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";
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
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   CDK5_HUMAN              Reviewed;         292 AA.
AC   Q00535; A1XKG3;
DT   01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT   15-DEC-1998, sequence version 3.
DT   28-JAN-2026, entry version 248.
DE   RecName: Full=Cyclin-dependent kinase 5 {ECO:0000312|HGNC:HGNC:1774};
DE            EC=2.7.11.1;
DE   AltName: Full=Cell division protein kinase 5 {ECO:0000305};
DE   AltName: Full=Cyclin-dependent-like kinase 5;
DE   AltName: Full=Serine/threonine-protein kinase PSSALRE {ECO:0000250|UniProtKB:Q03114};
DE   AltName: Full=Tau protein kinase II catalytic subunit {ECO:0000250|UniProtKB:Q02399};
DE            Short=TPKII catalytic subunit {ECO:0000250|UniProtKB:Q02399};
GN   Name=CDK5 {ECO:0000312|HGNC:HGNC:1774};
GN   Synonyms=CDKN5 {ECO:0000312|HGNC:HGNC:1774},
GN   PSSALRE {ECO:0000250|UniProtKB:P49615};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Fetal brain;
RX   PubMed=1639063; DOI=10.1002/j.1460-2075.1992.tb05360.x;
RA   Meyerson M., Enders G.H., Wu C.-L., Su L.-K., Gorka C., Nelson C.,
RA   Harlow E., Tsai L.-H.;
RT   "A family of human cdc2-related protein kinases.";
RL   EMBO J. 11:2909-2917(1992).
RN   [2]
RP   SEQUENCE REVISION.
RA   Meyerson M.;
RL   Submitted (FEB-1993) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, INTERACTION WITH CTNNB1, AND FUNCTION IN WNT/B-CATENIN
RP   SIGNALING PATHWAY.
RC   TISSUE=Testis;
RX   PubMed=19693690; DOI=10.1007/s11033-009-9752-7;
RA   Li Q., Liu X., Zhang M., Ye G., Qiao Q., Ling Y., Wu Y., Zhang Y., Yu L.;
RT   "Characterization of a novel human CDK5 splicing variant that inhibits
RT   Wnt/beta-catenin signaling.";
RL   Mol. Biol. Rep. 37:2415-2421(2010).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Hu X., Xu Y., Zhang B., Peng X., Yuan J., Qiang B.;
RL   Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12853948; DOI=10.1038/nature01782;
RA   Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA   Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA   Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA   Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA   Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA   Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA   Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA   Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA   Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA   Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA   Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA   Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA   Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA   Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA   Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA   Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA   Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA   McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA   Wilson R.K.;
RT   "The DNA sequence of human chromosome 7.";
RL   Nature 424:157-164(2003).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [8]
RP   ACTIVITY REGULATION BY ROSCOVITINE AND OLOMOUCINE.
RX   PubMed=9030781; DOI=10.1111/j.1432-1033.1997.t01-2-00527.x;
RA   Meijer L., Borgne A., Mulner O., Chong J.P.J., Blow J.J., Inagaki N.,
RA   Inagaki M., Delcros J.-G., Moulinoux J.-P.;
RT   "Biochemical and cellular effects of roscovitine, a potent and selective
RT   inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5.";
RL   Eur. J. Biochem. 243:527-536(1997).
RN   [9]
RP   FUNCTION IN AXON GROWTH.
RX   PubMed=9822744; DOI=10.1523/jneurosci.18-23-09858.1998;
RA   Paglini G., Pigino G., Kunda P., Morfini G., Maccioni R., Quiroga S.,
RA   Ferreira A., Caceres A.;
RT   "Evidence for the participation of the neuron-specific CDK5 activator P35
RT   during laminin-enhanced axonal growth.";
RL   J. Neurosci. 18:9858-9869(1998).
RN   [10]
RP   PHOSPHORYLATION AT SER-159.
RX   PubMed=10500146; DOI=10.1073/pnas.96.20.11156;
RA   Sharma P., Sharma M., Amin N.D., Albers R.W., Pant H.C.;
RT   "Regulation of cyclin-dependent kinase 5 catalytic activity by
RT   phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:11156-11160(1999).
RN   [11]
RP   FUNCTION AS P35/CDK5R1 KINASE.
RX   PubMed=12393264; DOI=10.1016/s0169-328x(02)00409-6;
RA   Kerokoski P., Suuronen T., Salminen A., Soininen H., Pirttilae T.;
RT   "Influence of phosphorylation of p35, an activator of cyclin-dependent
RT   kinase 5 (cdk5), on the proteolysis of p35.";
RL   Brain Res. Mol. Brain Res. 106:50-56(2002).
RN   [12]
RP   INTERACTION WITH AATK.
RX   PubMed=14521924; DOI=10.1016/j.bbrc.2003.08.143;
RA   Honma N., Asada A., Takeshita S., Enomoto M., Yamakawa E., Tsutsumi K.,
RA   Saito T., Satoh T., Itoh H., Kaziro Y., Kishimoto T., Hisanaga S.;
RT   "Apoptosis-associated tyrosine kinase is a Cdk5 activator p35 binding
RT   protein.";
RL   Biochem. Biophys. Res. Commun. 310:398-404(2003).
RN   [13]
RP   FUNCTION AS MEF2A KINASE, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RX   PubMed=12691662; DOI=10.1016/s0896-6273(03)00191-0;
RA   Gong X., Tang X., Wiedmann M., Wang X., Peng J., Zheng D., Blair L.A.C.,
RA   Marshall J., Mao Z.;
RT   "Cdk5-mediated inhibition of the protective effects of transcription factor
RT   MEF2 in neurotoxicity-induced apoptosis.";
RL   Neuron 38:33-46(2003).
RN   [14]
RP   FUNCTION AS P35 KINASE, SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX   PubMed=15992363; DOI=10.1111/j.1471-4159.2005.03301.x;
RA   Zhu Y.-S., Saito T., Asada A., Maekawa S., Hisanaga S.;
RT   "Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by
RT   membrane dissociation.";
RL   J. Neurochem. 94:1535-1545(2005).
RN   [15]
RP   FUNCTION AS P35/CDK5R KINASE.
RX   PubMed=17121855; DOI=10.1074/jbc.m610541200;
RA   Kamei H., Saito T., Ozawa M., Fujita Y., Asada A., Bibb J.A., Saido T.C.,
RA   Sorimachi H., Hisanaga S.;
RT   "Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25
RT   by site-specific phosphorylation.";
RL   J. Biol. Chem. 282:1687-1694(2007).
