
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   VAR_SEQ         147..175
FT                   /note="VHEGSGETSQKETSTCDICQFGAECDEDA -> GRSCLFTYLKIYWWILLCI
FT                   FTYVCSISDI (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:16439095"
FT                   /id="VSP_024973"
FT   VAR_SEQ         176..374
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:16439095"
FT                   /id="VSP_024974"
FT   VAR_SEQ         344..346
FT                   /note="KCP -> AKL (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:17974005, ECO:0000303|Ref.7"
FT                   /id="VSP_014312"
FT   VAR_SEQ         347..374
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:17974005, ECO:0000303|Ref.7"
FT                   /id="VSP_014313"
FT   CONFLICT        28
FT                   /note="M -> V (in Ref. 8; BAD96411)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        63
FT                   /note="E -> G (in Ref. 6; BAC11030)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        222
FT                   /note="M -> T (in Ref. 8; BAD96411)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        339
FT                   /note="L -> H (in Ref. 8; BAD96411)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   374 AA;  41428 MW;  44452F680FEBDCDB CRC64;
     MVLWESPRQC SSWTLCEGFC WLLLLPVMLL IVARPVKLAA FPTSLSDCQT PTGWNCSGYD
     DRENDLFLCD TNTCKFDGEC LRIGDTVTCV CQFKCNNDYV PVCGSNGESY QNECYLRQAA
     CKQQSEILVV SEGSCATDAG SGSGDGVHEG SGETSQKETS TCDICQFGAE CDEDAEDVWC
     VCNIDCSQTN FNPLCASDGK SYDNACQIKE ASCQKQEKIE VMSLGRCQDN TTTTTKSEDG
     HYARTDYAEN ANKLEESARE HHIPCPEHYN GFCMHGKCEH SINMQEPSCR CDAGYTGQHC
     EKKDYSVLYV VPGPVRFQYV LIAAVIGTIQ IAVICVVVLC ITRKCPRSNR IHRQKQNTGH
     YSSDNTTRAS TRLI
//
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};
CC   ---------------------------------------------------------------------------
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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   UBB_HUMAN               Reviewed;         229 AA.
AC   P0CG47; P02248; P02249; P02250; P62988; Q29120; Q6LBL4; Q6LDU5; Q8WYN8;
AC   Q91887; Q91888; Q9BWD6; Q9BX98; Q9UEF2; Q9UEG1; Q9UEK8; Q9UPK7;
DT   10-AUG-2010, integrated into UniProtKB/Swiss-Prot.
DT   10-AUG-2010, sequence version 1.
DT   28-JAN-2026, entry version 132.
DE   RecName: Full=Polyubiquitin-B;
DE   Contains:
DE     RecName: Full=Ubiquitin;
DE   Flags: Precursor;
GN   Name=UBB;
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].
RC   TISSUE=Blood;
RX   PubMed=3029682; DOI=10.1093/nar/15.2.443;
RA   Baker R.T., Board P.G.;
RT   "The human ubiquitin gene family: structure of a gene and pseudogenes from
RT   the Ub B subfamily.";
RL   Nucleic Acids Res. 15:443-463(1987).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=14745543; DOI=10.1007/s00239-003-2532-4;
RA   Tachikui H., Saitou N., Nakajima T., Hayasaka I., Ishida T., Inoue I.;
RT   "Lineage-specific homogenization of the polyubiquitin gene among human and
RT   great apes.";
RL   J. Mol. Evol. 57:737-744(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16625196; DOI=10.1038/nature04689;
RA   Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA   Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA   Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA   Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA   DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA   Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA   Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA   LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA   Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA   Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA   Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA   Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA   Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT   "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT   human lineage.";
RL   Nature 440:1045-1049(2006).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, Liver, 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   [5]
RP   PROTEIN SEQUENCE OF 1-27; 30-42 AND 55-72, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RC   TISSUE=Fetal brain cortex;
RA   Lubec G., Chen W.-Q., Sun Y.;
RL   Submitted (DEC-2008) to UniProtKB.
RN   [6]
RP   PROTEIN SEQUENCE OF 1-74.
RX   PubMed=1128706; DOI=10.1038/255423a0;
RA   Schlesinger D.H., Goldstein G.;
RT   "Molecular conservation of 74 amino acid sequence of ubiquitin between
RT   cattle and man.";
RL   Nature 255:423-424(1975).
RN   [7]
RP   PROTEIN SEQUENCE OF 1-27 AND 43-54, UBIQUITINATION AT LYS-6; LYS-11 AND
RP   LYS-48, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=16443603; DOI=10.1074/jbc.m512786200;
RA   Cripps D., Thomas S.N., Jeng Y., Yang F., Davies P., Yang A.J.;
RT   "Alzheimer disease-specific conformation of hyperphosphorylated paired
RT   helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6
RT   ubiquitin conjugation.";
RL   J. Biol. Chem. 281:10825-10838(2006).
RN   [8]
RP   FUNCTION, UBIQUITINATION AT LYS-11; LYS-29; LYS-48 AND LYS-63, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=16543144; DOI=10.1016/j.molcel.2006.02.018;
RA   Huang F., Kirkpatrick D., Jiang X., Gygi S.P., Sorkin A.;
RT   "Differential regulation of EGF receptor internalization and degradation by
RT   multiubiquitination within the kinase domain.";
RL   Mol. Cell 21:737-748(2006).
RN   [9]
RP   UBIQUITINATION AT LYS-27.
RX   PubMed=15466860; DOI=10.1074/jbc.m402916200;
RA   Okumura F., Hatakeyama S., Matsumoto M., Kamura T., Nakayama K.;
RT   "Functional regulation of FEZ1 by the U-box-type ubiquitin ligase E4B
RT   contributes to neuritogenesis.";
RL   J. Biol. Chem. 279:53533-53543(2004).
RN   [10]
RP   UBIQUITINATION AT LYS-63, AND MUTAGENESIS OF LYS-48 AND LYS-63.
RX   PubMed=18719106; DOI=10.1073/pnas.0805685105;
RA   Motegi A., Liaw H.-J., Lee K.-Y., Roest H.P., Maas A., Wu X., Moinova H.,
RA   Markowitz S.D., Ding H., Hoeijmakers J.H.J., Myung K.;
RT   "Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH
RT   prevents genomic instability from stalled replication forks.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:12411-12416(2008).
RN   [11]
RP   REVIEW, AND FUNCTION.
RX   PubMed=19754430; DOI=10.1042/bst0370937;
RA   Komander D.;
RT   "The emerging complexity of protein ubiquitination.";
RL   Biochem. Soc. Trans. 37:937-953(2009).
RN   [12]
RP   CLEAVAGE BY UCHL3 (VARIANT UBB(+1)).
RX   PubMed=21762696; DOI=10.1016/j.febslet.2011.06.037;
RA   Dennissen F.J., Kholod N., Hermes D.J., Kemmerling N., Steinbusch H.W.,
RA   Dantuma N.P., van Leeuwen F.W.;
RT   "Mutant ubiquitin (UBB(+1)) associated with neurodegenerative disorders is
RT   hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3).";
RL   FEBS Lett. 585:2568-2574(2011).
RN   [13]
RP   IDENTIFICATION OF VARIANT UBB(+1).
RX   PubMed=9422699; DOI=10.1126/science.279.5348.242;
RA   van Leeuwen F.W., de Kleijn D.P., van den Hurk H.H., Neubauer A.,
RA   Sonnemans M.A., Sluijs J.A., Koycu S., Ramdjielal R.D., Salehi A.,
RA   Martens G.J., Grosveld F.G., Peter J., Burbach H., Hol E.M.;
RT   "Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in
RT   Alzheimer's and Down patients.";
RL   Science 279:242-247(1998).
RN   [14]
RP   TISSUE SPECIFICITY (VARIANT UBB(+1)).
RX   PubMed=14597671; DOI=10.1096/fj.03-0205com;
RA   Fischer D.F., De Vos R.A., Van Dijk R., De Vrij F.M., Proper E.A.,
RA   Sonnemans M.A., Verhage M.C., Sluijs J.A., Hobo B., Zouambia M.,
RA   Steur E.N., Kamphorst W., Hol E.M., Van Leeuwen F.W.;
RT   "Disease-specific accumulation of mutant ubiquitin as a marker for
RT   proteasomal dysfunction in the brain.";
RL   FASEB J. 17:2014-2024(2003).
RN   [15]
RP   PHOSPHORYLATION AT SER-65, AND MUTAGENESIS OF SER-65.
RX   PubMed=24660806; DOI=10.1042/bj20140334;
RA   Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S.,
RA   Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.;
RT   "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at
RT   Ser65.";
RL   Biochem. J. 460:127-139(2014).
RN   [16]
RP   SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-65, AND MUTAGENESIS OF SER-65.
RX   PubMed=24751536; DOI=10.1083/jcb.201402104;
RA   Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A.,
RA   Banerjee S., Youle R.J.;
RT   "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase
RT   activity.";
RL   J. Cell Biol. 205:143-153(2014).
RN   [17]
RP   PHOSPHORYLATION AT SER-65, AND MUTAGENESIS OF SER-65.
RX   PubMed=24784582; DOI=10.1038/nature13392;
RA   Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y.,
RA   Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F.,
RA   Saeki Y., Tanaka K., Matsuda N.;
RT   "Ubiquitin is phosphorylated by PINK1 to activate parkin.";
RL   Nature 510:162-166(2014).
RN   [18]
RP   PHOSPHORYLATION AT SER-65.
RX   PubMed=25527291; DOI=10.15252/embj.201489847;
RA   Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N.,
RA   Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.;
RT   "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain
RT   assembly and hydrolysis.";
RL   EMBO J. 34:307-325(2015).
RN   [19]
RP   ADP-RIBOSYLATION AT GLY-76, AND MUTAGENESIS OF HIS-68; ARG-72; ARG-74 AND
RP   GLY-76.
RX   PubMed=28525742; DOI=10.1016/j.molcel.2017.04.028;
RA   Yang C.S., Jividen K., Spencer A., Dworak N., Ni L., Oostdyk L.T.,
RA   Chatterjee M., Kusmider B., Reon B., Parlak M., Gorbunova V., Abbas T.,
RA   Jeffery E., Sherman N.E., Paschal B.M.;
RT   "Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase
RT   Dtx3L/Parp9.";
RL   Mol. Cell 66:503-516(2017).
RN   [20]
RP   ADP-RIBOSYLATION AT THR-66 (MICROBIAL INFECTION).
RX   PubMed=32330457; DOI=10.1016/j.molcel.2020.03.016;
RA   Yan F., Huang C., Wang X., Tan J., Cheng S., Wan M., Wang Z., Wang S.,
RA   Luo S., Li A., Guo X., Feng M., Liu X., Zhu Y., Zhou Y.;
RT   "Threonine ADP-ribosylation of ubiquitin by a bacterial effector family
RT   blocks host ubiquitination.";
RL   Mol. Cell 78:641-652(2020).
RN   [21]
RP   FUNCTION (UBIQUITIN), AND UBIQUITINATION AT LYS-29.
RX   PubMed=34239127; DOI=10.1038/s41589-021-00823-5;
RA   Yu Y., Zheng Q., Erramilli S.K., Pan M., Park S., Xie Y., Li J., Fei J.,
RA   Kossiakoff A.A., Liu L., Zhao M.;
RT   "K29-linked ubiquitin signaling regulates proteotoxic stress response and
RT   cell cycle.";
RL   Nat. Chem. Biol. 17:896-905(2021).
RN   [22] {ECO:0007744|PDB:6BYH, ECO:0007744|PDB:6C16}
RP   X-RAY CRYSTALLOGRAPHY (2.61 ANGSTROMS) OF 152-228 IN COMPLEX WITH SKP1;
RP   KMD2A AND KMD2B, AND INTERACTION WITH SKP1-KDM2A AND SKP1-KDM2B COMPLEXES.
RX   PubMed=30033217; DOI=10.1016/j.str.2018.06.004;
RA   Gorelik M., Manczyk N., Pavlenco A., Kurinov I., Sidhu S.S., Sicheri F.;
RT   "A Structure-Based Strategy for Engineering Selective Ubiquitin Variant
RT   Inhibitors of Skp1-Cul1-F-Box Ubiquitin Ligases.";
RL   Structure 26:1226-1236.E3(2018).
RN   [23]
RP   X-RAY CRYSTALLOGRAPHY (3.03 ANGSTROMS) OF 1-76 IN COMPLEX WITH ZRANB1, AND
RP   UBIQUITINATION AT LYS-29.
RX   PubMed=25752573; DOI=10.1016/j.molcel.2015.01.041;
RA   Kristariyanto Y.A., Abdul Rehman S.A., Campbell D.G., Morrice N.A.,
RA   Johnson C., Toth R., Kulathu Y.;
RT   "K29-selective ubiquitin binding domain reveals structural basis of
RT   specificity and heterotypic nature of K29 polyubiquitin.";
RL   Mol. Cell 58:83-94(2015).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (1.68 ANGSTROMS) OF 1-76 IN COMPLEX WITH ZRANB1, AND
RP   UBIQUITINATION AT LYS-29 AND LYS-33.
RX   PubMed=25752577; DOI=10.1016/j.molcel.2015.01.042;
RA   Michel M.A., Elliott P.R., Swatek K.N., Simicek M., Pruneda J.N.,
RA   Wagstaff J.L., Freund S.M., Komander D.;
RT   "Assembly and specific recognition of K29- and K33-linked polyubiquitin.";
RL   Mol. Cell 58:95-109(2015).
RN   [25] {ECO:0007744|PDB:5CAW}
RP   X-RAY CRYSTALLOGRAPHY (2.62 ANGSTROMS) OF 153-228, AND PHOSPHORYLATION AT
RP   SER-65.
RX   PubMed=26161729; DOI=10.1038/nature14879;
RA   Wauer T., Simicek M., Schubert A., Komander D.;
RT   "Mechanism of phospho-ubiquitin-induced PARKIN activation.";
RL   Nature 524:370-374(2015).
RN   [26]
RP   ERRATUM OF PUBMED:26161729.
RX   PubMed=26416742; DOI=10.1038/nature15531;
RA   Wauer T., Simicek M., Schubert A., Komander D.;
RL   Nature 526:728-728(2015).
RN   [27] {ECO:0007744|PDB:5VZM}
RP   STRUCTURE BY NMR OF 153-228 IN COMPLEX WITH REV1.
RX   PubMed=29778604; DOI=10.1016/j.jmb.2018.05.017;
RA   Cui G., Botuyan M.V., Mer G.;
RT   "Structural Basis for the Interaction of Mutasome Assembly Factor REV1 with
RT   Ubiquitin.";
RL   J. Mol. Biol. 430:2042-2050(2018).
CC   -!- FUNCTION: [Ubiquitin]: Exists either covalently attached to another
CC       protein, or free (unanchored). When covalently bound, it is conjugated
CC       to target proteins via an isopeptide bond either as a monomer
CC       (monoubiquitin), a polymer linked via different Lys residues of the
CC       ubiquitin (polyubiquitin chains) or a linear polymer linked via the
CC       initiator Met of the ubiquitin (linear polyubiquitin chains).
CC       Polyubiquitin chains, when attached to a target protein, have different
CC       functions depending on the Lys residue of the ubiquitin that is linked:
CC       Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved
CC       in ERAD (endoplasmic reticulum-associated degradation) and in cell-
CC       cycle regulation; Lys-29-linked is involved in proteotoxic stress
CC       response and cell cycle; Lys-33-linked is involved in kinase
CC       modification; Lys-48-linked is involved in protein degradation via the
CC       proteasome; Lys-63-linked is involved in endocytosis, DNA-damage
CC       responses as well as in signaling processes leading to activation of
CC       the transcription factor NF-kappa-B. Linear polymer chains formed via
CC       attachment by the initiator Met lead to cell signaling. Ubiquitin is
CC       usually conjugated to Lys residues of target proteins, however, in rare
CC       cases, conjugation to Cys or Ser residues has been observed. When
CC       polyubiquitin is free (unanchored-polyubiquitin), it also has distinct
CC       roles, such as in activation of protein kinases, and in signaling.
CC       {ECO:0000269|PubMed:16543144, ECO:0000269|PubMed:34239127,
CC       ECO:0000303|PubMed:19754430}.
CC   -!- SUBUNIT: Interacts with SKP1-KMD2A and SKP1-KMD2B complexes. Interacts
CC       with REV1 (PubMed:29778604). {ECO:0000269|PubMed:29778604,
CC       ECO:0000269|PubMed:30033217}.
CC   -!- INTERACTION:
CC       P0CG47; P05067: APP; NbExp=3; IntAct=EBI-413034, EBI-77613;
CC       P0CG47; Q8IVM0: CCDC50; NbExp=2; IntAct=EBI-413034, EBI-723996;
CC       P0CG47; Q9H305: CDIP1; NbExp=3; IntAct=EBI-413034, EBI-2876678;
CC       P0CG47; Q6ZTR5: CFAP47; NbExp=2; IntAct=EBI-413034, EBI-9996254;
CC       P0CG47; A0PJX0: CIB4; NbExp=2; IntAct=EBI-413034, EBI-12868028;
CC       P0CG47; O75881: CYP7B1; NbExp=2; IntAct=EBI-413034, EBI-21841279;
CC       P0CG47; Q15038: DAZAP2; NbExp=7; IntAct=EBI-413034, EBI-724310;
CC       P0CG47; Q6ICB0: DESI1; NbExp=3; IntAct=EBI-413034, EBI-2806959;
CC       P0CG47; P28562: DUSP1; NbExp=2; IntAct=EBI-413034, EBI-975493;
CC       P0CG47; Q9UKT6: FBXL21P; NbExp=2; IntAct=EBI-413034, EBI-21842236;
CC       P0CG47; Q9UJY5: GGA1; NbExp=3; IntAct=EBI-413034, EBI-447141;
CC       P0CG47; Q9NZ52: GGA3; NbExp=2; IntAct=EBI-413034, EBI-447404;
CC       P0CG47; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-413034, EBI-81279;
CC       P0CG47; Q99759: MAP3K3; NbExp=2; IntAct=EBI-413034, EBI-307281;
CC       P0CG47; P33993: MCM7; NbExp=2; IntAct=EBI-413034, EBI-355924;
CC       P0CG47; Q8N3F0: MTURN; NbExp=3; IntAct=EBI-413034, EBI-11980301;
CC       P0CG47; P46934: NEDD4; NbExp=2; IntAct=EBI-413034, EBI-726944;
CC       P0CG47; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-413034, EBI-1058491;
CC       P0CG47; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-413034, EBI-25830200;
CC       P0CG47; Q96CS7: PLEKHB2; NbExp=3; IntAct=EBI-413034, EBI-373552;
CC       P0CG47; Q9NRQ2: PLSCR4; NbExp=3; IntAct=EBI-413034, EBI-769257;
CC       P0CG47; O60260-5: PRKN; NbExp=6; IntAct=EBI-413034, EBI-21251460;
CC       P0CG47; Q9UJ41: RABGEF1; NbExp=6; IntAct=EBI-413034, EBI-913954;
CC       P0CG47; P54727: RAD23B; NbExp=5; IntAct=EBI-413034, EBI-954531;
CC       P0CG47; Q9Y3C5: RNF11; NbExp=4; IntAct=EBI-413034, EBI-396669;
CC       P0CG47; Q68DV7: RNF43; NbExp=2; IntAct=EBI-413034, EBI-1647060;
CC       P0CG47; Q8N488: RYBP; NbExp=3; IntAct=EBI-413034, EBI-752324;
CC       P0CG47; O00560: SDCBP; NbExp=3; IntAct=EBI-413034, EBI-727004;
CC       P0CG47; Q9HAU4: SMURF2; NbExp=4; IntAct=EBI-413034, EBI-396727;
CC       P0CG47; P00441: SOD1; NbExp=3; IntAct=EBI-413034, EBI-990792;
CC       P0CG47; O75886: STAM2; NbExp=3; IntAct=EBI-413034, EBI-373258;
CC       P0CG47; O95630: STAMBP; NbExp=4; IntAct=EBI-413034, EBI-396676;
CC       P0CG47; Q86VP1: TAX1BP1; NbExp=3; IntAct=EBI-413034, EBI-529518;
CC       P0CG47; P19438: TNFRSF1A; NbExp=2; IntAct=EBI-413034, EBI-299451;
CC       P0CG47; Q13077: TRAF1; NbExp=3; IntAct=EBI-413034, EBI-359224;
CC       P0CG47; Q9BSL1: UBAC1; NbExp=5; IntAct=EBI-413034, EBI-749370;
CC       P0CG47; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-413034, EBI-947187;
CC       P0CG47; P45974-2: USP5; NbExp=3; IntAct=EBI-413034, EBI-12072186;
CC       P0CG47; Q8NA23-2: WDR31; NbExp=3; IntAct=EBI-413034, EBI-25835937;
CC       P0CG47; Q60592: Mast2; Xeno; NbExp=2; IntAct=EBI-413034, EBI-493888;
CC       P0CG47; Q9DLK6: NP; Xeno; NbExp=2; IntAct=EBI-413034, EBI-8433218;
CC       P0CG47; P24610: Pax3; Xeno; NbExp=2; IntAct=EBI-413034, EBI-1208116;
CC   -!- SUBCELLULAR LOCATION: [Ubiquitin]: Cytoplasm {ECO:0000250}. Nucleus
CC       {ECO:0000250}. Mitochondrion outer membrane
CC       {ECO:0000269|PubMed:24751536}; Peripheral membrane protein
CC       {ECO:0000305|PubMed:24751536}.
CC   -!- PTM: [Ubiquitin]: Phosphorylated at Ser-65 by PINK1 during mitophagy
CC       (PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25527291,
CC       PubMed:26161729). Phosphorylated ubiquitin specifically binds and
CC       activates parkin (PRKN), triggering mitophagy (PubMed:24660806,
CC       PubMed:24751536, PubMed:24784582, PubMed:25527291, PubMed:26161729).
CC       Phosphorylation does not affect E1-mediated E2 charging of ubiquitin
CC       but affects discharging of E2 enzymes to form polyubiquitin chains. It
CC       also affects deubiquitination by deubiquitinase enzymes such as USP30
CC       (PubMed:25527291). {ECO:0000269|PubMed:24660806,
CC       ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582,
CC       ECO:0000269|PubMed:25527291, ECO:0000269|PubMed:26161729}.
CC   -!- PTM: [Ubiquitin]: Mono-ADP-ribosylated at the C-terminus by PARP9, a
CC       component of the PPAR9-DTX3L complex. ADP-ribosylation requires
CC       processing by E1 and E2 enzymes and prevents ubiquitin conjugation to
CC       substrates such as histones. {ECO:0000269|PubMed:28525742}.
CC   -!- PTM: [Ubiquitin]: (Microbial infection) Mono-ADP-ribosylated at Thr-66
CC       by the C.violaceum CteC virulence factor. ADP-ribosylation causes the
CC       shutdown of polyubiquitin synthesis and disrupts the recognition and
CC       reversal of polyubiquitin. {ECO:0000269|PubMed:32330457}.
CC   -!- MISCELLANEOUS: Ubiquitin is encoded by 4 different genes. UBA52 and
CC       RPS27A genes code for a single copy of ubiquitin fused to the ribosomal
CC       proteins eL40 and eS31, respectively. UBB and UBC genes code for a
CC       polyubiquitin precursor with exact head to tail repeats, the number of
CC       repeats differ between species and strains.
CC   -!- MISCELLANEOUS: The mRNA encoding variant UBB(+1) is produced by an
CC       unknown mechanism involving the deletion of a GT dinucleotide in the
CC       close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is
CC       found in normal brain, but the encoded protein accumulates only in
CC       brain neurofibrillary tangles and neuritic plaques in Alzheimer disease
CC       and other tauopathies, as well as polyglutaminopathies
CC       (PubMed:14597671). UBB(+1) variant cannot be used for
CC       polyubiquitination, is not effectively degraded by the proteasome when
CC       ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by
CC       deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus
CC       can be cleaved by UCHL3 (PubMed:21762696).
CC       {ECO:0000305|PubMed:14597671, ECO:0000305|PubMed:21762696,
CC       ECO:0000305|PubMed:9422699}.
CC   -!- MISCELLANEOUS: For a better understanding, features related to
CC       ubiquitin are only indicated for the first chain.
CC   -!- SIMILARITY: Belongs to the ubiquitin family. {ECO:0000305}.
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DR   EMBL; X04803; CAA28495.1; -; Genomic_DNA.
DR   EMBL; AB089617; BAC56955.1; -; Genomic_DNA.
DR   EMBL; AC093484; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC000379; AAH00379.1; -; mRNA.
DR   EMBL; BC009301; AAH09301.1; -; mRNA.
DR   EMBL; BC015127; AAH15127.1; -; mRNA.
DR   EMBL; BC026301; AAH26301.1; -; mRNA.
DR   EMBL; BC031027; AAH31027.1; -; mRNA.
DR   EMBL; BC046123; AAH46123.1; -; mRNA.
DR   CCDS; CCDS11177.1; -.
DR   PIR; A26437; UQHUB.
DR   RefSeq; NP_001268645.1; NM_001281716.2.
DR   RefSeq; NP_001268646.1; NM_001281717.1.
DR   RefSeq; NP_001268647.1; NM_001281718.1.
DR   RefSeq; NP_001268648.1; NM_001281719.1.
DR   RefSeq; NP_001268649.1; NM_001281720.2.
DR   RefSeq; NP_061828.1; NM_018955.4.
DR   PDB; 2KHW; NMR; -; B=153-228.
DR   PDB; 2MBB; NMR; -; B=153-228.
DR   PDB; 2MRO; NMR; -; A=153-228.
DR   PDB; 2MSG; NMR; -; A=153-224.
DR   PDB; 2N13; NMR; -; B=153-228, C=153-229.
DR   PDB; 4UEL; X-ray; 2.30 A; B=153-228.
DR   PDB; 4UF6; X-ray; 3.69 A; B/E/H/K=153-227.
DR   PDB; 4WHV; X-ray; 8.30 A; A/F/G/L=153-228.
DR   PDB; 4WLR; X-ray; 2.00 A; C=153-228.
DR   PDB; 4WUR; X-ray; 3.16 A; B=153-228.
DR   PDB; 4XOF; X-ray; 1.15 A; A=153-228.
DR   PDB; 4ZFR; X-ray; 1.72 A; B=153-228.
DR   PDB; 4ZFT; X-ray; 2.30 A; B/D=153-228.
DR   PDB; 4ZPZ; X-ray; 1.54 A; A/B=153-225.
DR   PDB; 4ZUX; X-ray; 3.82 A; X/c/h/m=153-228.
DR   PDB; 5BNB; X-ray; 2.49 A; E/F/G/I=153-229.
DR   PDB; 5CAW; X-ray; 2.62 A; B/D=153-228.
DR   PDB; 5CRA; X-ray; 2.64 A; C/D=153-227.
DR   PDB; 5CVM; X-ray; 1.90 A; B=153-211.
DR   PDB; 5CVN; X-ray; 3.36 A; D=153-228.
DR   PDB; 5CVO; X-ray; 3.88 A; C/F=153-228.
DR   PDB; 5D0K; X-ray; 2.65 A; B/E/H/K=153-228.
DR   PDB; 5D0M; X-ray; 1.91 A; B=153-228.
DR   PDB; 5DFL; X-ray; 2.10 A; B=153-228.
DR   PDB; 5DK8; X-ray; 1.32 A; A/B=154-227.
DR   PDB; 5E6J; X-ray; 2.85 A; C/F=153-227.
DR   PDB; 5EDV; X-ray; 3.48 A; E/F/G/H=153-228.
DR   PDB; 5EMZ; X-ray; 1.66 A; A/B/C/D/E/F=1-76.
DR   PDB; 5EYA; X-ray; 2.40 A; C/D=153-228.
DR   PDB; 5GJQ; EM; 4.50 A; y=153-228.
DR   PDB; 5GO7; X-ray; 1.80 A; A=1-76.
DR   PDB; 5GO8; X-ray; 2.21 A; A=1-76.
DR   PDB; 5GOB; X-ray; 1.15 A; A=1-76.
DR   PDB; 5GOC; X-ray; 1.73 A; A=1-76.
DR   PDB; 5GOD; X-ray; 1.15 A; A/B=1-76.
DR   PDB; 5GOG; X-ray; 1.98 A; A=1-76.
DR   PDB; 5GOH; X-ray; 1.95 A; A=1-76.
DR   PDB; 5GOI; X-ray; 1.59 A; A/B=1-76.
DR   PDB; 5GOJ; X-ray; 1.55 A; A=1-76.
DR   PDB; 5GOK; X-ray; 1.84 A; A=1-76.
DR   PDB; 5H7S; X-ray; 3.49 A; E/F=1-76.
DR   PDB; 5IBK; X-ray; 2.50 A; C/F=151-226.
DR   PDB; 5IFR; X-ray; 2.20 A; B=153-227.
DR   PDB; 5JBY; X-ray; 1.99 A; A/C/E=153-228.
DR   PDB; 5JG6; X-ray; 2.00 A; B/C=76-153.
DR   PDB; 5JP3; X-ray; 2.90 A; B/D/F/H=153-227.
DR   PDB; 5JTJ; X-ray; 3.32 A; B=153-228.
DR   PDB; 5JTV; X-ray; 3.31 A; B/D/F/H=1-76.
DR   PDB; 5K9P; X-ray; 1.55 A; A=153-228.
DR   PDB; 5KGF; EM; 4.54 A; M/O=153-228.
DR   PDB; 5KHY; X-ray; 3.50 A; A=153-225, B=153-227.
DR   PDB; 5KYC; X-ray; 1.43 A; C=153-228.
DR   PDB; 5KYD; X-ray; 1.62 A; D=153-228.
DR   PDB; 5KYE; X-ray; 1.97 A; C/D=153-228.
DR   PDB; 5KYF; X-ray; 1.45 A; C=153-228.
DR   PDB; 5L8H; X-ray; 1.85 A; B=1-76.
DR   PDB; 5L8W; X-ray; 2.79 A; C=1-75.
DR   PDB; 5L9T; EM; 6.40 A; S=1-73.
DR   PDB; 5LN1; X-ray; 3.14 A; U=1-76.
DR   PDB; 5LRV; X-ray; 2.80 A; B=1-76, C=1-75.
DR   PDB; 5LRW; X-ray; 2.00 A; B/D=1-75.
DR   PDB; 5LRX; X-ray; 2.85 A; B/D=1-76.
DR   PDB; 5M93; X-ray; 1.79 A; A/B/C=1-76.
DR   PDB; 5MNJ; X-ray; 2.16 A; B/F=1-76.
DR   PDB; 5N2W; X-ray; 2.68 A; B=1-76.
DR   PDB; 5N38; X-ray; 2.60 A; B=1-76.
DR   PDB; 5NL5; X-ray; 1.96 A; A/B/C=1-76.
DR   PDB; 5NLJ; X-ray; 1.53 A; A/B/C=1-76.
DR   PDB; 5NVG; X-ray; 1.07 A; A=1-76.
DR   PDB; 5O44; X-ray; 3.14 A; B/C=1-74, D/F=1-76.
DR   PDB; 5O6T; X-ray; 1.57 A; C/D=1-76.
DR   PDB; 5OHK; X-ray; 2.34 A; B=1-76.
DR   PDB; 5OHL; X-ray; 2.50 A; I/J/K/L/M/N/O/P=1-76.
DR   PDB; 5OHN; X-ray; 3.60 A; B/D=1-76.
DR   PDB; 5OHP; X-ray; 2.80 A; B/C=1-76.