RN   [16]
RP   FUNCTION AS CTNNB1 AND CTNND2 KINASE, INTERACTION WITH CTNNB1 AND CTNND2,
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=17009320; DOI=10.1002/jcb.21041;
RA   Munoz J.P., Huichalaf C.H., Orellana D., Maccioni R.B.;
RT   "cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal
RT   cells.";
RL   J. Cell. Biochem. 100:738-749(2007).
RN   [17]
RP   FUNCTION AS P53/TP53 KINASE, INTERACTION WITH P53/TP53, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=17591690; DOI=10.1242/jcs.03468;
RA   Lee J.-H., Kim H.-S., Lee S.-J., Kim K.-T.;
RT   "Stabilization and activation of p53 induced by Cdk5 contributes to
RT   neuronal cell death.";
RL   J. Cell Sci. 120:2259-2271(2007).
RN   [18]
RP   FUNCTION AS PXN KINASE.
RX   PubMed=18042622; DOI=10.1242/jcs.018218;
RA   Miyamoto Y., Yamauchi J., Chan J.R., Okada A., Tomooka Y., Hisanaga S.,
RA   Tanoue A.;
RT   "Cdk5 regulates differentiation of oligodendrocyte precursor cells through
RT   the direct phosphorylation of paxillin.";
RL   J. Cell Sci. 120:4355-4366(2007).
RN   [19]
RP   FUNCTION AS HUNTINGTIN KINASE, AND ACTIVITY REGULATION BY ROSCOVITINE.
RX   PubMed=17611284; DOI=10.1523/jneurosci.1831-07.2007;
RA   Anne S.L., Saudou F., Humbert S.;
RT   "Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by
RT   DNA damage and regulates wild-type and mutant huntingtin toxicity in
RT   neurons.";
RL   J. Neurosci. 27:7318-7328(2007).
RN   [20]
RP   FUNCTION AS P35/CDK5R KINASE, INTERACTION WITH P35/CDK5R, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=17671990; DOI=10.1002/jnr.21438;
RA   Sato K., Zhu Y.-S., Saito T., Yotsumoto K., Asada A., Hasegawa M.,
RA   Hisanaga S.;
RT   "Regulation of membrane association and kinase activity of Cdk5-p35 by
RT   phosphorylation of p35.";
RL   J. Neurosci. Res. 85:3071-3078(2007).
RN   [21]
RP   PHOSPHORYLATION AT TYR-15 BY EPHA4.
RX   PubMed=17143272; DOI=10.1038/nn1811;
RA   Fu W.Y., Chen Y., Sahin M., Zhao X.S., Shi L., Bikoff J.B., Lai K.O.,
RA   Yung W.H., Fu A.K., Greenberg M.E., Ip N.Y.;
RT   "Cdk5 regulates EphA4-mediated dendritic spine retraction through an
RT   ephexin1-dependent mechanism.";
RL   Nat. Neurosci. 10:67-76(2007).
RN   [22]
RP   SUBCELLULAR LOCATION.
RX   PubMed=18507738; DOI=10.1111/j.1471-4159.2008.05500.x;
RA   Asada A., Yamamoto N., Gohda M., Saito T., Hayashi N., Hisanaga S.;
RT   "Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear
RT   localization of active cyclin-dependent kinase 5 complexes.";
RL   J. Neurochem. 106:1325-1336(2008).
RN   [23]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [24]
RP   FUNCTION AS HDAC REGULATOR.
RX   PubMed=19081376; DOI=10.1016/j.neuron.2008.10.015;
RA   Kim D., Frank C.L., Dobbin M.M., Tsunemoto R.K., Tu W., Peng P.L.,
RA   Guan J.S., Lee B.H., Moy L.Y., Giusti P., Broodie N., Mazitschek R.,
RA   Delalle I., Haggarty S.J., Neve R.L., Lu Y., Tsai L.H.;
RT   "Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.";
RL   Neuron 60:803-817(2008).
RN   [25]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [26]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-72, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [27]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-56, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19608861; DOI=10.1126/science.1175371;
RA   Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA   Olsen J.V., Mann M.;
RT   "Lysine acetylation targets protein complexes and co-regulates major
RT   cellular functions.";
RL   Science 325:834-840(2009).
RN   [28]
RP   FUNCTION IN ANGIOGENESIS.
RX   PubMed=20826806; DOI=10.1074/jbc.m110.126177;
RA   Liebl J., Weitensteiner S.B., Vereb G., Takacs L., Fuerst R., Vollmar A.M.,
RA   Zahler S.;
RT   "Cyclin-dependent kinase 5 regulates endothelial cell migration and
RT   angiogenesis.";
RL   J. Biol. Chem. 285:35932-35943(2010).
RN   [29]
RP   FUNCTION AS NOS3 KINASE.
RX   PubMed=20213743; DOI=10.1002/jcb.22515;
RA   Lee C.-H., Wei Y.-W., Huang Y.-T., Lin Y.-T., Lee Y.-C., Lee K.-H.,
RA   Lu P.-J.;
RT   "CDK5 phosphorylates eNOS at Ser-113 and regulates NO production.";
RL   J. Cell. Biochem. 110:112-117(2010).
RN   [30]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [31]
RP   INHIBITORS.
RX   PubMed=21144757; DOI=10.1016/j.bmc.2010.11.022;
RA   Jain P., Flaherty P.T., Yi S., Chopra I., Bleasdell G., Lipay J.,
RA   Ferandin Y., Meijer L., Madura J.D.;
RT   "Design, synthesis, and testing of an 6-O-linked series of benzimidazole
RT   based inhibitors of CDK5/p25.";
RL   Bioorg. Med. Chem. 19:359-373(2011).
RN   [32]
RP   FUNCTION AS SRC KINASE.
RX   PubMed=21442427; DOI=10.1007/s00018-011-0638-1;
RA   Pan Q., Qiao F., Gao C., Norman B., Optican L., Zelenka P.S.;
RT   "Cdk5 targets active Src for ubiquitin-dependent degradation by
RT   phosphorylating Src(S75).";
RL   Cell. Mol. Life Sci. 68:3425-3436(2011).
RN   [33]
RP   FUNCTION AS VIM KINASE, AND SUBCELLULAR LOCATION.
RX   PubMed=21465480; DOI=10.1002/jcp.22782;
RA   Lee K.Y., Liu L., Jin Y., Fu S.B., Rosales J.L.;
RT   "Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion
RT   by neutrophils.";
RL   J. Cell. Physiol. 227:739-750(2012).
RN   [34]
RP   ACTIVITY REGULATION, AND INTERACTION WITH GSTP1.
RX   PubMed=21668448; DOI=10.1111/j.1471-4159.2011.07343.x;
RA   Sun K.H., Chang K.H., Clawson S., Ghosh S., Mirzaei H., Regnier F.,
RA   Shah K.;
RT   "Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase
RT   activity.";
RL   J. Neurochem. 118:902-914(2011).
RN   [35]
RP   FUNCTION AS TONEBP/NFAT5 KINASE.
RX   PubMed=21209322; DOI=10.1091/mbc.e10-08-0681;
RA   Gallazzini M., Heussler G.E., Kunin M., Izumi Y., Burg M.B., Ferraris J.D.;
RT   "High NaCl-induced activation of CDK5 increases phosphorylation of the
RT   osmoprotective transcription factor TonEBP/OREBP at threonine 135, which
RT   contributes to its rapid nuclear localization.";
RL   Mol. Biol. Cell 22:703-714(2011).
RN   [36]
RP   FUNCTION AS SH3GLB1 KINASE.
RX   PubMed=21499257; DOI=10.1038/ncb2217;
RA   Wong A.S., Lee R.H., Cheung A.Y., Yeung P.K., Chung S.K., Cheung Z.H.,
RA   Ip N.Y.;
RT   "Cdk5-mediated phosphorylation of endophilin B1 is required for induced
RT   autophagy in models of Parkinson's disease.";
RL   Nat. Cell Biol. 13:568-579(2011).
RN   [37]
RP   FUNCTION AS EPRS KINASE.
RX   PubMed=21220307; DOI=10.1073/pnas.1011275108;
RA   Arif A., Jia J., Moodt R.A., DiCorleto P.E., Fox P.L.;
RT   "Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent
RT   kinase 5 dictates transcript-selective translational control.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:1415-1420(2011).
RN   [38]
RP   REVIEW.
RX   PubMed=11584302; DOI=10.1038/35096019;
RA   Dhavan R., Tsai L.H.;
RT   "A decade of CDK5.";
RL   Nat. Rev. Mol. Cell Biol. 2:749-759(2001).
RN   [39]
RP   REVIEW ON INHIBITORS, AND GENE FAMILY.
RX   PubMed=19238148; DOI=10.1038/nrc2602;
RA   Malumbres M., Barbacid M.;
RT   "Cell cycle, CDKs and cancer: a changing paradigm.";
RL   Nat. Rev. Cancer 9:153-166(2009).
RN   [40]
RP   REVIEW ON NEURONAL PHYSIOLOGY.
RX   PubMed=19782409; DOI=10.1016/j.tins.2009.07.002;
RA   Jessberger S., Gage F.H., Eisch A.J., Lagace D.C.;
RT   "Making a neuron: Cdk5 in embryonic and adult neurogenesis.";
RL   Trends Neurosci. 32:575-582(2009).
RN   [41]
RP   FUNCTION.
RX   PubMed=20061803; DOI=10.4161/cc.9.2.10466;
RA   Lalioti V., Pulido D., Sandoval I.V.;
RT   "Cdk5, the multifunctional surveyor.";
RL   Cell Cycle 9:284-311(2010).
RN   [42]
RP   REVIEW ON REGULATION.
RX   PubMed=21044075; DOI=10.1111/j.1471-4159.2010.07050.x;
RA   Hisanaga S., Endo R.;
RT   "Regulation and role of cyclin-dependent kinase activity in neuronal
RT   survival and death.";
RL   J. Neurochem. 115:1309-1321(2010).
RN   [43]
RP   REVIEW ON NEURON DEVELOPMENT.
RX   PubMed=21415596; DOI=10.4161/cc.10.8.15328;
RA   Zhang J., Herrup K.;
RT   "Nucleocytoplasmic Cdk5 is involved in neuronal cell cycle and death in
RT   post-mitotic neurons.";
RL   Cell Cycle 10:1208-1214(2011).
RN   [44]
RP   REVIEW ON NEURON DEVELOPMENT.
RX   PubMed=21600237; DOI=10.1016/j.mad.2011.04.011;
RA   Zhu J., Li W., Mao Z.;
RT   "Cdk5: Mediator of neuronal development, death and the response to DNA
RT   damage.";
RL   Mech. Ageing Dev. 132:389-394(2011).
RN   [45]
RP   REVIEW ON NEURONS.
RX   PubMed=21473899; DOI=10.1016/j.pneurobio.2011.03.006;
RA   Lopes J.P., Agostinho P.;
RT   "Cdk5: multitasking between physiological and pathological conditions.";
RL   Prog. Neurobiol. 94:49-63(2011).
RN   [46]
RP   FUNCTION, AND INTERACTION WITH CLOCK.
RX   PubMed=24235147; DOI=10.1074/jbc.m113.494856;
RA   Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H.,
RA   Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.;
RT   "Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein
RT   by direct phosphorylation.";
RL   J. Biol. Chem. 288:36878-36889(2013).
RN   [47]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-17, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [48]
RP   INVOLVEMENT IN LIS7.
RX   PubMed=25560765; DOI=10.1007/s00439-014-1522-5;
RA   Magen D., Ofir A., Berger L., Goldsher D., Eran A., Katib N., Nijem Y.,
RA   Vlodavsky E., Tzur S., Zur S., Behar D.M., Fellig Y., Mandel H.;
RT   "Autosomal recessive lissencephaly with cerebellar hypoplasia is associated
RT   with a loss-of-function mutation in CDK5.";
RL   Hum. Genet. 134:305-314(2015).
RN   [49]
RP   X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH P25, AND MUTAGENESIS
RP   OF SER-159.
RX   PubMed=11583627; DOI=10.1016/s1097-2765(01)00343-4;
RA   Tarricone C., Dhavan R., Peng J., Areces L.B., Tsai L.-H., Musacchio A.;
RT   "Structure and regulation of the CDK5-p25(nck5a) complex.";
RL   Mol. Cell 8:657-669(2001).
RN   [50]
RP   X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
RX   PubMed=16039528; DOI=10.1016/j.chembiol.2005.05.011;
RA   Ahn J.S., Radhakrishnan M.L., Mapelli M., Choi S., Tidor B., Cuny G.D.,
RA   Musacchio A., Yeh L.A., Kosik K.S.;
RT   "Defining Cdk5 ligand chemical space with small molecule inhibitors of tau
RT   phosphorylation.";
RL   Chem. Biol. 12:811-823(2005).
RN   [51]
RP   X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEX WITH INHIBITORS AND P25,
RP   AND PHOSPHORYLATION AT TYR-15.