DR   PDB; 5TOF; X-ray; 1.12 A; A=1-76.
DR   PDB; 5TOG; X-ray; 1.08 A; A=1-76.
DR   PDB; 5TUT; X-ray; 2.60 A; B=1-76.
DR   PDB; 5TXK; X-ray; 1.84 A; B=1-76.
DR   PDB; 5UJL; NMR; -; A/B=1-76.
DR   PDB; 5UJN; NMR; -; A/B=1-76.
DR   PDB; 5ULF; X-ray; 1.80 A; B/D=1-76.
DR   PDB; 5ULH; X-ray; 1.95 A; B=1-76.
DR   PDB; 5ULK; X-ray; 2.38 A; B=1-76.
DR   PDB; 5V1Y; X-ray; 1.42 A; C/D=1-76.
DR   PDB; 5V1Z; X-ray; 2.00 A; C/D=1-76.
DR   PDB; 5VEY; NMR; -; B=1-76.
DR   PDB; 5VF0; NMR; -; A=1-76.
DR   PDB; 5VNZ; X-ray; 3.41 A; C/F=1-76.
DR   PDB; 5VO0; X-ray; 3.90 A; C/F=1-76.
DR   PDB; 5VZM; NMR; -; A=153-228.
DR   PDB; 5VZW; X-ray; 2.28 A; C/D=153-228.
DR   PDB; 5W46; X-ray; 1.18 A; A/B=153-228.
DR   PDB; 5WFI; X-ray; 1.85 A; C/D=1-76.
DR   PDB; 5X3M; X-ray; 1.82 A; A=1-76.
DR   PDB; 5X3N; X-ray; 1.65 A; A=1-76.
DR   PDB; 5X3O; X-ray; 2.19 A; A=1-76.
DR   PDB; 5XBO; NMR; -; A=1-76.
DR   PDB; 5XDP; X-ray; 2.38 A; A=1-76.
DR   PDB; 5XK4; NMR; -; A=153-228.
DR   PDB; 5XK5; NMR; -; A=153-228.
DR   PDB; 5XPK; X-ray; 2.27 A; A=153-228.
DR   PDB; 5YDR; X-ray; 2.00 A; A/D=153-225.
DR   PDB; 5YIJ; X-ray; 3.18 A; C/D/G=153-228.
DR   PDB; 5YIK; X-ray; 3.10 A; C/D/F=153-228.
DR   PDB; 5YMY; NMR; -; A/B=1-76.
DR   PDB; 5YT6; X-ray; 1.50 A; A/C/E/G=1-76.
DR   PDB; 5ZBU; X-ray; 3.20 A; E=1-76.
DR   PDB; 5ZD0; NMR; -; A=153-228.
DR   PDB; 6ASR; X-ray; 2.36 A; A/C=153-228.
DR   PDB; 6BVA; X-ray; 2.66 A; A/B=76-152.
DR   PDB; 6BYH; X-ray; 2.61 A; C/D/H=76-152.
DR   PDB; 6C16; X-ray; 3.27 A; D/H=77-152.
DR   PDB; 6CP2; X-ray; 2.90 A; C=75-152.
DR   PDB; 6DGF; X-ray; 2.34 A; B=1-74.
DR   PDB; 6EI1; X-ray; 1.73 A; B=153-227.
DR   PDB; 6FDK; X-ray; 1.60 A; B=1-76.
DR   PDB; 6FGE; X-ray; 1.74 A; C=153-227.
DR   PDB; 6FTX; EM; 4.50 A; N/O=1-76.
DR   PDB; 6FX4; X-ray; 2.50 A; B/D=1-76.
DR   PDB; 6FYH; X-ray; 2.91 A; B=1-76.
DR   PDB; 6GLC; X-ray; 1.80 A; B=153-228.
DR   PDB; 6GZS; X-ray; 1.90 A; B=1-75.
DR   PDB; 6H4H; X-ray; 3.50 A; C/D=1-75.
DR   PDB; 6HEI; X-ray; 1.64 A; B=1-75.
DR   PDB; 6HEK; X-ray; 3.03 A; B/D=1-76.
DR   PDB; 6IF1; X-ray; 2.47 A; C/D=1-76.
DR   PDB; 6ISU; X-ray; 1.87 A; B/C=1-76.
DR   PDB; 6JB6; X-ray; 2.70 A; B=1-76.
DR   PDB; 6JB7; X-ray; 2.10 A; B=1-76.
DR   PDB; 6JMA; EM; 6.80 A; Y=1-76.
DR   PDB; 6K4I; NMR; -; A=1-76.
DR   PDB; 6K9P; X-ray; 2.05 A; G=1-76.
DR   PDB; 6KOW; NMR; -; A=1-76.
DR   PDB; 6KOX; NMR; -; A=1-76.
DR   PDB; 6LP2; X-ray; 2.48 A; C=1-75.
DR   PDB; 6MSB; EM; 3.00 A; u/w=1-76.
DR   PDB; 6MSD; EM; 3.20 A; u/w=1-76.
DR   PDB; 6MSE; EM; 3.30 A; u=1-76.
DR   PDB; 6MSG; EM; 3.50 A; u=1-76.
DR   PDB; 6N13; NMR; -; D=1-76.
DR   PDB; 6NJ9; EM; 2.96 A; L/N=1-76.
DR   PDB; 6NJG; X-ray; 2.35 A; A=1-78.
DR   PDB; 6O96; EM; 3.50 A; L=1-76.
DR   PDB; 6OAM; X-ray; 2.50 A; C/D=1-75.
DR   PDB; 6PGV; X-ray; 2.30 A; B=1-75.
DR   PDB; 6PZV; X-ray; 3.01 A; A/B/E/F=1-76.
DR   PDB; 6QF8; NMR; -; A=1-76.
DR   PDB; 6QK9; X-ray; 2.23 A; A/B/C/D/E/F/G/H/I/J/K/L=1-74.
DR   PDB; 6QML; X-ray; 2.10 A; B/E=1-76.
DR   PDB; 6TBM; EM; 20.00 A; R=153-227.
DR   PDB; 6UH5; EM; 3.50 A; Q=1-76.
DR   PDB; 6XAA; X-ray; 2.70 A; B=1-76.
DR   PDB; 6XQC; NMR; -; A=1-76.
DR   PDB; 6XZ1; X-ray; 2.30 A; C/D=1-75.
DR   PDB; 7AY2; X-ray; 3.20 A; C/F=1-75.
DR   PDB; 7BBD; X-ray; 2.20 A; B=1-74.
DR   PDB; 7BU0; X-ray; 2.43 A; C/D=1-75.
DR   PDB; 7CAP; X-ray; 1.33 A; A/B/C=1-76.
DR   PDB; 7DNI; EM; 3.20 A; E/F/G/H/I/J/K/L=1-76.
DR   PDB; 7DNJ; EM; 3.30 A; E/F/G/H/I/J/K/L=1-76.
DR   PDB; 7E8I; EM; 3.10 A; L=153-228.
DR   PDB; 7F7X; NMR; -; A=1-76.
DR   PDB; 7JMS; X-ray; 2.78 A; B/D/F/H=1-75.
DR   PDB; 7LYC; EM; 2.94 A; K=1-76.
DR   PDB; 7M2K; X-ray; 2.47 A; B/D/F/H=1-76.
DR   PDB; 7MC9; X-ray; 3.10 A; B/D/F/H/J/L/N/P=1-76.
DR   PDB; 7MEY; EM; 3.67 A; C/D=1-75.
DR   PDB; 7MYF; X-ray; 3.00 A; B=1-75.
DR   PDB; 7MYH; X-ray; 2.39 A; B=1-75.
DR   PDB; 7NBB; X-ray; 1.55 A; A/E=153-224, B/C/F/G=153-228.
DR   PDB; 7NPO; X-ray; 2.19 A; A=153-224, B/C=153-228.
DR   PDB; 7OJE; X-ray; 2.05 A; B/D=1-76.
DR   PDB; 7OJX; X-ray; 2.40 A; C/D/E=1-76.
DR   PDB; 7QO4; EM; 7.00 A; 9=153-228.
DR   PDB; 7QO5; EM; 6.00 A; 9=153-228.
DR   PDB; 7RBR; X-ray; 1.88 A; B=1-77.
DR   PDB; 7RMA; X-ray; 2.00 A; A=1-76.
DR   PDB; 7UD5; EM; 4.25 A; O=153-228.
DR   PDB; 7US1; X-ray; 2.48 A; B/C=153-226.
DR   PDB; 7UV5; X-ray; 1.45 A; C=1-76.
DR   PDB; 7W38; EM; 3.10 A; u=1-76.
DR   PDB; 7W39; EM; 3.20 A; u=1-76.
DR   PDB; 7W3A; EM; 3.50 A; y=1-76.
DR   PDB; 7W3B; EM; 3.60 A; y=1-76.
DR   PDB; 7W3C; EM; 3.40 A; y=1-76.
DR   PDB; 7W3F; EM; 3.30 A; y=1-76.
DR   PDB; 7W3G; EM; 3.20 A; y=1-76.
DR   PDB; 7W3H; EM; 3.20 A; y=1-76.
DR   PDB; 7W3I; EM; 3.50 A; y=1-76.
DR   PDB; 7W3J; EM; 3.50 A; y=1-76.
DR   PDB; 7W3K; EM; 3.60 A; y=1-76.
DR   PDB; 7W3M; EM; 3.50 A; y=1-76.
DR   PDB; 7W3U; X-ray; 3.13 A; D/E/F=153-227.
DR   PDB; 7W54; X-ray; 2.64 A; C/D/E/F=153-227.
DR   PDB; 7XCR; EM; 2.57 A; L=1-76.
DR   PDB; 7XCT; EM; 2.72 A; L/N=1-76.
DR   PDB; 7YQK; EM; 3.38 A; O=153-227.
DR   PDB; 8A67; X-ray; 1.86 A; A/E=153-224, B/C/F/G=153-228.
DR   PDB; 8BS9; X-ray; 1.90 A; B/D=153-227.
DR   PDB; 8C07; EM; 3.30 A; I/K=153-228.
DR   PDB; 8C61; X-ray; 2.50 A; B/E/H/K=153-227, C/F/I/L=153-228.
DR   PDB; 8CMR; X-ray; 2.24 A; B/D=77-228.
DR   PDB; 8DMQ; X-ray; 2.19 A; C/D=153-227.
DR   PDB; 8DMS; X-ray; 2.15 A; C/D=153-227.
DR   PDB; 8DU4; EM; 3.55 A; O=153-228.
DR   PDB; 8EFW; X-ray; 2.81 A; C=153-228.
DR   PDB; 8EFX; X-ray; 1.85 A; B=153-228.
DR   PDB; 8EHO; X-ray; 2.85 A; B/D/F=153-227.
DR   PDB; 8G6G; EM; 2.93 A; K=153-228.
DR   PDB; 8G6H; EM; 3.06 A; K=153-228.
DR   PDB; 8G6Q; EM; 3.41 A; K=153-228.
DR   PDB; 8G6S; EM; 3.47 A; K=153-228.
DR   PDB; 8GRM; EM; 3.05 A; O=153-228.
DR   PDB; 8H1T; EM; 3.00 A; M=153-228.
DR   PDB; 8HQY; EM; 3.05 A; U=153-226.
DR   PDB; 8IC9; X-ray; 1.25 A; A/B/C/D=153-228.
DR   PDB; 8ITP; X-ray; 3.00 A; A/C=153-228.
DR   PDB; 8J1P; EM; 3.31 A; C/D/E=153-228.
DR   PDB; 8K0G; EM; 3.80 A; u/v/w/x=153-228.
DR   PDB; 8OYP; X-ray; 2.44 A; C/D=77-152.
DR   PDB; 8PP6; EM; 3.18 A; M=153-225.
DR   PDB; 8Q00; X-ray; 1.62 A; B/D=153-228.
DR   PDB; 8RQI; X-ray; 1.94 A; B=153-227.
DR   PDB; 8SN3; EM; 3.80 A; M=170-228.
DR   PDB; 8SN4; EM; 3.70 A; M=170-228.
DR   PDB; 8SN5; EM; 3.90 A; M=170-228.
DR   PDB; 8SN6; EM; 3.70 A; M=170-228.
DR   PDB; 8SN7; EM; 3.70 A; M=170-228.
DR   PDB; 8SN8; EM; 3.70 A; M=170-228.
DR   PDB; 8SN9; EM; 3.90 A; M=170-228.
DR   PDB; 8SNA; EM; 4.00 A; M=170-228.
DR   PDB; 8T2D; X-ray; 1.75 A; B=153-226.
DR   PDB; 8TXV; EM; 3.80 A; M=170-228.
DR   PDB; 8TXW; EM; 3.60 A; M=170-228.
DR   PDB; 8TXX; EM; 3.70 A; M=170-228.
DR   PDB; 8V25; EM; 3.32 A; K=153-228.
DR   PDB; 8V26; EM; 3.33 A; K=153-228.
DR   PDB; 8V27; EM; 3.34 A; K=153-228.
DR   PDB; 8V28; EM; 3.36 A; K=153-228.
DR   PDB; 8W31; X-ray; 2.50 A; B/C=153-227.
DR   PDB; 8WG5; EM; 3.05 A; U=153-227.
DR   PDB; 8XEP; X-ray; 2.95 A; B/C=153-228.
DR   PDB; 9AVT; X-ray; 1.50 A; A/B=153-228.
DR   PDB; 9AVW; X-ray; 1.75 A; A/B=77-228.
DR   PDB; 9AZJ; X-ray; 3.32 A; F/S/Z=153-228.
DR   PDB; 9B0Z; X-ray; 2.41 A; C/D/G=77-228.
DR   PDB; 9B12; X-ray; 1.81 A; A/B=77-228.
DR   PDB; 9C5E; NMR; -; B=153-227.
DR   PDB; 9EMK; X-ray; 2.17 A; B/D/F=153-228.
DR   PDB; 9F5T; X-ray; 2.56 A; B/D=77-228.
DR   PDB; 9FN4; X-ray; 2.15 A; B=77-228.
DR   PDB; 9FPA; X-ray; 2.18 A; B=77-228.
DR   PDB; 9G7G; X-ray; 1.89 A; B/D/F/H/J/L/N/P/R/T/V/X=153-227.
DR   PDB; 9GKM; EM; 3.69 A; D=153-228.
DR   PDB; 9HNW; EM; 3.04 A; C=153-227, D=153-228.
DR   PDBsum; 2KHW; -.
DR   PDBsum; 2MBB; -.
DR   PDBsum; 2MRO; -.
DR   PDBsum; 2MSG; -.
DR   PDBsum; 2N13; -.
DR   PDBsum; 4UEL; -.
DR   PDBsum; 4UF6; -.
DR   PDBsum; 4WHV; -.
DR   PDBsum; 4WLR; -.
DR   PDBsum; 4WUR; -.
DR   PDBsum; 4XOF; -.
DR   PDBsum; 4ZFR; -.
DR   PDBsum; 4ZFT; -.
DR   PDBsum; 4ZPZ; -.
DR   PDBsum; 4ZUX; -.
DR   PDBsum; 5BNB; -.
DR   PDBsum; 5CAW; -.
DR   PDBsum; 5CRA; -.
DR   PDBsum; 5CVM; -.
DR   PDBsum; 5CVN; -.
DR   PDBsum; 5CVO; -.
DR   PDBsum; 5D0K; -.
DR   PDBsum; 5D0M; -.
DR   PDBsum; 5DFL; -.
DR   PDBsum; 5DK8; -.
DR   PDBsum; 5E6J; -.
DR   PDBsum; 5EDV; -.
DR   PDBsum; 5EMZ; -.
DR   PDBsum; 5EYA; -.
DR   PDBsum; 5GJQ; -.
DR   PDBsum; 5GO7; -.
DR   PDBsum; 5GO8; -.