RX   PubMed=15689152; DOI=10.1021/jm049323m;
RA   Mapelli M., Massimiliano L., Crovace C., Seeliger M.A., Tsai L.H.,
RA   Meijer L., Musacchio A.;
RT   "Mechanism of CDK5/p25 binding by CDK inhibitors.";
RL   J. Med. Chem. 48:671-679(2005).
RN   [52]
RP   VARIANT [LARGE SCALE ANALYSIS] ASP-225.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
CC   -!- FUNCTION: Proline-directed serine/threonine-protein kinase essential
CC       for neuronal cell cycle arrest and differentiation and may be involved
CC       in apoptotic cell death in neuronal diseases by triggering abortive
CC       cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins.
CC       Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1,
CC       SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16,
CC       RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53,
CC       HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM.
CC       Regulates several neuronal development and physiological processes
CC       including neuronal survival, migration and differentiation, axonal and
CC       neurite growth, synaptogenesis, oligodendrocyte differentiation,
CC       synaptic plasticity and neurotransmission, by phosphorylating key
CC       proteins. Negatively regulates the CACNA1B/CAV2.2 -mediated Ca(2+)
CC       release probability at hippocampal neuronal soma and synaptic terminals
CC       (By similarity). Activated by interaction with CDK5R1 (p35) and CDK5R2
CC       (p39), especially in postmitotic neurons, and promotes CDK5R1 (p35)
CC       expression in an autostimulation loop. Phosphorylates many downstream
CC       substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1,
CC       RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2,
CC       MAP1B), and modulates actin dynamics to regulate neurite growth and/or
CC       spine morphogenesis. Also phosphorylates exocytosis associated proteins
CC       such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as
CC       endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at
CC       synaptic terminals. In the mature central nervous system (CNS),
CC       regulates neurotransmitter movements by phosphorylating substrates
CC       associated with neurotransmitter release and synapse plasticity;
CC       synaptic vesicle exocytosis, vesicles fusion with the presynaptic
CC       membrane, and endocytosis. Promotes cell survival by activating anti-
CC       apoptotic proteins BCL2 and STAT3, and negatively regulating of
CC       JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to
CC       genotoxic and oxidative stresses enhances its stabilization by
CC       preventing ubiquitin ligase-mediated proteasomal degradation, and
CC       induces transactivation of p53/TP53 target genes, thus regulating
CC       apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by
CC       preventing calpain-mediated proteolysis producing p25/CDK5R1 and
CC       avoiding ubiquitin ligase-mediated proteasomal degradation. During
CC       aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits
CC       cell-cycle activity and double-strand DNA breaks that precedes neuronal
CC       death by deregulating HDAC1. DNA damage triggered phosphorylation of
CC       huntingtin/HTT in nuclei of neurons protects neurons against
CC       polyglutamine expansion as well as DNA damage mediated toxicity.
CC       Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in
CC       matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs)
CC       differentiation. Negative regulator of Wnt/beta-catenin signaling
CC       pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of
CC       translation) pathway, which suppresses expression of a post-
CC       transcriptional regulon of proinflammatory genes in myeloid cells;
CC       phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase
CC       (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly
CC       of the GAIT complex. Phosphorylation of SH3GLB1 is required for
CC       autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5
CC       in response to osmotic stress mediates its rapid nuclear localization.
CC       MEF2 is inactivated by phosphorylation in nucleus in response to
CC       neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-
CC       endodeoxyribonuclease is repressed by phosphorylation, resulting in
CC       accumulation of DNA damage and contributing to neuronal death. NOS3
CC       phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC
CC       phosphorylation mediates its ubiquitin-dependent degradation and thus
CC       leads to cytoskeletal reorganization. May regulate endothelial cell
CC       migration and angiogenesis via the modulation of lamellipodia
CC       formation. Involved in dendritic spine morphogenesis by mediating the
CC       EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the
CC       regulation of the circadian clock by modulating the function of CLOCK
CC       protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates
CC       the transcriptional activity of the CLOCK-BMAL1 heterodimer in
CC       association with altered stability and subcellular distribution.
CC       {ECO:0000250|UniProtKB:Q03114, ECO:0000269|PubMed:12393264,
CC       ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363,
CC       ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:17121855,
CC       ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17611284,
CC       ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:18042622,
CC       ECO:0000269|PubMed:19081376, ECO:0000269|PubMed:19693690,
CC       ECO:0000269|PubMed:20061803, ECO:0000269|PubMed:20213743,
CC       ECO:0000269|PubMed:20826806, ECO:0000269|PubMed:21209322,
CC       ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:21442427,
CC       ECO:0000269|PubMed:21465480, ECO:0000269|PubMed:21499257,
CC       ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:9822744}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC   -!- ACTIVITY REGULATION: Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-
CC       benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-
CC       6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine.
CC       Activated by CDK5R1 (p35) and CDK5R2 (p39) during the development of
CC       the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (p39) by
CC       proteasome result in down regulation of kinase activity, during this
CC       process, CDK5 phosphorylates p35 and induces its ubiquitination and
CC       subsequent degradation. Kinase activity is mainly determined by the
CC       amount of p35 available and subcellular location; reversible
CC       association to plasma membrane inhibits activity. Long-term
CC       inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5
CC       triggers cell death. The pro-death activity of hyperactivated CDK5 is
CC       suppressed by membrane association of CDK5, via myristoylation of p35.
CC       Brain-derived neurotrophic factor, glial-derived neurotrophic factor,
CC       nerve growth factor (NGF), retinoic acid, laminin and neuregulin
CC       promote activity. Neurotoxicity enhances nuclear activity, thus leading
CC       to MEF2 phosphorylation and inhibition prior to apoptosis of cortical
CC       neurons. Repression by GSTP1 via p25/p35 translocation prevents
CC       neurodegeneration. {ECO:0000269|PubMed:12691662,
CC       ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17611284,
CC       ECO:0000269|PubMed:21668448, ECO:0000269|PubMed:9030781}.
CC   -!- SUBUNIT: Heterodimer composed of a catalytic subunit CDK5 and a
CC       regulatory subunit CDK5R1 (p25) and macromolecular complex composed of
CC       at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only
CC       the heterodimer shows kinase activity. Under neurotoxic stress and
CC       neuronal injury conditions, p35 is cleaved by calpain to generate p25
CC       that hyperactivates CDK5, that becomes functionally disabled and often
CC       toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts
CC       with CABLES1 and CABLES2 (By similarity). Interacts with AATK and
CC       GSTP1. Binds to HDAC1 when in complex with p25. Interaction with
CC       myristoylation p35 promotes CDK5 association with membranes. Both
CC       isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with
CC       delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons.
CC       Interacts with EPHA4; may mediate the activation of NGEF by EPHA4.
CC       Interacts with PTK2/FAK1 (By similarity). The complex p35/CDK5
CC       interacts with CLOCK. Interacts with HTR6 (By similarity).
CC       {ECO:0000250, ECO:0000250|UniProtKB:P49615,
CC       ECO:0000269|PubMed:11583627, ECO:0000269|PubMed:14521924,
CC       ECO:0000269|PubMed:15689152, ECO:0000269|PubMed:17009320,
CC       ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17671990,
CC       ECO:0000269|PubMed:19693690, ECO:0000269|PubMed:21668448,
CC       ECO:0000269|PubMed:24235147}.
CC   -!- INTERACTION:
CC       Q00535; P61158: ACTR3; NbExp=3; IntAct=EBI-1041567, EBI-351428;
CC       Q00535; P05067: APP; NbExp=3; IntAct=EBI-1041567, EBI-77613;
CC       Q00535; P23560-2: BDNF; NbExp=3; IntAct=EBI-1041567, EBI-12275524;
CC       Q00535; Q8TDN4: CABLES1; NbExp=8; IntAct=EBI-1041567, EBI-604615;
CC       Q00535; P14635: CCNB1; NbExp=8; IntAct=EBI-1041567, EBI-495332;
CC       Q00535; P24863: CCNC; NbExp=2; IntAct=EBI-1041567, EBI-395261;
CC       Q00535; P30279: CCND2; NbExp=18; IntAct=EBI-1041567, EBI-748789;
CC       Q00535; P30281: CCND3; NbExp=12; IntAct=EBI-1041567, EBI-375013;
CC       Q00535; Q14094: CCNI; NbExp=6; IntAct=EBI-1041567, EBI-1104653;
CC       Q00535; Q15078: CDK5R1; NbExp=15; IntAct=EBI-1041567, EBI-746189;
CC       Q00535; P38936: CDKN1A; NbExp=7; IntAct=EBI-1041567, EBI-375077;
CC       Q00535; P46527: CDKN1B; NbExp=14; IntAct=EBI-1041567, EBI-519280;
CC       Q00535; Q9UJC3: HOOK1; NbExp=3; IntAct=EBI-1041567, EBI-746704;
CC       Q00535; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-1041567, EBI-16439278;
CC       Q00535; Q9Y6R0: NUMBL; NbExp=3; IntAct=EBI-1041567, EBI-945925;
CC       Q00535; P37231-2: PPARG; NbExp=2; IntAct=EBI-1041567, EBI-781416;
CC       Q00535; P62937: PPIA; NbExp=3; IntAct=EBI-1041567, EBI-437708;
CC       Q00535; O60260-5: PRKN; NbExp=3; IntAct=EBI-1041567, EBI-21251460;
CC       Q00535; Q5MJ70: SPDYA; NbExp=3; IntAct=EBI-1041567, EBI-7125479;
CC       Q00535; A6NLX3: SPDYE4; NbExp=4; IntAct=EBI-1041567, EBI-12047907;
CC       Q00535; P20226: TBP; NbExp=3; IntAct=EBI-1041567, EBI-355371;
CC       Q00535; P09936: UCHL1; NbExp=2; IntAct=EBI-1041567, EBI-714860;
CC   -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC       {ECO:0000269|PubMed:12691662}. Nucleus {ECO:0000269|PubMed:12691662}.
CC       Cell membrane {ECO:0000269|PubMed:17009320}; Peripheral membrane
CC       protein. Perikaryon. Cell projection, lamellipodium
CC       {ECO:0000250|UniProtKB:P49615}. Cell projection, growth cone
CC       {ECO:0000250|UniProtKB:P49615}. Postsynaptic density
CC       {ECO:0000250|UniProtKB:Q03114}. Synapse {ECO:0000250|UniProtKB:Q03114}.
CC       Note=In axonal growth cone with extension to the peripheral
CC       lamellipodia (By similarity). Under neurotoxic stress and neuronal
CC       injury conditions, CDK5R (p35) is cleaved by calpain to generate CDK5R1
CC       (p25) in response to increased intracellular calcium. The elevated
CC       level of p25, when in complex with CDK5, leads to its subcellular
CC       misallocation as well as its hyperactivation. Colocalizes with CTNND2
CC       in the cell body of neuronal cells, and with CTNNB1 in the cell-cell
CC       contacts and plasma membrane of undifferentiated and differentiated
CC       neuroblastoma cells. Reversibly attached to the plasma membrane in an
CC       inactive form when complexed to dephosphorylated p35 or CDK5R2 (p39),
CC       p35 phosphorylation releases this attachment and activates CDK5.
CC       {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q00535-1; Sequence=Displayed;
CC       Name=2; Synonyms=CDK5-SV {ECO:0000303|PubMed:19693690};
CC         IsoId=Q00535-2; Sequence=VSP_041948;
CC   -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed
CC       (PubMed:17009320, PubMed:19693690). Accumulates in cortical neurons (at
CC       protein level) (PubMed:17009320). {ECO:0000269|PubMed:17009320,
CC       ECO:0000269|PubMed:19693690}.
CC   -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in the testis, skeletal
CC       muscle, colon, bone marrow and ovary. {ECO:0000269|PubMed:19693690}.
CC   -!- PTM: Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by
CC       casein kinase 1 promotes kinase activity. By contrast, phosphorylation
CC       at Thr-14 inhibits activity. {ECO:0000269|PubMed:10500146,
CC       ECO:0000269|PubMed:15689152, ECO:0000269|PubMed:17143272}.
CC   -!- PTM: Phosphorylation at Ser-159 is essential for maximal catalytic
CC       activity. {ECO:0000269|PubMed:10500146}.
CC   -!- DISEASE: Lissencephaly 7, with cerebellar hypoplasia (LIS7)
CC       [MIM:616342]: A form of lissencephaly, a disorder of cortical
CC       development characterized by agyria or pachygyria and disorganization
CC       of the clear neuronal lamination of normal six-layered cortex. LIS7
CC       patients manifest lack of psychomotor development, facial dysmorphism,
CC       arthrogryposis, and early-onset intractable seizures resulting in death
CC       in infancy. {ECO:0000269|PubMed:25560765}. Note=The disease is caused
CC       by variants affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: Dysregulation of CDK5 is associated with
CC       neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-
CC       Pick type C diseases, ischemia, and amyotrophic lateral sclerosis.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; X66364; CAA47007.1; -; mRNA.
DR   EMBL; DQ411039; ABD66016.1; -; mRNA.