DR   PDBsum; 5GOB; -.
DR   PDBsum; 5GOC; -.
DR   PDBsum; 5GOD; -.
DR   PDBsum; 5GOG; -.
DR   PDBsum; 5GOH; -.
DR   PDBsum; 5GOI; -.
DR   PDBsum; 5GOJ; -.
DR   PDBsum; 5GOK; -.
DR   PDBsum; 5H7S; -.
DR   PDBsum; 5IBK; -.
DR   PDBsum; 5IFR; -.
DR   PDBsum; 5JBY; -.
DR   PDBsum; 5JG6; -.
DR   PDBsum; 5JP3; -.
DR   PDBsum; 5JTJ; -.
DR   PDBsum; 5JTV; -.
DR   PDBsum; 5K9P; -.
DR   PDBsum; 5KGF; -.
DR   PDBsum; 5KHY; -.
DR   PDBsum; 5KYC; -.
DR   PDBsum; 5KYD; -.
DR   PDBsum; 5KYE; -.
DR   PDBsum; 5KYF; -.
DR   PDBsum; 5L8H; -.
DR   PDBsum; 5L8W; -.
DR   PDBsum; 5L9T; -.
DR   PDBsum; 5LN1; -.
DR   PDBsum; 5LRV; -.
DR   PDBsum; 5LRW; -.
DR   PDBsum; 5LRX; -.
DR   PDBsum; 5M93; -.
DR   PDBsum; 5MNJ; -.
DR   PDBsum; 5N2W; -.
DR   PDBsum; 5N38; -.
DR   PDBsum; 5NL5; -.
DR   PDBsum; 5NLJ; -.
DR   PDBsum; 5NVG; -.
DR   PDBsum; 5O44; -.
DR   PDBsum; 5O6T; -.
DR   PDBsum; 5OHK; -.
DR   PDBsum; 5OHL; -.
DR   PDBsum; 5OHN; -.
DR   PDBsum; 5OHP; -.
DR   PDBsum; 5TOF; -.
DR   PDBsum; 5TOG; -.
DR   PDBsum; 5TUT; -.
DR   PDBsum; 5TXK; -.
DR   PDBsum; 5UJL; -.
DR   PDBsum; 5UJN; -.
DR   PDBsum; 5ULF; -.
DR   PDBsum; 5ULH; -.
DR   PDBsum; 5ULK; -.
DR   PDBsum; 5V1Y; -.
DR   PDBsum; 5V1Z; -.
DR   PDBsum; 5VEY; -.
DR   PDBsum; 5VF0; -.
DR   PDBsum; 5VNZ; -.
DR   PDBsum; 5VO0; -.
DR   PDBsum; 5VZM; -.
DR   PDBsum; 5VZW; -.
DR   PDBsum; 5W46; -.
DR   PDBsum; 5WFI; -.
DR   PDBsum; 5X3M; -.
DR   PDBsum; 5X3N; -.
DR   PDBsum; 5X3O; -.
DR   PDBsum; 5XBO; -.
DR   PDBsum; 5XDP; -.
DR   PDBsum; 5XK4; -.
DR   PDBsum; 5XK5; -.
DR   PDBsum; 5XPK; -.
DR   PDBsum; 5YDR; -.
DR   PDBsum; 5YIJ; -.
DR   PDBsum; 5YIK; -.
DR   PDBsum; 5YMY; -.
DR   PDBsum; 5YT6; -.
DR   PDBsum; 5ZBU; -.
DR   PDBsum; 5ZD0; -.
DR   PDBsum; 6ASR; -.
DR   PDBsum; 6BVA; -.
DR   PDBsum; 6BYH; -.
DR   PDBsum; 6C16; -.
DR   PDBsum; 6CP2; -.
DR   PDBsum; 6DGF; -.
DR   PDBsum; 6EI1; -.
DR   PDBsum; 6FDK; -.
DR   PDBsum; 6FGE; -.
DR   PDBsum; 6FTX; -.
DR   PDBsum; 6FX4; -.
DR   PDBsum; 6FYH; -.
DR   PDBsum; 6GLC; -.
DR   PDBsum; 6GZS; -.
DR   PDBsum; 6H4H; -.
DR   PDBsum; 6HEI; -.
DR   PDBsum; 6HEK; -.
DR   PDBsum; 6IF1; -.
DR   PDBsum; 6ISU; -.
DR   PDBsum; 6JB6; -.
DR   PDBsum; 6JB7; -.
DR   PDBsum; 6JMA; -.
DR   PDBsum; 6K4I; -.
DR   PDBsum; 6K9P; -.
DR   PDBsum; 6KOW; -.
DR   PDBsum; 6KOX; -.
DR   PDBsum; 6LP2; -.
DR   PDBsum; 6MSB; -.
DR   PDBsum; 6MSD; -.
DR   PDBsum; 6MSE; -.
DR   PDBsum; 6MSG; -.
DR   PDBsum; 6N13; -.
DR   PDBsum; 6NJ9; -.
DR   PDBsum; 6NJG; -.
DR   PDBsum; 6O96; -.
DR   PDBsum; 6OAM; -.
DR   PDBsum; 6PGV; -.
DR   PDBsum; 6PZV; -.
DR   PDBsum; 6QF8; -.
DR   PDBsum; 6QK9; -.
DR   PDBsum; 6QML; -.
DR   PDBsum; 6TBM; -.
DR   PDBsum; 6UH5; -.
DR   PDBsum; 6XAA; -.
DR   PDBsum; 6XQC; -.
DR   PDBsum; 6XZ1; -.
DR   PDBsum; 7AY2; -.
DR   PDBsum; 7BBD; -.
DR   PDBsum; 7BU0; -.
DR   PDBsum; 7CAP; -.
DR   PDBsum; 7DNI; -.
DR   PDBsum; 7DNJ; -.
DR   PDBsum; 7E8I; -.
DR   PDBsum; 7F7X; -.
DR   PDBsum; 7JMS; -.
DR   PDBsum; 7LYC; -.
DR   PDBsum; 7M2K; -.
DR   PDBsum; 7MC9; -.
DR   PDBsum; 7MEY; -.
DR   PDBsum; 7MYF; -.
DR   PDBsum; 7MYH; -.
DR   PDBsum; 7NBB; -.
DR   PDBsum; 7NPO; -.
DR   PDBsum; 7OJE; -.
DR   PDBsum; 7OJX; -.
DR   PDBsum; 7QO4; -.
DR   PDBsum; 7QO5; -.
DR   PDBsum; 7RBR; -.
DR   PDBsum; 7RMA; -.
DR   PDBsum; 7UD5; -.
DR   PDBsum; 7US1; -.
DR   PDBsum; 7UV5; -.
DR   PDBsum; 7W38; -.
DR   PDBsum; 7W39; -.
DR   PDBsum; 7W3A; -.
DR   PDBsum; 7W3B; -.
DR   PDBsum; 7W3C; -.
DR   PDBsum; 7W3F; -.
DR   PDBsum; 7W3G; -.
DR   PDBsum; 7W3H; -.
DR   PDBsum; 7W3I; -.
DR   PDBsum; 7W3J; -.
DR   PDBsum; 7W3K; -.
DR   PDBsum; 7W3M; -.
DR   PDBsum; 7W3U; -.
DR   PDBsum; 7W54; -.
DR   PDBsum; 7XCR; -.
DR   PDBsum; 7XCT; -.
DR   PDBsum; 7YQK; -.
DR   PDBsum; 8A67; -.
DR   PDBsum; 8BS9; -.
DR   PDBsum; 8C07; -.
DR   PDBsum; 8C61; -.
DR   PDBsum; 8CMR; -.
DR   PDBsum; 8DMQ; -.
DR   PDBsum; 8DMS; -.
DR   PDBsum; 8DU4; -.
DR   PDBsum; 8EFW; -.
DR   PDBsum; 8EFX; -.
DR   PDBsum; 8EHO; -.
DR   PDBsum; 8G6G; -.
DR   PDBsum; 8G6H; -.
DR   PDBsum; 8G6Q; -.
DR   PDBsum; 8G6S; -.
DR   PDBsum; 8GRM; -.
DR   PDBsum; 8H1T; -.
DR   PDBsum; 8HQY; -.
DR   PDBsum; 8IC9; -.
DR   PDBsum; 8ITP; -.
DR   PDBsum; 8J1P; -.
DR   PDBsum; 8K0G; -.
DR   PDBsum; 8OYP; -.
DR   PDBsum; 8PP6; -.
DR   PDBsum; 8Q00; -.
DR   PDBsum; 8RQI; -.
DR   PDBsum; 8SN3; -.
DR   PDBsum; 8SN4; -.
DR   PDBsum; 8SN5; -.
DR   PDBsum; 8SN6; -.
DR   PDBsum; 8SN7; -.
DR   PDBsum; 8SN8; -.
DR   PDBsum; 8SN9; -.
DR   PDBsum; 8SNA; -.
DR   PDBsum; 8T2D; -.
DR   PDBsum; 8TXV; -.
DR   PDBsum; 8TXW; -.
DR   PDBsum; 8TXX; -.
DR   PDBsum; 8V25; -.
DR   PDBsum; 8V26; -.
DR   PDBsum; 8V27; -.
DR   PDBsum; 8V28; -.
DR   PDBsum; 8W31; -.
DR   PDBsum; 8WG5; -.
DR   PDBsum; 8XEP; -.
DR   PDBsum; 9AVT; -.
DR   PDBsum; 9AVW; -.
DR   PDBsum; 9AZJ; -.
DR   PDBsum; 9B0Z; -.
DR   PDBsum; 9B12; -.
DR   PDBsum; 9C5E; -.
DR   PDBsum; 9EMK; -.
DR   PDBsum; 9F5T; -.
DR   PDBsum; 9FN4; -.
DR   PDBsum; 9FPA; -.
DR   PDBsum; 9G7G; -.
DR   PDBsum; 9GKM; -.
DR   PDBsum; 9HNW; -.
DR   AlphaFoldDB; P0CG47; -.
DR   BMRB; P0CG47; -.
DR   EMDB; EMD-14083; -.
DR   EMDB; EMD-14084; -.
DR   EMDB; EMD-16356; -.
DR   EMDB; EMD-23592; -.
DR   EMDB; EMD-23807; -.
DR   EMDB; EMD-29767; -.
DR   EMDB; EMD-29769; -.
DR   EMDB; EMD-29778; -.
DR   EMDB; EMD-29781; -.
DR   EMDB; EMD-30784; -.
DR   EMDB; EMD-30785; -.
DR   EMDB; EMD-32273; -.
DR   EMDB; EMD-32274; -.
DR   EMDB; EMD-32275; -.
DR   EMDB; EMD-32276; -.
DR   EMDB; EMD-32277; -.
DR   EMDB; EMD-32278; -.
DR   EMDB; EMD-32279; -.
DR   EMDB; EMD-32280; -.
DR   EMDB; EMD-32281; -.
DR   EMDB; EMD-32282; -.
DR   EMDB; EMD-32283; -.
DR   EMDB; EMD-32284; -.
DR   EMDB; EMD-33126; -.
DR   EMDB; EMD-33127; -.
DR   EMDB; EMD-34207; -.
DR   EMDB; EMD-34431; -.
DR   EMDB; EMD-35929; -.
DR   EMDB; EMD-36605; -.
DR   EMDB; EMD-36645; -.
DR   EMDB; EMD-36764; -.
DR   EMDB; EMD-40611; -.
DR   EMDB; EMD-40612; -.
DR   EMDB; EMD-40613; -.
DR   EMDB; EMD-40614; -.
DR   EMDB; EMD-40615; -.
DR   EMDB; EMD-40616; -.
DR   EMDB; EMD-40617; -.
DR   EMDB; EMD-40618; -.
DR   EMDB; EMD-41706; -.
DR   EMDB; EMD-41707; -.
DR   EMDB; EMD-41708; -.
DR   EMDB; EMD-42898; -.
DR   EMDB; EMD-42899; -.
DR   EMDB; EMD-42900; -.
DR   EMDB; EMD-42901; -.
DR   EMDB; EMD-4318; -.
DR   EMDB; EMD-46728; -.
DR   EMDB; EMD-46733; -.
DR   EMDB; EMD-46771; -.
DR   EMDB; EMD-46822; -.
DR   EMDB; EMD-47889; -.
DR   EMDB; EMD-51429; -.
DR   EMDB; EMD-52316; -.
DR   EMDB; EMD-8246; -.
DR   EMDB; EMD-9216; -.
DR   EMDB; EMD-9217; -.
DR   EMDB; EMD-9218; -.
DR   EMDB; EMD-9219; -.
DR   EMDB; EMD-9384; -.
DR   EMDB; EMD-9511; -.
DR   EMDB; EMD-9844; -.
DR   SASBDB; P0CG47; -.
DR   SMR; P0CG47; -.
DR   BioGRID; 113162; 430.
DR   FunCoup; P0CG47; 2058.
DR   IntAct; P0CG47; 338.
DR   MINT; P0CG47; -.
DR   STRING; 9606.ENSP00000478771; -.
DR   ChEMBL; CHEMBL4523178; -.
DR   DrugBank; DB02542; (4s)-5-Fluoro-L-Leucine.
DR   MoonDB; P0CG47; Predicted.
DR   GlyGen; P0CG47; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P0CG47; -.
DR   MetOSite; P0CG47; -.
DR   PhosphoSitePlus; P0CG47; -.
DR   SwissPalm; P0CG47; -.
DR   BioMuta; UBB; -.
DR   DMDM; 302595875; -.
DR   jPOST; P0CG47; -.
DR   MassIVE; P0CG47; -.
DR   PaxDb; 9606-ENSP00000304697; -.
DR   PeptideAtlas; P0CG47; -.
DR   ProteomicsDB; 52474; -.
DR   Pumba; P0CG47; -.
DR   TopDownProteomics; P0CG47; -.
DR   ABCD; P0CG47; 3 sequenced antibodies.
DR   Antibodypedia; 4579; 564 antibodies from 42 providers.
DR   DNASU; 7314; -.
DR   Ensembl; ENST00000302182.8; ENSP00000304697.3; ENSG00000170315.15.
DR   Ensembl; ENST00000395837.1; ENSP00000379178.1; ENSG00000170315.15.
DR   Ensembl; ENST00000395839.5; ENSP00000379180.1; ENSG00000170315.15.
DR   Ensembl; ENST00000614404.1; ENSP00000478771.1; ENSG00000170315.15.
DR   GeneID; 7314; -.
DR   KEGG; hsa:7314; -.
DR   MANE-Select; ENST00000302182.8; ENSP00000304697.3; NM_018955.4; NP_061828.1.
DR   AGR; HGNC:12463; -.
DR   CTD; 7314; -.
DR   DisGeNET; 7314; -.
DR   GeneCards; UBB; -.
DR   HGNC; HGNC:12463; UBB.
DR   HPA; ENSG00000170315; Low tissue specificity.
DR   MalaCards; UBB; -.
DR   MIM; 191339; gene.
DR   OpenTargets; ENSG00000170315; -.
DR   Orphanet; 99771; Bifid uvula.
DR   Orphanet; 101023; Cleft hard palate.
DR   Orphanet; 99772; Cleft velum.
DR   Orphanet; 155878; Submucosal cleft palate.
DR   VEuPathDB; HostDB:ENSG00000170315; -.
DR   eggNOG; KOG0001; Eukaryota.
DR   GeneTree; ENSGT00940000162439; -.
DR   InParanoid; P0CG47; -.
DR   OMA; NTNMQIF; -.
DR   OrthoDB; 9979733at2759; -.
DR   PAN-GO; P0CG47; 6 GO annotations based on evolutionary models.
DR   PhylomeDB; P0CG47; -.
DR   BioCyc; MetaCyc:ENSG00000170315-MONOMER; -.
DR   PathwayCommons; P0CG47; -.
DR   Reactome; R-HSA-110312; Translesion synthesis by REV1.