DR   EMBL; AY049778; AAL15435.1; -; mRNA.
DR   EMBL; BT006680; AAP35326.1; -; mRNA.
DR   EMBL; AC010973; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC005115; AAH05115.1; -; mRNA.
DR   CCDS; CCDS47748.1; -. [Q00535-1]
DR   CCDS; CCDS55184.1; -. [Q00535-2]
DR   PIR; S23386; S23386.
DR   RefSeq; NP_001157882.1; NM_001164410.3. [Q00535-2]
DR   RefSeq; NP_004926.1; NM_004935.4. [Q00535-1]
DR   PDB; 1H4L; X-ray; 2.65 A; A/B=1-292.
DR   PDB; 1UNG; X-ray; 2.30 A; A/B=1-292.
DR   PDB; 1UNH; X-ray; 2.35 A; A/B=1-292.
DR   PDB; 1UNL; X-ray; 2.20 A; A/B=1-292.
DR   PDB; 3O0G; X-ray; 1.95 A; A/B=1-292.
DR   PDB; 4AU8; X-ray; 1.90 A; A/B=2-292.
DR   PDB; 7VDP; X-ray; 2.09 A; A/B=2-292.
DR   PDB; 7VDQ; X-ray; 2.91 A; A/B=2-292.
DR   PDB; 7VDR; X-ray; 2.55 A; A/B=2-292.
DR   PDB; 7VDS; X-ray; 3.05 A; A/B=2-292.
DR   PDBsum; 1H4L; -.
DR   PDBsum; 1UNG; -.
DR   PDBsum; 1UNH; -.
DR   PDBsum; 1UNL; -.
DR   PDBsum; 3O0G; -.
DR   PDBsum; 4AU8; -.
DR   PDBsum; 7VDP; -.
DR   PDBsum; 7VDQ; -.
DR   PDBsum; 7VDR; -.
DR   PDBsum; 7VDS; -.
DR   AlphaFoldDB; Q00535; -.
DR   SMR; Q00535; -.
DR   BioGRID; 107455; 220.
DR   ComplexPortal; CPX-2201; Cyclin-dependent protein kinase 5 holoenzyme complex, p35 variant.
DR   ComplexPortal; CPX-3141; Cyclin-dependent protein kinase 5 holoenzyme complex, p39 variant.
DR   ComplexPortal; CPX-3142; Cyclin-dependent protein kinase 5 holoenzyme complex, p25 variant.
DR   CORUM; Q00535; -.
DR   DIP; DIP-24221N; -.
DR   ELM; Q00535; -.
DR   FunCoup; Q00535; 1204.
DR   IntAct; Q00535; 115.
DR   MINT; Q00535; -.
DR   STRING; 9606.ENSP00000419782; -.
DR   BindingDB; Q00535; -.
DR   ChEMBL; CHEMBL4036; -.
DR   DrugBank; DB07364; 6-PHENYL[5H]PYRROLO[2,3-B]PYRAZINE.
DR   DrugBank; DB04014; Alsterpaullone.
DR   DrugBank; DB03496; Alvocidib.
DR   DrugBank; DB02950; Hymenialdisine.
DR   DrugBank; DB02052; Indirubin-3'-monoxime.
DR   DrugBank; DB02116; Olomoucine.
DR   DrugBank; DB02733; Purvalanol.
DR   DrugBank; DB03428; SU9516.
DR   DrugBank; DB15442; Trilaciclib.
DR   DrugCentral; Q00535; -.
DR   GuidetoPHARMACOLOGY; 1977; -.
DR   GlyCosmos; Q00535; 4 sites, 1 glycan.
DR   GlyGen; Q00535; 4 sites, 1 O-linked glycan (4 sites).
DR   iPTMnet; Q00535; -.
DR   PhosphoSitePlus; Q00535; -.
DR   SwissPalm; Q00535; -.
DR   BioMuta; CDK5; -.
DR   DMDM; 4033704; -.
DR   CPTAC; CPTAC-2934; -.
DR   jPOST; Q00535; -.
DR   MassIVE; Q00535; -.
DR   PaxDb; 9606-ENSP00000419782; -.
DR   PeptideAtlas; Q00535; -.
DR   ProteomicsDB; 57852; -. [Q00535-1]
DR   ProteomicsDB; 57853; -. [Q00535-2]
DR   Pumba; Q00535; -.
DR   Antibodypedia; 4556; 1032 antibodies from 44 providers.
DR   DNASU; 1020; -.
DR   Ensembl; ENST00000297518.4; ENSP00000297518.4; ENSG00000164885.14. [Q00535-2]
DR   Ensembl; ENST00000485972.6; ENSP00000419782.1; ENSG00000164885.14. [Q00535-1]
DR   GeneID; 1020; -.
DR   KEGG; hsa:1020; -.
DR   MANE-Select; ENST00000485972.6; ENSP00000419782.1; NM_004935.4; NP_004926.1.
DR   UCSC; uc003wir.3; human. [Q00535-1]
DR   AGR; HGNC:1774; -.
DR   CIViC; 1020; 1 evidence item across 1 molecular profile.
DR   ClinPGx; PA26310; -.
DR   CTD; 1020; -.
DR   DisGeNET; 1020; -.
DR   GeneCards; CDK5; -.
DR   HGNC; HGNC:1774; CDK5.
DR   HPA; ENSG00000164885; Tissue enhanced (brain).
DR   MalaCards; CDK5; -.
DR   MIM; 123831; gene.
DR   MIM; 616342; phenotype.
DR   OpenTargets; ENSG00000164885; -.
DR   VEuPathDB; HostDB:ENSG00000164885; -.
DR   eggNOG; KOG0662; Eukaryota.
DR   GeneTree; ENSGT00940000160805; -.
DR   HOGENOM; CLU_000288_181_1_1; -.
DR   InParanoid; Q00535; -.
DR   OMA; NWQIFVP; -.
DR   OrthoDB; 1732493at2759; -.
DR   PAN-GO; Q00535; 8 GO annotations based on evolutionary models.
DR   PhylomeDB; Q00535; -.
DR   BRENDA; 2.7.11.1; 2681.
DR   BRENDA; 2.7.11.22; 2681.
DR   PathwayCommons; Q00535; -.
DR   Reactome; R-HSA-180024; DARPP-32 events.
DR   Reactome; R-HSA-399956; CRMPs in Sema3A signaling.
DR   Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   Reactome; R-HSA-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
DR   Reactome; R-HSA-9031628; NGF-stimulated transcription.
DR   Reactome; R-HSA-9032845; Activated NTRK2 signals through CDK5.