DR   Reactome; R-HSA-110314; Recognition of DNA damage by PCNA-containing replication complex.
DR   Reactome; R-HSA-110320; Translesion Synthesis by POLH.
DR   Reactome; R-HSA-1169091; Activation of NF-kappaB in B cells.
DR   Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR   Reactome; R-HSA-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR   Reactome; R-HSA-1236382; Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants.
DR   Reactome; R-HSA-1236974; ER-Phagosome pathway.
DR   Reactome; R-HSA-1253288; Downregulation of ERBB4 signaling.
DR   Reactome; R-HSA-1295596; Spry regulation of FGF signaling.
DR   Reactome; R-HSA-1358803; Downregulation of ERBB2:ERBB3 signaling.
DR   Reactome; R-HSA-162588; Budding and maturation of HIV virion.
DR   Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR   Reactome; R-HSA-168927; TICAM1, RIP1-mediated IKK complex recruitment.
DR   Reactome; R-HSA-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta.
DR   Reactome; R-HSA-174048; APC/C:Cdc20 mediated degradation of Cyclin B.
DR   Reactome; R-HSA-174084; Autodegradation of Cdh1 by Cdh1:APC/C.
DR   Reactome; R-HSA-174113; SCF-beta-TrCP mediated degradation of Emi1.
DR   Reactome; R-HSA-174154; APC/C:Cdc20 mediated degradation of Securin.
DR   Reactome; R-HSA-174178; APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1.
DR   Reactome; R-HSA-174184; Cdc20:Phospho-APC/C mediated degradation of Cyclin A.
DR   Reactome; R-HSA-174490; Membrane binding and targetting of GAG proteins.
DR   Reactome; R-HSA-175474; Assembly Of The HIV Virion.
DR   Reactome; R-HSA-179409; APC-Cdc20 mediated degradation of Nek2A.
DR   Reactome; R-HSA-180534; Vpu mediated degradation of CD4.
DR   Reactome; R-HSA-180585; Vif-mediated degradation of APOBEC3G.
DR   Reactome; R-HSA-182971; EGFR downregulation.
DR   Reactome; R-HSA-187577; SCF(Skp2)-mediated degradation of p27/p21.
DR   Reactome; R-HSA-195253; Degradation of beta-catenin by the destruction complex.
DR   Reactome; R-HSA-201681; TCF dependent signaling in response to WNT.
DR   Reactome; R-HSA-202424; Downstream TCR signaling.
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-211733; Regulation of activated PAK-2p34 by proteasome mediated degradation.
DR   Reactome; R-HSA-2122947; NOTCH1 Intracellular Domain Regulates Transcription.
DR   Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus.
DR   Reactome; R-HSA-2173788; Downregulation of TGF-beta receptor signaling.
DR   Reactome; R-HSA-2173791; TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
DR   Reactome; R-HSA-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
DR   Reactome; R-HSA-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
DR   Reactome; R-HSA-2467813; Separation of Sister Chromatids.
DR   Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
DR   Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP).
DR   Reactome; R-HSA-2559585; Oncogene Induced Senescence.
DR   Reactome; R-HSA-2565942; Regulation of PLK1 Activity at G2/M Transition.
DR   Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants.
DR   Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR   Reactome; R-HSA-2691232; Constitutive Signaling by NOTCH1 HD Domain Mutants.
DR   Reactome; R-HSA-2871837; FCERI mediated NF-kB activation.
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-3134975; Regulation of innate immune responses to cytosolic DNA.
DR   Reactome; R-HSA-3322077; Glycogen synthesis.
DR   Reactome; R-HSA-349425; Autodegradation of the E3 ubiquitin ligase COP1.
DR   Reactome; R-HSA-3769402; Deactivation of the beta-catenin transactivating complex.
DR   Reactome; R-HSA-3785653; Myoclonic epilepsy of Lafora.
DR   Reactome; R-HSA-382556; ABC-family proteins mediated transport.
DR   Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR   Reactome; R-HSA-450302; activated TAK1 mediates p38 MAPK activation.
DR   Reactome; R-HSA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR   Reactome; R-HSA-450408; AUF1 (hnRNP D0) binds and destabilizes mRNA.
DR   Reactome; R-HSA-4608870; Asymmetric localization of PCP proteins.
DR   Reactome; R-HSA-4641257; Degradation of AXIN.
DR   Reactome; R-HSA-4641258; Degradation of DVL.
DR   Reactome; R-HSA-4641263; Regulation of FZD by ubiquitination.
DR   Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy.
DR   Reactome; R-HSA-532668; N-glycan trimming in the ER and Calnexin/Calreticulin cycle.
DR   Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR   Reactome; R-HSA-5357956; TNFR1-induced NF-kappa-B signaling pathway.
DR   Reactome; R-HSA-5358346; Hedgehog ligand biogenesis.
DR   Reactome; R-HSA-5362768; Hh mutants are degraded by ERAD.
DR   Reactome; R-HSA-5607761; Dectin-1 mediated noncanonical NF-kB signaling.
DR   Reactome; R-HSA-5607764; CLEC7A (Dectin-1) signaling.
DR   Reactome; R-HSA-5610780; Degradation of GLI1 by the proteasome.
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-5632684; Hedgehog 'on' state.
DR   Reactome; R-HSA-5654726; Negative regulation of FGFR1 signaling.
DR   Reactome; R-HSA-5654727; Negative regulation of FGFR2 signaling.
DR   Reactome; R-HSA-5654732; Negative regulation of FGFR3 signaling.
DR   Reactome; R-HSA-5654733; Negative regulation of FGFR4 signaling.
DR   Reactome; R-HSA-5655862; Translesion synthesis by POLK.
DR   Reactome; R-HSA-5656121; Translesion synthesis by POLI.
DR   Reactome; R-HSA-5656169; Termination of translesion DNA synthesis.
DR   Reactome; R-HSA-5658442; Regulation of RAS by GAPs.
DR   Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway.
DR   Reactome; R-HSA-5675221; Negative regulation of MAPK pathway.
DR   Reactome; R-HSA-5675482; Regulation of necroptotic cell death.
DR   Reactome; R-HSA-5676590; NIK-->noncanonical NF-kB signaling.
DR   Reactome; R-HSA-5678895; Defective CFTR causes cystic fibrosis.
DR   Reactome; R-HSA-5684264; MAP3K8 (TPL2)-dependent MAPK1/3 activation.
DR   Reactome; R-HSA-5685942; HDR through Homologous Recombination (HRR).
DR   Reactome; R-HSA-5687128; MAPK6/MAPK4 signaling.
DR   Reactome; R-HSA-5689603; UCH proteinases.
DR   Reactome; R-HSA-5689877; Josephin domain DUBs.
DR   Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR   Reactome; R-HSA-5689896; Ovarian tumor domain proteases.
DR   Reactome; R-HSA-5689901; Metalloprotease DUBs.
DR   Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR   Reactome; R-HSA-5693607; Processing of DNA double-strand break ends.
DR   Reactome; R-HSA-5696394; DNA Damage Recognition in GG-NER.
DR   Reactome; R-HSA-5696395; Formation of Incision Complex in GG-NER.
DR   Reactome; R-HSA-5696397; Gap-filling DNA repair synthesis and ligation in GG-NER.
DR   Reactome; R-HSA-5696400; Dual Incision in GG-NER.
DR   Reactome; R-HSA-6781823; Formation of TC-NER Pre-Incision Complex.
DR   Reactome; R-HSA-6781827; Transcription-Coupled Nucleotide Excision Repair (TC-NER).
DR   Reactome; R-HSA-6782135; Dual incision in TC-NER.
DR   Reactome; R-HSA-6782210; Gap-filling DNA repair synthesis and ligation in TC-NER.
DR   Reactome; R-HSA-6783310; Fanconi Anemia Pathway.
DR   Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
DR   Reactome; R-HSA-6804760; Regulation of TP53 Activity through Methylation.
DR   Reactome; R-HSA-6807004; Negative regulation of MET activity.
DR   Reactome; R-HSA-68867; Assembly of the pre-replicative complex.
DR   Reactome; R-HSA-68949; Orc1 removal from chromatin.
DR   Reactome; R-HSA-69017; CDK-mediated phosphorylation and removal of Cdc6.
DR   Reactome; R-HSA-69231; Cyclin D associated events in G1.
DR   Reactome; R-HSA-69481; G2/M Checkpoints.
DR   Reactome; R-HSA-69541; Stabilization of p53.
DR   Reactome; R-HSA-69601; Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A.
DR   Reactome; R-HSA-75815; Ubiquitin-dependent degradation of Cyclin D.
DR   Reactome; R-HSA-8849469; PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1.
DR   Reactome; R-HSA-8852276; The role of GTSE1 in G2/M progression after G2 checkpoint.
DR   Reactome; R-HSA-8854050; FBXL7 down-regulates AURKA during mitotic entry and in early mitosis.
DR   Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR   Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
DR   Reactome; R-HSA-8863795; Downregulation of ERBB2 signaling.
DR   Reactome; R-HSA-8866427; VLDLR internalisation and degradation.
DR   Reactome; R-HSA-8866652; Synthesis of active ubiquitin: roles of E1 and E2 enzymes.
DR   Reactome; R-HSA-8866654; E3 ubiquitin ligases ubiquitinate target proteins.
DR   Reactome; R-HSA-8875360; InlB-mediated entry of Listeria monocytogenes into host cell.
DR   Reactome; R-HSA-8876493; InlA-mediated entry of Listeria monocytogenes into host cells.
DR   Reactome; R-HSA-8939236; RUNX1 regulates transcription of genes involved in differentiation of HSCs.
DR   Reactome; R-HSA-8939902; Regulation of RUNX2 expression and activity.
DR   Reactome; R-HSA-8941858; Regulation of RUNX3 expression and activity.
DR   Reactome; R-HSA-8948747; Regulation of PTEN localization.
DR   Reactome; R-HSA-8948751; Regulation of PTEN stability and activity.
DR   Reactome; R-HSA-8951664; Neddylation.
DR   Reactome; R-HSA-901032; ER Quality Control Compartment (ERQC).
DR   Reactome; R-HSA-9010553; Regulation of expression of SLITs and ROBOs.
DR   Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR   Reactome; R-HSA-9013973; TICAM1-dependent activation of IRF3/IRF7.
DR   Reactome; R-HSA-9014325; TICAM1,TRAF6-dependent induction of TAK1 complex.
DR   Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR   Reactome; R-HSA-9033241; Peroxisomal protein import.
DR   Reactome; R-HSA-909733; Interferon alpha/beta signaling.
DR   Reactome; R-HSA-912631; Regulation of signaling by CBL.
DR   Reactome; R-HSA-917729; Endosomal Sorting Complex Required For Transport (ESCRT).
DR   Reactome; R-HSA-917937; Iron uptake and transport.
DR   Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR   Reactome; R-HSA-936964; Activation of IRF3, IRF7 mediated by TBK1, IKKEpsilon (IKBKE).
DR   Reactome; R-HSA-937039; IRAK1 recruits IKK complex.
DR   Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1.
DR   Reactome; R-HSA-937042; IRAK2 mediated activation of TAK1 complex.
DR   Reactome; R-HSA-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex.
DR   Reactome; R-HSA-9604323; Negative regulation of NOTCH4 signaling.
DR   Reactome; R-HSA-9613829; Chaperone Mediated Autophagy.
DR   Reactome; R-HSA-9615710; Late endosomal microautophagy.
DR   Reactome; R-HSA-9636383; Prevention of phagosomal-lysosomal fusion.
DR   Reactome; R-HSA-9637628; Modulation by Mtb of host immune system.
DR   Reactome; R-HSA-9645460; Alpha-protein kinase 1 signaling pathway.
DR   Reactome; R-HSA-9646399; Aggrephagy.
DR   Reactome; R-HSA-9648002; RAS processing.
DR   Reactome; R-HSA-9664873; Pexophagy.
DR   Reactome; R-HSA-9680350; Signaling by CSF1 (M-CSF) in myeloid cells.
DR   Reactome; R-HSA-9683683; Maturation of protein E.
DR   Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses.
DR   Reactome; R-HSA-9694493; Maturation of protein E.
DR   Reactome; R-HSA-9705462; Inactivation of CSF3 (G-CSF) signaling.
DR   Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR   Reactome; R-HSA-9706369; Negative regulation of FLT3.
DR   Reactome; R-HSA-9706377; FLT3 signaling by CBL mutants.
DR   Reactome; R-HSA-9708530; Regulation of BACH1 activity.
DR   Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants.
DR   Reactome; R-HSA-975110; TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
DR   Reactome; R-HSA-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
DR   Reactome; R-HSA-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
DR   Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway.
DR   Reactome; R-HSA-9758274; Regulation of NF-kappa B signaling.
DR   Reactome; R-HSA-9762114; GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2.
DR   Reactome; R-HSA-9766229; Degradation of CDH1.
DR   Reactome; R-HSA-977225; Amyloid fiber formation.
DR   Reactome; R-HSA-9824878; Regulation of TBK1, IKKEpsilon (IKBKE)-mediated activation of IRF3, IRF7.
DR   Reactome; R-HSA-9828211; Regulation of TBK1, IKKEpsilon-mediated activation of IRF3, IRF7 upon TLR3 ligation.
DR   Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR   Reactome; R-HSA-9833109; Evasion by RSV of host interferon responses.
DR   Reactome; R-HSA-9861718; Regulation of pyruvate metabolism.
DR   Reactome; R-HSA-9932298; Degradation of CRY and PER proteins.
DR   SignaLink; P0CG47; -.
DR   SIGNOR; P0CG47; -.
DR   Agora; ENSG00000170315; -.
DR   BioGRID-ORCS; 7314; 372 hits in 1066 CRISPR screens.
DR   ChiTaRS; UBB; human.
DR   EvolutionaryTrace; P0CG47; -.
DR   GeneWiki; Ubiquitin_B; -.
DR   GenomeRNAi; 7314; -.
DR   Pharos; P0CG47; Tbio.
DR   PRO; PR:P0CG47; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; P0CG47; protein.
DR   Bgee; ENSG00000170315; Expressed in adult organism and 214 other cell types or tissues.
DR   ExpressionAtlas; P0CG47; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR   GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR   GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR   GO; GO:0043005; C:neuron projection; IDA:MGI.
DR   GO; GO:0043025; C:neuronal cell body; IDA:MGI.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0031982; C:vesicle; HDA:UniProtKB.
DR   GO; GO:0031386; F:protein tag activity; IBA:GO_Central.
DR   GO; GO:0030170; F:pyridoxal phosphate binding; ISS:UniProtKB.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IBA:GO_Central.
DR   GO; GO:0097009; P:energy homeostasis; IEA:Ensembl.
DR   GO; GO:0060613; P:fat pad development; IEA:Ensembl.
DR   GO; GO:0008585; P:female gonad development; IEA:Ensembl.
DR   GO; GO:0007144; P:female meiosis I; IEA:Ensembl.
DR   GO; GO:0021888; P:hypothalamus gonadotrophin-releasing hormone neuron development; IEA:Ensembl.
DR   GO; GO:0007141; P:male meiosis I; IEA:Ensembl.
DR   GO; GO:0047497; P:mitochondrion transport along microtubule; IDA:MGI.
DR   GO; GO:0019941; P:modification-dependent protein catabolic process; IBA:GO_Central.
DR   GO; GO:0048812; P:neuron projection morphogenesis; IMP:MGI.
DR   GO; GO:1902255; P:positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IDA:MGI.
DR   GO; GO:1902527; P:positive regulation of protein monoubiquitination; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0051289; P:protein homotetramerization; ISS:UniProtKB.
DR   GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR   GO; GO:0051881; P:regulation of mitochondrial membrane potential; IDA:MGI.
DR   GO; GO:0043523; P:regulation of neuron apoptotic process; IDA:MGI.
DR   GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IDA:MGI.
DR   GO; GO:0072520; P:seminiferous tubule development; IEA:Ensembl.