DR   Reactome; R-HSA-9768919; NPAS4 regulates expression of target genes.
DR   Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR   Reactome; R-HSA-9841922; MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis.
DR   Reactome; R-HSA-9931529; Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK.
DR   Reactome; R-HSA-9931530; Phosphorylation and nuclear translocation of the CRY:PER:kinase complex.
DR   SignaLink; Q00535; -.
DR   SIGNOR; Q00535; -.
DR   Agora; ENSG00000164885; -.
DR   BioGRID-ORCS; 1020; 27 hits in 1199 CRISPR screens.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; CDK5; human.
DR   EvolutionaryTrace; Q00535; -.
DR   GeneWiki; Cyclin-dependent_kinase_5; -.
DR   GenomeRNAi; 1020; -.
DR   Pharos; Q00535; Tchem.
DR   PRO; PR:Q00535; -.
DR   Proteomes; UP000005640; Chromosome 7.
DR   RNAct; Q00535; protein.
DR   Bgee; ENSG00000164885; Expressed in right frontal lobe and 156 other cell types or tissues.
DR   ExpressionAtlas; Q00535; baseline and differential.
DR   GO; GO:0030424; C:axon; ISS:UniProtKB.
DR   GO; GO:0030054; C:cell junction; IDA:HPA.
DR   GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IPI:ComplexPortal.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR   GO; GO:0030175; C:filopodium; IEA:Ensembl.
DR   GO; GO:0030426; C:growth cone; ISS:UniProtKB.
DR   GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR   GO; GO:0031594; C:neuromuscular junction; ISS:UniProtKB.
DR   GO; GO:0043005; C:neuron projection; ISS:ARUK-UCL.
DR   GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR   GO; GO:0098793; C:presynapse; IEA:GOC.
DR   GO; GO:0016533; C:protein kinase 5 complex; IPI:ComplexPortal.
DR   GO; GO:0030549; F:acetylcholine receptor activator activity; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR   GO; GO:0005176; F:ErbB-2 class receptor binding; ISS:UniProtKB.
DR   GO; GO:0043125; F:ErbB-3 class receptor binding; ISS:UniProtKB.
DR   GO; GO:0051879; F:Hsp90 protein binding; IEA:Ensembl.
DR   GO; GO:0035255; F:ionotropic glutamate receptor binding; IPI:ARUK-UCL.
DR   GO; GO:0016301; F:kinase activity; ISS:UniProtKB.
DR   GO; GO:0002039; F:p53 binding; IEA:Ensembl.
DR   GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0030547; F:signaling receptor inhibitor activity; IMP:ARUK-UCL.
DR   GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR   GO; GO:0050321; F:tau-protein kinase activity; ISS:UniProtKB.
DR   GO; GO:0030036; P:actin cytoskeleton organization; TAS:UniProtKB.
DR   GO; GO:0048675; P:axon extension; TAS:UniProtKB.
DR   GO; GO:0007409; P:axonogenesis; IBA:GO_Central.
DR   GO; GO:0048148; P:behavioral response to cocaine; IEA:Ensembl.
DR   GO; GO:0070509; P:calcium ion import; IEA:Ensembl.
DR   GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR   GO; GO:0007160; P:cell-matrix adhesion; IEA:Ensembl.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; ISS:ARUK-UCL.
DR   GO; GO:0021954; P:central nervous system neuron development; IEA:Ensembl.
DR   GO; GO:0021697; P:cerebellar cortex formation; IEA:Ensembl.
DR   GO; GO:0007268; P:chemical synaptic transmission; TAS:UniProtKB.
DR   GO; GO:0022038; P:corpus callosum development; IEA:Ensembl.
DR   GO; GO:0048813; P:dendrite morphogenesis; IEA:Ensembl.
DR   GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl.
DR   GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR   GO; GO:0006886; P:intracellular protein transport; IEA:Ensembl.
DR   GO; GO:0021819; P:layer formation in cerebral cortex; IEA:Ensembl.
DR   GO; GO:0000226; P:microtubule cytoskeleton organization; TAS:ARUK-UCL.
DR   GO; GO:0008045; P:motor neuron axon guidance; IEA:Ensembl.
DR   GO; GO:0030517; P:negative regulation of axon extension; IEA:Ensembl.
DR   GO; GO:1903234; P:negative regulation of calcium ion-dependent exocytosis of neurotransmitter; ISS:ARUK-UCL.
DR   GO; GO:0045786; P:negative regulation of cell cycle; IEA:Ensembl.
DR   GO; GO:0045892; P:negative regulation of DNA-templated transcription; IMP:DFLAT.
DR   GO; GO:0046826; P:negative regulation of protein export from nucleus; IEA:Ensembl.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; IEA:Ensembl.
DR   GO; GO:0045861; P:negative regulation of proteolysis; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0031914; P:negative regulation of synaptic plasticity; IEA:Ensembl.
DR   GO; GO:0051402; P:neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
DR   GO; GO:0001764; P:neuron migration; TAS:UniProtKB.
DR   GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR   GO; GO:0048709; P:oligodendrocyte differentiation; IDA:UniProtKB.
DR   GO; GO:0045956; P:positive regulation of calcium ion-dependent exocytosis; IEA:Ensembl.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR   GO; GO:0099533; P:positive regulation of presynaptic cytosolic calcium concentration; ISS:ARUK-UCL.
DR   GO; GO:0090314; P:positive regulation of protein targeting to membrane; IEA:Ensembl.
DR   GO; GO:0035418; P:protein localization to synapse; IEA:Ensembl.
DR   GO; GO:0032801; P:receptor catabolic process; IEA:Ensembl.
DR   GO; GO:0043113; P:receptor clustering; IEA:Ensembl.
DR   GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB.
DR   GO; GO:0051726; P:regulation of cell cycle; TAS:UniProtKB.
DR   GO; GO:1901987; P:regulation of cell cycle phase transition; IBA:GO_Central.
DR   GO; GO:0030334; P:regulation of cell migration; IEA:Ensembl.
DR   GO; GO:0061001; P:regulation of dendritic spine morphogenesis; ISS:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR   GO; GO:1903076; P:regulation of protein localization to plasma membrane; ISS:ARUK-UCL.
DR   GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR   GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; ISS:ARUK-UCL.
DR   GO; GO:1903421; P:regulation of synaptic vesicle recycling; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR   GO; GO:0014044; P:Schwann cell development; IEA:Ensembl.
DR   GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR   GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl.
DR   GO; GO:0007416; P:synapse assembly; TAS:UniProtKB.
DR   GO; GO:0001963; P:synaptic transmission, dopaminergic; IEA:Ensembl.