DR   CDD; cd01803; Ubl_ubiquitin; 3.
DR   FunFam; 3.10.20.90:FF:000158; Polyubiquitin 5; 3.
DR   Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 3.
DR   InterPro; IPR000626; Ubiquitin-like_dom.
DR   InterPro; IPR029071; Ubiquitin-like_domsf.
DR   InterPro; IPR019954; Ubiquitin_CS.
DR   InterPro; IPR019956; Ubiquitin_dom.
DR   InterPro; IPR050158; Ubiquitin_ubiquitin-like.
DR   PANTHER; PTHR10666; UBIQUITIN; 1.
DR   Pfam; PF00240; ubiquitin; 3.
DR   PRINTS; PR00348; UBIQUITIN.
DR   SMART; SM00213; UBQ; 3.
DR   SUPFAM; SSF54236; Ubiquitin-like; 3.
DR   PROSITE; PS00299; UBIQUITIN_1; 3.
DR   PROSITE; PS50053; UBIQUITIN_2; 3.
PE   1: Evidence at protein level;
KW   3D-structure; ADP-ribosylation; Cytoplasm; Direct protein sequencing;
KW   Isopeptide bond; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW   Nucleus; Phosphoprotein; Reference proteome; Repeat; Ubl conjugation.
FT   CHAIN           1..76
FT                   /note="Ubiquitin"
FT                   /id="PRO_0000396174"
FT   CHAIN           77..152
FT                   /note="Ubiquitin"
FT                   /id="PRO_0000396175"
FT   CHAIN           153..228
FT                   /note="Ubiquitin"
FT                   /id="PRO_0000396176"
FT   PROPEP          229
FT                   /id="PRO_0000396177"
FT   DOMAIN          1..76
FT                   /note="Ubiquitin-like 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00214"
FT   DOMAIN          77..152
FT                   /note="Ubiquitin-like 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00214"
FT   DOMAIN          153..228
FT                   /note="Ubiquitin-like 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00214"
FT   SITE            54
FT                   /note="Interacts with activating enzyme"
FT   SITE            68
FT                   /note="Essential for function"
FT   SITE            72
FT                   /note="Interacts with activating enzyme"
FT   MOD_RES         65
FT                   /note="Phosphoserine; by PINK1"
FT                   /evidence="ECO:0000269|PubMed:24660806,
FT                   ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582,
FT                   ECO:0000269|PubMed:25527291"
FT   MOD_RES         66
FT                   /note="(Microbial infection) ADP-ribosylthreonine"
FT                   /evidence="ECO:0000269|PubMed:32330457"
FT   MOD_RES         76
FT                   /note="ADP-ribosylglycine"
FT                   /evidence="ECO:0000269|PubMed:28525742"
FT   CROSSLNK        6
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:16443603"
FT   CROSSLNK        11
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:16443603,
FT                   ECO:0000269|PubMed:16543144"
FT   CROSSLNK        27
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000305|PubMed:15466860"
FT   CROSSLNK        29
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:16543144,
FT                   ECO:0000269|PubMed:25752573, ECO:0000269|PubMed:25752577,
FT                   ECO:0000269|PubMed:34239127"
FT   CROSSLNK        33
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:25752577"
FT   CROSSLNK        48
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:16443603,
FT                   ECO:0000269|PubMed:16543144"
FT   CROSSLNK        63
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000269|PubMed:16543144,
FT                   ECO:0000269|PubMed:18719106"
FT   CROSSLNK        76
FT                   /note="Glycyl lysine isopeptide (Gly-Lys) (interchain with
FT                   K-? in acceptor proteins)"
FT   VARIANT         76..229
FT                   /note="GMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLE
FT                   DGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKE
FT                   GIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGC -> YADLREDPDRQD
FT                   HHPGSGAQ (in UBB(+1); loss of polyubiquitination; impairs
FT                   the ubiquitin-proteasome pathway; refractory to disassembly
FT                   by DUBs; slow degradation by UCHL3)"
FT                   /id="VAR_066248"
FT   MUTAGEN         48
FT                   /note="K->R: No effect on HLTF-mediated polyubiquitination
FT                   of PCNA."
FT                   /evidence="ECO:0000269|PubMed:18719106"
FT   MUTAGEN         63
FT                   /note="K->R: Abolishes HLTF-mediated polyubiquitination of
FT                   PCNA."
FT                   /evidence="ECO:0000269|PubMed:18719106"
FT   MUTAGEN         65
FT                   /note="S->A: Prevents phosphorylation in case of mitophagy.
FT                   Decreased localization of PRKN to mitochondria."
FT                   /evidence="ECO:0000269|PubMed:24660806,
FT                   ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582"
FT   MUTAGEN         65
FT                   /note="S->D: Phosphomimetic mutant that binds and activates
FT                   PRKN."
FT                   /evidence="ECO:0000269|PubMed:24751536"
FT   MUTAGEN         65
FT                   /note="S->E: Phosphomimetic mutant that binds and activates
FT                   PRKN."
FT                   /evidence="ECO:0000269|PubMed:24751536"
FT   MUTAGEN         68
FT                   /note="H->G: Loss of DTX3L-mediated polyubiquitination of
FT                   histone H3 and H4."
FT                   /evidence="ECO:0000269|PubMed:28525742"
FT   MUTAGEN         72
FT                   /note="R->G: No effect on ADP-ribosylation."
FT                   /evidence="ECO:0000269|PubMed:28525742"
FT   MUTAGEN         72
FT                   /note="R->K: No effect on ADP-ribosylation, when associated
FT                   with K-74."
FT                   /evidence="ECO:0000269|PubMed:28525742"
FT   MUTAGEN         74
FT                   /note="R->G: No effect on ADP-ribosylation."
FT                   /evidence="ECO:0000269|PubMed:28525742"
FT   MUTAGEN         74
FT                   /note="R->K: No effect on ADP-ribosylation, when associated
FT                   with K-72."
FT                   /evidence="ECO:0000269|PubMed:28525742"
FT   MUTAGEN         76
FT                   /note="G->A: Loss of ADP-ribosylation."
FT                   /evidence="ECO:0000269|PubMed:28525742"
FT   STRAND          78..82
FT                   /evidence="ECO:0007829|PDB:9AVW"
FT   STRAND          84..86
FT                   /evidence="ECO:0007829|PDB:7MYH"
FT   STRAND          88..92
FT                   /evidence="ECO:0007829|PDB:9AVW"
FT   HELIX           99..110
FT                   /evidence="ECO:0007829|PDB:9AVW"
FT   HELIX           114..116
FT                   /evidence="ECO:0007829|PDB:9AVW"
FT   STRAND          117..121
FT                   /evidence="ECO:0007829|PDB:9AVW"
FT   HELIX           133..135
FT                   /evidence="ECO:0007829|PDB:9AVW"
FT   STRAND          142..147
FT                   /evidence="ECO:0007829|PDB:9AVW"
FT   STRAND          154..159
FT                   /evidence="ECO:0007829|PDB:5NVG"
FT   STRAND          160..162
FT                   /evidence="ECO:0007829|PDB:7NBB"
FT   STRAND          164..168
FT                   /evidence="ECO:0007829|PDB:5NVG"
FT   STRAND          171..174
FT                   /evidence="ECO:0007829|PDB:5XPK"
FT   HELIX           175..186
FT                   /evidence="ECO:0007829|PDB:5NVG"
FT   HELIX           190..192
FT                   /evidence="ECO:0007829|PDB:5NVG"
FT   STRAND          193..197
FT                   /evidence="ECO:0007829|PDB:5NVG"
FT   STRAND          200..202
FT                   /evidence="ECO:0007829|PDB:7UV5"
FT   STRAND          206..208
FT                   /evidence="ECO:0007829|PDB:5GO7"
FT   HELIX           209..211
FT                   /evidence="ECO:0007829|PDB:5NVG"
FT   STRAND          218..223
FT                   /evidence="ECO:0007829|PDB:5NVG"
FT   STRAND          226..228
FT                   /evidence="ECO:0007829|PDB:8EFW"
SQ   SEQUENCE   229 AA;  25762 MW;  33011162F1C48BB1 CRC64;
     MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN
     IQKESTLHLV LRLRGGMQIF VKTLTGKTIT LEVEPSDTIE NVKAKIQDKE GIPPDQQRLI
     FAGKQLEDGR TLSDYNIQKE STLHLVLRLR GGMQIFVKTL TGKTITLEVE PSDTIENVKA
     KIQDKEGIPP DQQRLIFAGK QLEDGRTLSD YNIQKESTLH LVLRLRGGC
//
ID   UCHL1_HUMAN             Reviewed;         223 AA.
AC   P09936; Q4W5K6; Q71UM0;
DT   01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1990, sequence version 2.
DT   28-JAN-2026, entry version 248.
DE   RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1;
DE            Short=UCH-L1;
DE            EC=3.4.19.12 {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
DE   AltName: Full=Neuron cytoplasmic protein 9.5;
DE   AltName: Full=PGP 9.5;
DE            Short=PGP9.5;
DE   AltName: Full=Ubiquitin thioesterase L1;
DE   Flags: Precursor;
GN   Name=UCHL1;
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 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   [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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lung, and Muscle;
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 [MRNA] OF 1-15.
RX   PubMed=2163617; DOI=10.1042/bj2680521;
RA   Day I.N.M., Hinks L.J., Thompson R.J.;
RT   "The structure of the human gene encoding protein gene product 9.5
RT   (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase.";
RL   Biochem. J. 268:521-524(1990).
RN   [5]
RP   PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION,
RP   IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY.
RX   PubMed=14722078; DOI=10.1074/jbc.m314124200;
RA   Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S.,
RA   Li L.;
RT   "Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal
RT   hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's
RT   diseases.";
RL   J. Biol. Chem. 279:13256-13264(2004).
RN   [6]
RP   PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RC   TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA   Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL   Submitted (DEC-2008) to UniProtKB.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE.
RX   PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3;
RA   Day I.N.M., Thompson R.J.;
RT   "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel
RT   cytoplasmic marker for neurones and neuroendocrine cells.";
RL   FEBS Lett. 210:157-160(1987).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, FUNCTION, CATALYTIC ACTIVITY,
RP   BIOPHYSICOCHEMICAL PROPERTIES, VARIANT PARK5 MET-93, AND CHARACTERIZATION
RP   OF VARIANT PARK5 MET-93.
RX   PubMed=9774100; DOI=10.1038/26652;
RA   Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G.,
RA   Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C.,
RA   Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.;
RT   "The ubiquitin pathway in Parkinson's disease.";
RL   Nature 395:451-452(1998).
RN   [9]
RP   PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151.
RX   PubMed=1849484; DOI=10.1016/0014-5793(91)80300-r;
RA   Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.;
RT   "Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured
RT   human MRC-5 fibroblasts of normal origin and is strongly down-regulated in
RT   their SV40 transformed counterparts.";
RL   FEBS Lett. 280:235-240(1991).
RN   [10]
RP   PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151.
RX   PubMed=1286667; DOI=10.1002/elps.11501301199;
RA   Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA   Vandekerckhove J.;
RT   "Microsequences of 145 proteins recorded in the two-dimensional gel protein
RT   database of normal human epidermal keratinocytes.";
RL   Electrophoresis 13:960-969(1992).
RN   [11]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90;
RP   HIS-97; HIS-161 AND ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=8639624; DOI=10.1021/bi960099f;
RA   Larsen C.N., Price J.S., Wilkinson K.D.;
RT   "Substrate binding and catalysis by ubiquitin C-terminal hydrolases:
RT   identification of two active site residues.";
RL   Biochemistry 35:6735-6744(1996).
RN   [12]
RP   TISSUE SPECIFICITY.
RX   PubMed=9790970; DOI=10.1006/bbrc.1998.9532;
RA   Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.;
RT   "Cleavage of the C-terminus of NEDD8 by UCH-L3.";
RL   Biochem. Biophys. Res. Commun. 251:688-692(1998).
RN   [13]
RP   FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND
RP   CHARACTERIZATION OF VARIANT TYR-18.
RX   PubMed=12408865; DOI=10.1016/s0092-8674(02)01012-7;
RA   Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.;
RT   "The UCH-L1 gene encodes two opposing enzymatic activities that affect
RT   alpha-synuclein degradation and Parkinson's disease susceptibility.";
RL   Cell 111:209-218(2002).
RN   [14]
RP   INTERACTION WITH COPS5.
RX   PubMed=12082530; DOI=10.1038/sj.onc.1205390;
RA   Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J.,
RA   Yochem R., Ratovitski E., Sidransky D., Jen J.;
RT   "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1).";
RL   Oncogene 21:3003-3010(2002).
RN   [15]
RP   CATALYTIC ACTIVITY, AND ACTIVE SITE.
RX   PubMed=16475834; DOI=10.1021/bi052135t;
RA   Case A., Stein R.L.;
RT   "Mechanistic studies of ubiquitin C-terminal hydrolase L1.";
RL   Biochemistry 45:2443-2452(2006).
RN   [16]
RP   SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220.
RX   PubMed=19261853; DOI=10.1073/pnas.0806474106;
RA   Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A., Cookson M.R.,
RA   Liu Y., Logan T., Lansbury P.T. Jr.;
RT   "Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein
RT   neurotoxicity and is a therapeutic target for Parkinson's disease.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009).
RN   [17]
RP   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   [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=22212137; DOI=10.1111/j.1471-4159.2011.07644.x;
RA   Zhang M., Deng Y., Luo Y., Zhang S., Zou H., Cai F., Wada K., Song W.;
RT   "Control of BACE1 degradation and APP processing by ubiquitin carboxyl-
RT   terminal hydrolase L1.";
RL   J. Neurochem. 120:1129-1138(2012).
RN   [20]
RP   FUNCTION, CATALYTIC ACTIVITY, VARIANTS SPG79B ALA-7 AND MET-93,
RP   CHARACTERIZATION OF VARIANT SPG79B ALA-7, AND MUTAGENESIS OF CYS-90.
RX   PubMed=23359680; DOI=10.1073/pnas.1222732110;
RA   Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M., Choi M.,
RA   Delil S., Caglayan A.O., Baranoski J.F., Erturk O., Yalcinkaya C.,
RA   Karacorlu M., Dincer A., Johnson M.H., Mane S., Chandra S.S., Louvi A.,
RA   Boggon T.J., Lifton R.P., Horwich A.L., Gunel M.;
RT   "Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads
RT   to early-onset progressive neurodegeneration.";
RL   Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013).
RN   [21]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-90.
RX   PubMed=25615526; DOI=10.1038/ncomms7153;
RA   Goto Y., Zeng L., Yeom C.J., Zhu Y., Morinibu A., Shinomiya K.,
RA   Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M.,
RA   Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond E.M.,
RA   Hiraoka M., Harada H.;
RT   "UCHL1 provides diagnostic and antimetastatic strategies due to its
RT   deubiquitinating effect on HIF-1alpha.";
RL   Nat. Commun. 6:6153-6153(2015).
RN   [22]
RP   IDENTIFICATION BY MASS SPECTROMETRY (ISOFORMS 2 AND 3), AND ACETYLATION AT
RP   MET-1 (ISOFORMS 1; 2 AND 3).
RX   PubMed=37316325; DOI=10.26508/lsa.202301972;
RA   Bogaert A., Fijalkowska D., Staes A., Van de Steene T., Vuylsteke M.,
RA   Stadler C., Eyckerman S., Spirohn K., Hao T., Calderwood M.A., Gevaert K.;
RT   "N-terminal proteoforms may engage in different protein complexes.";
RL   Life. Sci Alliance 6:0-0(2023).
RN   [23]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT.
RX   PubMed=16537382; DOI=10.1073/pnas.0510403103;
RA   Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K., Ray S.S.,
RA   Lansbury P.T., Ringe D., Petsko G.A.;
RT   "Structural basis for conformational plasticity of the Parkinson's disease-
RT   associated ubiquitin hydrolase UCH-L1.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN
RP   COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF
RP   CYS-90 AND PHE-204.
RX   PubMed=20439756; DOI=10.1073/pnas.0910870107;
RA   Boudreaux D.A., Maiti T.K., Davies C.W., Das C.;
RT   "Ubiquitin vinyl methyl ester binding orients the misaligned active site of
RT   the ubiquitin hydrolase UCHL1 into productive conformation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010).
RN   [25]
RP   CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT
RP   TYR-18, MUTAGENESIS OF CYS-90, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL
RP   PROPERTIES.
RX   PubMed=12705903; DOI=10.1016/s0006-291x(03)00555-2;
RA   Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y.,
RA   Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.;
RT   "Alterations of structure and hydrolase activity of parkinsonism-associated
RT   human ubiquitin carboxyl-terminal hydrolase L1 variants.";
RL   Biochem. Biophys. Res. Commun. 304:176-183(2003).
RN   [26]
RP   VARIANT MET-93.
RX   PubMed=10454131; DOI=10.1016/s0304-3940(99)00465-6;
RA   Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G.,
RA   De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B.,
RA   Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.;
RT   "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene
RT   is not observed in European cases with familial Parkinson's disease.";
RL   Neurosci. Lett. 270:1-4(1999).
RN   [27]
RP   VARIANT TYR-18.
RX   PubMed=10203348; DOI=10.1097/00001756-199902050-00040;
RA   Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K.,
RA   Lynch T., Hardy J., Farrer M.;
RT   "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal
RT   hydrolase gene in familial Parkinson's disease.";
RL   NeuroReport 10:427-429(1999).
RN   [28]
RP   VARIANT TYR-18.
RX   PubMed=11027850; DOI=10.1016/s0304-3940(00)01510-x;
RA   Mellick G.D., Silburn P.A.;
RT   "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does
RT   not confer protection against idiopathic Parkinson's disease.";
RL   Neurosci. Lett. 293:127-130(2000).
RN   [29]
RP   VARIANT TYR-18.
RX   PubMed=15048890; DOI=10.1002/ana.20017;
RG   UCHL1 global genetics consortium;
RA   Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T.,
RA   Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T.,
RA   Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.;
RT   "UCHL1 is a Parkinson's disease susceptibility gene.";
RL   Ann. Neurol. 55:512-521(2004).
RN   [30]
RP   ERRATUM OF PUBMED:15048890.
RG   UCHL1 global genetics consortium;
RA   Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T.,
RA   Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T.,
RA   Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.;
RL   Ann. Neurol. 55:899-899(2004).
RN   [31]
RP   VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON
RP   DISEASE.
RX   PubMed=16450370; DOI=10.1002/ana.20757;
RA   Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T.,
RA   Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P., Quinn N.P.,
RA   Lees A.J., Gibson J.M., Holton J.L., Revesz T., Goldstein D.B., Wood N.W.;
RT   "UCHL-1 is not a Parkinson's disease susceptibility gene.";
RL   Ann. Neurol. 59:627-633(2006).
RN   [32]
RP   CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN NEURONAL
RP   CELLS.
RX   PubMed=18411255; DOI=10.1093/hmg/ddn115;
RA   Kyratzi E., Pavlaki M., Stefanis L.;
RT   "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to
RT   neuronal cells.";
RL   Hum. Mol. Genet. 17:2160-2171(2008).
RN   [33]
RP   VARIANT TYR-18.
RX   PubMed=21268678; DOI=10.3109/13816810.2010.544360;
RA   Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A., Andreasen N.,
RA   Tasa G., Juronen E., Blennow K., Zetterberg H., Zetterberg M.;
RT   "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in
RT   patients with cataracts.";
RL   Ophthalmic Genet. 32:75-79(2011).
RN   [34]
RP   VARIANTS SPG79B GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS
RP   SPG79B GLN-178 AND ASP-216.
RX   PubMed=28007905; DOI=10.1093/hmg/ddw391;
RA   Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y.,
RA   Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D., Bjoeraas M.,
RA   Tallaksen C.M., Selmer K.K.;
RT   "Novel UCHL1 mutations reveal new insights into ubiquitin processing.";
RL   Hum. Mol. Genet. 26:1031-1040(2017).
RN   [35]
RP   VARIANTS SPG79A 2-GLN--ALA-223 DEL; 25-GLN--ALA-223 DEL; LEU-52 INS;
RP   178-ARG--ALA-223 DEL AND 211-GLU--ALA-223 DEL, AND INVOLVEMENT IN SPG79A.
RX   PubMed=35986737; DOI=10.1016/j.gim.2022.07.006;
RG   Genomics England Research Consortium;
RA   Park J., Tucci A., Cipriani V., Demidov G., Rocca C., Senderek J.,
RA   Butryn M., Velic A., Lam T., Galanaki E., Cali E., Vestito L.,
RA   Maroofian R., Deininger N., Rautenberg M., Admard J., Hahn G.A.,
RA   Bartels C., van Os N.J.H., Horvath R., Chinnery P.F., Tiet M.Y.,
RA   Hewamadduma C., Hadjivassiliou M., Tofaris G.K., Wood N.W., Hayer S.N.,
RA   Bender F., Menden B., Cordts I., Klein K., Nguyen H.P., Krauss J.K.,
RA   Blahak C., Strom T.M., Sturm M., van de Warrenburg B., Lerche H., Macek B.,
RA   Synofzik M., Ossowski S., Timmann D., Wolf M.E., Smedley D., Riess O.,
RA   Schoels L., Houlden H., Haack T.B., Hengel H.;
RT   "Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative
RT   disorder with spasticity, ataxia, neuropathy, and optic atrophy.";
RL   Genet. Med. 24:2079-2090(2022).
CC   -!- FUNCTION: Deubiquitinase that plays a role in the regulation of several
CC       processes such as maintenance of synaptic function, cardiac function,
CC       inflammatory response or osteoclastogenesis (PubMed:22212137,
CC       PubMed:23359680). Abrogates the ubiquitination of multiple proteins
CC       including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor
CC       protein cleaving enzyme 1/BACE1 (PubMed:22212137, PubMed:25615526). In
CC       addition, recognizes and hydrolyzes a peptide bond at the C-terminal
CC       glycine of ubiquitin to maintain a stable pool of monoubiquitin that is
CC       a key requirement for the ubiquitin-proteasome and the autophagy-
CC       lysosome pathways (PubMed:12408865, PubMed:8639624, PubMed:9774100).
CC       Regulates amyloid precursor protein/APP processing by promoting BACE1
CC       degradation resulting in decreased amyloid beta production
CC       (PubMed:22212137). Plays a role in the immune response by regulating
CC       the ability of MHC I molecules to reach cross-presentation compartments
CC       competent for generating Ag-MHC I complexes (By similarity). Mediates
CC       the 'Lys-48'-linked deubiquitination of the transcriptional coactivator
CC       WWTR1/TAZ leading to its stabilization and inhibition of
CC       osteoclastogenesis (By similarity). Deubiquitinates and stabilizes
CC       epidermal growth factor receptor EGFR to prevent its degradation and to
CC       activate its downstream mediators (By similarity). Modulates oxidative
CC       activity in skeletal muscle by regulating key mitochondrial oxidative
CC       proteins (By similarity). Enhances the activity of hypoxia-inducible
CC       factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated
CC       ubiquitination and consequently inhibiting its degradation
CC       (PubMed:25615526). {ECO:0000250|UniProtKB:Q9R0P9,
CC       ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:22212137,
CC       ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:25615526,
CC       ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC         and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC         residue protein attached to proteins as an intracellular targeting
CC         signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:12408865,
CC         ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834,
CC         ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680,
CC         ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624,
CC         ECO:0000269|PubMed:9774100};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903,
CC         ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
CC         KM=1.20 uM for ubiquitin ethyl ester {ECO:0000269|PubMed:12705903,
CC         ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100};
CC         Vmax=0.47 umol/min/mg enzyme toward Ub-AMC
CC         {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624,
CC         ECO:0000269|PubMed:9774100};
CC         Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester
CC         {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624,
CC         ECO:0000269|PubMed:9774100};
CC   -!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity).
CC       Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530,
CC       ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}.
CC   -!- INTERACTION:
CC       P09936; P63010-2: AP2B1; NbExp=3; IntAct=EBI-714860, EBI-11529439;
CC       P09936; P05067: APP; NbExp=5; IntAct=EBI-714860, EBI-77613;
CC       P09936; P05067-2: APP; NbExp=3; IntAct=EBI-714860, EBI-17264467;
CC       P09936; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-714860, EBI-10694449;
CC       P09936; P18847: ATF3; NbExp=3; IntAct=EBI-714860, EBI-712767;
CC       P09936; Q9H1Y0: ATG5; NbExp=4; IntAct=EBI-714860, EBI-1047414;
CC       P09936; O15392: BIRC5; NbExp=3; IntAct=EBI-714860, EBI-518823;
CC       P09936; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-714860, EBI-2837444;
CC       P09936; P83916: CBX1; NbExp=4; IntAct=EBI-714860, EBI-78129;
CC       P09936; P11802: CDK4; NbExp=4; IntAct=EBI-714860, EBI-295644;
CC       P09936; Q00535: CDK5; NbExp=2; IntAct=EBI-714860, EBI-1041567;
CC       P09936; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-714860, EBI-350590;
CC       P09936; Q92905: COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661;
CC       P09936; P00533: EGFR; NbExp=3; IntAct=EBI-714860, EBI-297353;
CC       P09936; O60739: EIF1B; NbExp=4; IntAct=EBI-714860, EBI-1043343;
CC       P09936; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-714860, EBI-9246952;
CC       P09936; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-714860, EBI-6448852;
CC       P09936; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-714860, EBI-25845242;
CC       P09936; Q14164: IKBKE; NbExp=4; IntAct=EBI-714860, EBI-307369;
CC       P09936; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-714860, EBI-21911304;
CC       P09936; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-714860, EBI-11985629;
CC       P09936; P13473-2: LAMP2; NbExp=3; IntAct=EBI-714860, EBI-21591415;
CC       P09936; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-714860, EBI-1108377;
CC       P09936; O95777: LSM8; NbExp=3; IntAct=EBI-714860, EBI-347779;
CC       P09936; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-714860, EBI-21250407;
CC       P09936; Q15843: NEDD8; NbExp=4; IntAct=EBI-714860, EBI-716247;
CC       P09936; O15381-5: NVL; NbExp=3; IntAct=EBI-714860, EBI-18577082;
CC       P09936; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-714860, EBI-22012354;
CC       P09936; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-714860, EBI-716063;
CC       P09936; P62826: RAN; NbExp=3; IntAct=EBI-714860, EBI-286642;
CC       P09936; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-714860, EBI-746555;
CC       P09936; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-714860, EBI-25829984;
CC       P09936; Q15554-4: TERF2; NbExp=3; IntAct=EBI-714860, EBI-25840535;
CC       P09936; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109;
CC       P09936; P04637: TP53; NbExp=3; IntAct=EBI-714860, EBI-366083;
CC       P09936; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-714860, EBI-359276;
CC       P09936; P19474: TRIM21; NbExp=3; IntAct=EBI-714860, EBI-81290;
CC       P09936; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-714860, EBI-749370;
CC       P09936; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-714860, EBI-10180829;
CC       P09936; P61086: UBE2K; NbExp=3; IntAct=EBI-714860, EBI-473850;
CC       P09936; Q9UK80: USP21; NbExp=4; IntAct=EBI-714860, EBI-373242;
CC       P09936; Q86WB0-2: ZC3HC1; NbExp=3; IntAct=EBI-714860, EBI-25894765;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}.
CC       Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853}; Lipid-
CC       anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of total UCHL1 is
CC       associated with membranes in brain. Localizes near and/or within
CC       mitochondria to potentially interact with mitochondrial proteins.
CC       {ECO:0000250|UniProtKB:Q9R0P9}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative initiation; Named isoforms=3;
CC       Name=1;
CC         IsoId=P09936-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P09936-2; Sequence=VSP_062524;
CC       Name=3;
CC         IsoId=P09936-3; Sequence=VSP_062523;
CC   -!- TISSUE SPECIFICITY: Found in neuronal cell bodies and processes
CC       throughout the neocortex (at protein level). Expressed in neurons and
CC       cells of the diffuse neuroendocrine system and their tumors. Weakly
CC       expressed in ovary. Down-regulated in brains from Parkinson disease and
CC       Alzheimer disease patients. {ECO:0000269|PubMed:14722078,
CC       ECO:0000269|PubMed:9790970}.
CC   -!- PTM: O-glycosylated. {ECO:0000250}.
CC   -!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex
CC       neurodegenerative disorder with manifestations ranging from typical
CC       Parkinson disease to dementia with Lewy bodies. Clinical features
CC       include parkinsonian symptoms (resting tremor, rigidity, postural
CC       instability and bradykinesia), dementia, diffuse Lewy body pathology,
CC       autonomic dysfunction, hallucinations and paranoia.
CC       {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903,
CC       ECO:0000269|PubMed:9774100}. Note=Disease susceptibility is associated
CC       with variants affecting the gene represented in this entry.
CC   -!- DISEASE: Spastic paraplegia 79A, autosomal dominant, with ataxia
CC       (SPG79A) [MIM:620221]: A form of spastic paraplegia, a
CC       neurodegenerative disorder characterized by a slow, gradual,
CC       progressive weakness and spasticity of the lower limbs. Rate of
CC       progression and the severity of symptoms are quite variable. Initial
CC       symptoms may include difficulty with balance, weakness and stiffness in
CC       the legs, muscle spasms, and dragging the toes when walking. In some
CC       forms of the disorder, bladder symptoms (such as incontinence) may
CC       appear, or the weakness and stiffness may spread to other parts of the
CC       body. SPG79A is a slowly progressive form characterized by late-onset
CC       spastic ataxia, neuropathy, and often optic atrophy.
CC       {ECO:0000269|PubMed:35986737}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Spastic paraplegia 79B, autosomal recessive (SPG79B)
CC       [MIM:615491]: A form of spastic paraplegia, a neurodegenerative
CC       disorder characterized by a slow, gradual, progressive weakness and
CC       spasticity of the lower limbs. Rate of progression and the severity of
CC       symptoms are quite variable. Initial symptoms may include difficulty
CC       with balance, weakness and stiffness in the legs, muscle spasms, and
CC       dragging the toes when walking. In some forms of the disorder, bladder
CC       symptoms (such as incontinence) may appear, or the weakness and
CC       stiffness may spread to other parts of the body. SPG79B is
CC       characterized by childhood onset blindness, cerebellar ataxia,
CC       nystagmus, dorsal column dysfunction, and spasticity with upper motor
CC       neuron dysfunction. {ECO:0000269|PubMed:23359680,
CC       ECO:0000269|PubMed:28007905}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179
CC       to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic
CC       acid have been observed in brains from Alzheimer disease (AD) and
CC       Parkinson disease (PD) patients. In AD, UCHL1 was found to be
CC       associated with neurofibrillary tangles. In contrast to UCHL3, does not
CC       hydrolyze a peptide bond at the C-terminal glycine of NEDD8.
CC   -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}.
CC   -!- CAUTION: PubMed:9774100 reports the association of mutation Ile93Met
CC       with Parkinson disease. However, according to PubMed:16450370 this
CC       association is uncertain and UCHL1 is not a susceptibility gene for
CC       Parkinson disease. {ECO:0000305}.
CC   -!- CAUTION: The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179
CC       and Cys-220 are subject of controversy and could be the artifactual
CC       results of sample handling. {ECO:0000305|PubMed:14722078}.
CC   -!- CAUTION: The homodimer may have ATP-independent ubiquitin ligase
CC       activity (PubMed:12408865). However, in another study, UCHL1 was shown
CC       to lack ubiquitin ligase activity (PubMed:23359680).
CC       {ECO:0000269|PubMed:23359680, ECO:0000305|PubMed:12408865}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAA28443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal hydrolase
CC       L1 entry;
CC       URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1";
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DR   EMBL; AC095043; AAY40923.1; -; Genomic_DNA.
DR   EMBL; CH471069; EAW92983.1; -; Genomic_DNA.
DR   EMBL; BC000332; AAH00332.1; -; mRNA.
DR   EMBL; BC005117; AAH05117.1; -; mRNA.
DR   EMBL; BC006305; AAH06305.1; -; mRNA.
DR   EMBL; X17377; CAA35249.1; -; Genomic_DNA.
DR   EMBL; X04741; CAA28443.1; ALT_INIT; mRNA.
DR   EMBL; AH007277; AAD09172.1; -; Genomic_DNA.
DR   CCDS; CCDS3462.1; -. [P09936-1]
DR   PIR; A25856; A25856.
DR   RefSeq; NP_004172.2; NM_004181.4. [P09936-1]
DR   PDB; 2ETL; X-ray; 2.40 A; A/B=1-223.
DR   PDB; 2LEN; NMR; -; A=1-223.
DR   PDB; 3IFW; X-ray; 2.40 A; A=1-223.
DR   PDB; 3IRT; X-ray; 2.80 A; A/B=1-223.
DR   PDB; 3KVF; X-ray; 2.80 A; A=1-223.
DR   PDB; 3KW5; X-ray; 2.83 A; A=1-223.
DR   PDB; 4DM9; X-ray; 2.35 A; A/B=1-223.
DR   PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223.
DR   PDB; 7ZM0; X-ray; 2.24 A; A/B/C/D/E/F/G/H/I/J=1-223.
DR   PDB; 8DY8; X-ray; 2.10 A; A/B=1-223.
DR   PDB; 8EDE; X-ray; 1.80 A; A/B=1-223.
DR   PDB; 8PW1; X-ray; 2.20 A; A/B/C/D/E/F/G/H/I/J=1-223.
DR   PDB; 8XI7; X-ray; 1.95 A; A/B=1-223.
DR   PDB; 9O4M; X-ray; 2.00 A; A/B=1-223.
DR   PDBsum; 2ETL; -.
DR   PDBsum; 2LEN; -.
DR   PDBsum; 3IFW; -.
DR   PDBsum; 3IRT; -.
DR   PDBsum; 3KVF; -.
DR   PDBsum; 3KW5; -.
DR   PDBsum; 4DM9; -.
DR   PDBsum; 4JKJ; -.
DR   PDBsum; 7ZM0; -.
DR   PDBsum; 8DY8; -.
DR   PDBsum; 8EDE; -.
DR   PDBsum; 8PW1; -.
DR   PDBsum; 8XI7; -.
DR   PDBsum; 9O4M; -.
DR   AlphaFoldDB; P09936; -.
DR   BMRB; P09936; -.
DR   SASBDB; P09936; -.
DR   SMR; P09936; -.
DR   BioGRID; 113192; 258.
DR   CORUM; P09936; -.
DR   DIP; DIP-36620N; -.
DR   FunCoup; P09936; 1475.
DR   IntAct; P09936; 199.
DR   MINT; P09936; -.
DR   STRING; 9606.ENSP00000284440; -.
DR   BindingDB; P09936; -.
DR   ChEMBL; CHEMBL6159; -.
DR   DrugBank; DB12695; Phenethyl Isothiocyanate.
DR   GuidetoPHARMACOLOGY; 2426; -.
DR   MEROPS; C12.001; -.
DR   GlyGen; P09936; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P09936; -.
DR   MetOSite; P09936; -.
DR   PhosphoSitePlus; P09936; -.
DR   SwissPalm; P09936; -.
DR   BioMuta; UCHL1; -.
DR   DMDM; 136681; -.
DR   CPTAC; CPTAC-601; -.
DR   CPTAC; CPTAC-602; -.
DR   jPOST; P09936; -.
DR   MassIVE; P09936; -.
DR   PaxDb; 9606-ENSP00000284440; -.
DR   PeptideAtlas; P09936; -.
DR   ProteomicsDB; 52282; -.
DR   Pumba; P09936; -.
DR   Antibodypedia; 1062; 2368 antibodies from 53 providers.
DR   DNASU; 7345; -.
DR   Ensembl; ENST00000284440.9; ENSP00000284440.4; ENSG00000154277.14. [P09936-1]
DR   Ensembl; ENST00000503431.5; ENSP00000422542.1; ENSG00000154277.14. [P09936-1]
DR   GeneID; 7345; -.
DR   KEGG; hsa:7345; -.
DR   MANE-Select; ENST00000284440.9; ENSP00000284440.4; NM_004181.5; NP_004172.2.
DR   AGR; HGNC:12513; -.
DR   ClinPGx; PA37160; -.
DR   CTD; 7345; -.
DR   DisGeNET; 7345; -.
DR   GeneCards; UCHL1; -.
DR   HGNC; HGNC:12513; UCHL1.
DR   HPA; ENSG00000154277; Group enriched (brain, pituitary gland).
DR   MalaCards; UCHL1; -.
DR   MIM; 191342; gene.
DR   MIM; 613643; phenotype.
DR   MIM; 615491; phenotype.
DR   MIM; 620221; phenotype.
DR   OpenTargets; ENSG00000154277; -.
DR   Orphanet; 352654; Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome.
DR   Orphanet; 2828; Young-onset Parkinson disease.
DR   VEuPathDB; HostDB:ENSG00000154277; -.
DR   eggNOG; KOG1415; Eukaryota.
DR   GeneTree; ENSGT00940000157306; -.
DR   HOGENOM; CLU_054406_2_0_1; -.
DR   InParanoid; P09936; -.
DR   OMA; AQTYSKH; -.
DR   OrthoDB; 427186at2759; -.
DR   PAN-GO; P09936; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P09936; -.
DR   BRENDA; 3.4.19.12; 2681.
DR   PathwayCommons; P09936; -.
DR   Reactome; R-HSA-5689603; UCH proteinases.
DR   SABIO-RK; P09936; -.
DR   SignaLink; P09936; -.
DR   SIGNOR; P09936; -.
DR   Agora; ENSG00000154277; -.
DR   BioGRID-ORCS; 7345; 9 hits in 1196 CRISPR screens.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; UCHL1; human.
DR   EvolutionaryTrace; P09936; -.
DR   GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -.
DR   GenomeRNAi; 7345; -.
DR   Pharos; P09936; Tchem.
DR   PRO; PR:P09936; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; P09936; protein.
DR   Bgee; ENSG00000154277; Expressed in pons and 169 other cell types or tissues.
DR   ExpressionAtlas; P09936; baseline and differential.
DR   GO; GO:1904115; C:axon cytoplasm; IEA:GOC.
DR   GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR   GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB.
DR   GO; GO:0043022; F:ribosome binding; IEA:Ensembl.
DR   GO; GO:0030547; F:signaling receptor inhibitor activity; IDA:BHF-UCL.
DR   GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL.
DR   GO; GO:0007628; P:adult walking behavior; IEA:Ensembl.
DR   GO; GO:0007412; P:axon target recognition; IEA:Ensembl.
DR   GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl.
DR   GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR   GO; GO:0042755; P:eating behavior; IEA:Ensembl.
DR   GO; GO:0002176; P:male germ cell proliferation; IEA:Ensembl.
DR   GO; GO:0055001; P:muscle cell development; IEA:Ensembl.
DR   GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL.
DR   GO; GO:0050905; P:neuromuscular process; IEA:Ensembl.
DR   GO; GO:0045821; P:positive regulation of glycolytic process; IMP:FlyBase.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0030163; P:protein catabolic process; IBA:GO_Central.
DR   GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR   CDD; cd09616; Peptidase_C12_UCH_L1_L3; 1.
DR   FunFam; 3.40.532.10:FF:000004; Ubiquitin carboxyl-terminal hydrolase; 1.
DR   Gene3D; 3.40.532.10; Peptidase C12, ubiquitin carboxyl-terminal hydrolase; 1.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   InterPro; IPR001578; Peptidase_C12_UCH.
DR   InterPro; IPR036959; Peptidase_C12_UCH_sf.
DR   InterPro; IPR057254; UCH_AS.
DR   PANTHER; PTHR10589; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1.
DR   PANTHER; PTHR10589:SF19; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L1; 1.
DR   Pfam; PF01088; Peptidase_C12; 1.
DR   PRINTS; PR00707; UBCTHYDRLASE.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   PROSITE; PS00140; UCH_1; 1.
DR   PROSITE; PS52048; UCH_DOMAIN; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative initiation; Cytoplasm;
KW   Direct protein sequencing; Disease variant; Endoplasmic reticulum;
KW   Glycoprotein; Hereditary spastic paraplegia; Hydrolase; Lipoprotein;
KW   Membrane; Neurodegeneration; Oxidation; Parkinson disease; Parkinsonism;
KW   Phosphoprotein; Prenylation; Protease; Proteomics identification;
KW   Reference proteome; Thiol protease; Ubl conjugation pathway.
FT   CHAIN           1..220
FT                   /note="Ubiquitin carboxyl-terminal hydrolase isozyme L1"
FT                   /id="PRO_0000211055"
FT   PROPEP          221..223
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000305"
FT                   /id="PRO_0000414311"
FT   DOMAIN          2..221
FT                   /note="UCH catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01393"
FT   REGION          5..10
FT                   /note="Interaction with ubiquitin"
FT                   /evidence="ECO:0000269|PubMed:20439756"
FT   REGION          211..216
FT                   /note="Interaction with ubiquitin"
FT                   /evidence="ECO:0000269|PubMed:20439756"
FT   ACT_SITE        90
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01393,
FT                   ECO:0000269|PubMed:20439756"
FT   ACT_SITE        161
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01393,
FT                   ECO:0000269|PubMed:20439756"
FT   SITE            1
FT                   /note="Susceptible to oxidation"
FT                   /evidence="ECO:0000269|PubMed:14722078"
FT   SITE            6
FT                   /note="Susceptible to oxidation"
FT                   /evidence="ECO:0000269|PubMed:14722078"
FT   SITE            12
FT                   /note="Susceptible to oxidation"
FT                   /evidence="ECO:0000269|PubMed:14722078"
FT   SITE            84
FT                   /note="Transition state stabilizer"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01393,
FT                   ECO:0000269|PubMed:8639624"
FT   SITE            124
FT                   /note="Susceptible to oxidation"
FT                   /evidence="ECO:0000269|PubMed:14722078"
FT   SITE            176
FT                   /note="Important for enzyme activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01393"
FT   SITE            179
FT                   /note="Susceptible to oxidation"
FT                   /evidence="ECO:0000269|PubMed:14722078"
FT   SITE            220
FT                   /note="Susceptible to oxidation"
FT                   /evidence="ECO:0000269|PubMed:14722078"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000269|PubMed:37316325"
FT   MOD_RES         125
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q00981"
FT   LIPID           220
FT                   /note="S-farnesyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:19261853"
FT   VAR_SEQ         1..11
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000269|PubMed:37316325"
FT                   /id="VSP_062523"
FT   VAR_SEQ         1..5
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000269|PubMed:37316325"
FT                   /id="VSP_062524"
FT   VARIANT         2..223
FT                   /note="Missing (in SPG79A)"
FT                   /evidence="ECO:0000269|PubMed:35986737"
FT                   /id="VAR_087898"
FT   VARIANT         7
FT                   /note="E -> A (in SPG79B; has decreased binding to
FT                   ubiquitin and significantly decreased hydrolase activity
FT                   compared to wild-type; dbSNP:rs397515634)"
FT                   /evidence="ECO:0000269|PubMed:23359680"
FT                   /id="VAR_070875"
FT   VARIANT         18
FT                   /note="S -> Y (it confers protection from oxidative stress
FT                   when expressed at physiological levels in neuroblastoma
FT                   cells and primary cortical neurons; loss of dimerization
FT                   ability; impaired ligase activity; dbSNP:rs5030732)"
FT                   /evidence="ECO:0000269|PubMed:10203348,
FT                   ECO:0000269|PubMed:11027850, ECO:0000269|PubMed:12408865,
FT                   ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:15048890,
FT                   ECO:0000269|PubMed:16450370, ECO:0000269|PubMed:18411255,
FT                   ECO:0000269|PubMed:21268678"
FT                   /id="VAR_015677"
FT   VARIANT         25..223
FT                   /note="Missing (in SPG79A)"
FT                   /evidence="ECO:0000269|PubMed:35986737"
FT                   /id="VAR_087899"
FT   VARIANT         52
FT                   /note="L -> LL (in SPG79A; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:35986737"
FT                   /id="VAR_087900"
FT   VARIANT         93
FT                   /note="I -> M (in PARK5; impaired enzymatic hydrolase
FT                   activity; has about a 50% reduction in catalytic activity
FT                   compared to wild-type protein; dbSNP:rs121917767)"
FT                   /evidence="ECO:0000269|PubMed:10454131,
FT                   ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903,
FT                   ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:9774100"
FT                   /id="VAR_015678"
FT   VARIANT         178..223
FT                   /note="Missing (in SPG79A)"
FT                   /evidence="ECO:0000269|PubMed:35986737"
FT                   /id="VAR_087901"
FT   VARIANT         178
FT                   /note="R -> Q (in SPG79B; increased hydrolase activity;
FT                   decreased protein abundance; dbSNP:rs768996179)"
FT                   /evidence="ECO:0000269|PubMed:28007905"
FT                   /id="VAR_078119"
FT   VARIANT         211..223
FT                   /note="Missing (in SPG79A)"
FT                   /evidence="ECO:0000269|PubMed:35986737"
FT                   /id="VAR_087902"
FT   VARIANT         216
FT                   /note="A -> D (in SPG79B; decreased protein abundance;
FT                   dbSNP:rs1057519600)"
FT                   /evidence="ECO:0000269|PubMed:28007905"
FT                   /id="VAR_078120"
FT   MUTAGEN         73
FT                   /note="Q->R: No effect on enzymatic parameters."
FT                   /evidence="ECO:0000269|PubMed:8639624"
FT   MUTAGEN         90
FT                   /note="C->S: Abolishes enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:12705903,
FT                   ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680,
FT                   ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624"
FT   MUTAGEN         97
FT                   /note="H->Q,N: 2-fold increase in affinity for ubiquitin
FT                   ethyl ester, slight reduction in enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:8639624"
FT   MUTAGEN         161
FT                   /note="H->D: 10000-fold decrease in enzymatic activity; no
FT                   change in affinity for ubiquitin ethyl ester."
FT                   /evidence="ECO:0000269|PubMed:8639624"
FT   MUTAGEN         161
FT                   /note="H->K,Q,N,Y: Abolishes enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:8639624"
FT   MUTAGEN         176
FT                   /note="D->N: 6-fold decrease in affinity for ubiquitin
FT                   ethyl ester; 97.5% decrease in enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:8639624"
FT   MUTAGEN         204
FT                   /note="F->A: Almost complete loss of activity."
FT                   /evidence="ECO:0000269|PubMed:20439756"
FT   HELIX           10..19
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          22..25
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          27..31
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           36..41
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          46..54
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           57..70
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   TURN            71..74
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          86..88
FT                   /evidence="ECO:0007829|PDB:2LEN"
FT   HELIX           90..100
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   TURN            101..105
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           113..120
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   TURN            121..123
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           126..135
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           137..147
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          160..168
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          171..175
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          179..181
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   STRAND          183..187
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           190..192
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           193..207
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   HELIX           211..213
FT                   /evidence="ECO:0007829|PDB:2LEN"
FT   STRAND          215..220
FT                   /evidence="ECO:0007829|PDB:8EDE"
FT   MOD_RES         P09936-2:1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000269|PubMed:37316325"
FT   MOD_RES         P09936-3:1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000269|PubMed:37316325"
SQ   SEQUENCE   223 AA;  24824 MW;  C9E972AC4DA5DA8A CRC64;
     MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE
     NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE
     TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP
     FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA
//