DR   GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl.
DR   GO; GO:0048488; P:synaptic vesicle endocytosis; TAS:UniProtKB.
DR   GO; GO:0016079; P:synaptic vesicle exocytosis; TAS:UniProtKB.
DR   GO; GO:0048489; P:synaptic vesicle transport; IBA:GO_Central.
DR   GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR   CDD; cd07839; STKc_CDK5; 1.
DR   FunFam; 3.30.200.20:FF:000144; Cyclin-dependent kinase 5; 1.
DR   FunFam; 1.10.510.10:FF:000184; cyclin-dependent kinase 5 homolog; 1.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR050108; CDK.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR24056; CELL DIVISION PROTEIN KINASE; 1.
DR   PANTHER; PTHR24056:SF46; CYCLIN-DEPENDENT KINASE 5; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding;
KW   Biological rhythms; Cell cycle; Cell division; Cell membrane;
KW   Cell projection; Cytoplasm; Kinase; Lissencephaly; Membrane;
KW   Neurodegeneration; Neurogenesis; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Proteomics identification; Reference proteome;
KW   Serine/threonine-protein kinase; Synapse; Transferase.
FT   CHAIN           1..292
FT                   /note="Cyclin-dependent kinase 5"
FT                   /id="PRO_0000085784"
FT   DOMAIN          4..286
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   ACT_SITE        126
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         10..18
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         33
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         15
FT                   /note="Phosphotyrosine; by ABL1, EPHA4 and FYN"
FT                   /evidence="ECO:0000269|PubMed:15689152,
FT                   ECO:0000269|PubMed:17143272"
FT   MOD_RES         17
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         56
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         72
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976,
FT                   ECO:0007744|PubMed:19369195"
FT   MOD_RES         159
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:10500146"
FT   VAR_SEQ         105..136
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:19693690"
FT                   /id="VSP_041948"
FT   VARIANT         225
FT                   /note="E -> D (in dbSNP:rs35186917)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_041977"
FT   MUTAGEN         159
FT                   /note="S->A: No phenotype."
FT                   /evidence="ECO:0000269|PubMed:11583627"
FT   MUTAGEN         159
FT                   /note="S->T: Impaired p35/p25 (CDK5R1) binding."
FT                   /evidence="ECO:0000269|PubMed:11583627"
FT   STRAND          4..12
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          14..23
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   TURN            24..26
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          29..36
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          40..42
FT                   /evidence="ECO:0007829|PDB:1UNG"
FT   HELIX           46..55
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          66..70
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          76..81
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          84..86
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           87..94
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           100..119
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           129..131
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          132..134
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          140..142
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           145..147
FT                   /evidence="ECO:0007829|PDB:1UNG"
FT   HELIX           165..167
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           170..173
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           182..196
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   TURN            197..199
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           208..219
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   TURN            224..226
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           228..232
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           248..250
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           257..266
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           271..273
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           277..281
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   HELIX           284..286
FT                   /evidence="ECO:0007829|PDB:4AU8"
FT   STRAND          287..289
FT                   /evidence="ECO:0007829|PDB:7VDQ"
SQ   SEQUENCE   292 AA;  33304 MW;  54D10495F017D527 CRC64;
     MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR EICLLKELKH
     KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP EIVKSFLFQL LKGLGFCHSR
     NVLHRDLKPQ NLLINRNGEL KLADFGLARA FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS
     TSIDMWSAGC IFAELANAGR PLFPGNDVDD QLKRIFRLLG TPTEEQWPSM TKLPDYKPYP
     MYPATTSLVN VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP
//
ID   DPYL2_HUMAN             Reviewed;         572 AA.
AC   Q16555; A8K5H2; B4DR31; D3DSS7; O00424;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   28-JAN-2026, entry version 231.
DE   RecName: Full=Dihydropyrimidinase-related protein 2;
DE            Short=DRP-2;
DE   AltName: Full=Collapsin response mediator protein 2;
DE            Short=CRMP-2;
DE   AltName: Full=N2A3;
DE   AltName: Full=Unc-33-like phosphoprotein 2;
DE            Short=ULIP-2;
GN   Name=DPYSL2; Synonyms=CRMP2, ULIP2;
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).
RX   PubMed=7637782; DOI=10.1038/376509a0;
RA   Goshima Y., Nakamura F., Strittmatter P., Strittmatter S.M.;
RT   "Collapsin-induced growth cone collapse mediated by an intracellular
RT   protein related to UNC-33.";
RL   Nature 376:509-514(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=8973361; DOI=10.1016/s0378-1119(96)00445-3;
RA   Hamajima N., Matsuda K., Sakata S., Tamaki N., Sasaki M., Nonaka M.;
RT   "A novel gene family defined by human dihydropyrimidinase and three related
RT   proteins with differential tissue distribution.";
RL   Gene 180:157-163(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Fetal liver;
RA   Zhou J., Chen Y., Gu J.R.;
RT   "A cDNA clone highly expressed in human brain and deleted in liver
RT   cancer.";
RL   Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=10574455; DOI=10.1093/dnares/6.5.291;
RA   Kitamura K., Takayama M., Hamajima N., Nakanishi M., Sasaki M., Endo Y.,
RA   Takemoto T., Kimura H., Iwaki M., Nonaka M.;
RT   "Characterization of the human dihydropyrimidinase-related protein 2 (DRP-
RT   2) gene.";
RL   DNA Res. 6:291-297(1999).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
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=16421571; DOI=10.1038/nature04406;
RA   Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA   Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA   Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA   Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA   Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA   Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA   Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA   Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA   Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA   O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA   Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA   Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA   Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA   Platzer M., Shimizu N., Lander E.S.;
RT   "DNA sequence and analysis of human chromosome 8.";
RL   Nature 439:331-335(2006).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Eye, 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   [9]
RP   PROTEIN SEQUENCE OF 44-56; 64-75; 147-157; 174-211; 239-254; 375-390;
RP   401-418; 424-467; 497-511 AND 533-552, AND IDENTIFICATION BY MASS
RP   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   [10]
RP   PHOSPHORYLATION AT SER-518; SER-522 AND THR-509, AND MUTAGENESIS OF
RP   SER-507; THR-509; THR-512; THR-514; SER-517; SER-518; THR-521 AND SER-522.
RX   PubMed=10757975; DOI=10.1021/bi992323h;
RA   Gu Y., Hamajima N., Ihara Y.;
RT   "Neurofibrillary tangle-associated collapsin response mediator protein-2
RT   (CRMP-2) is highly phosphorylated on Thr-509, Ser-518, and Ser-522.";
RL   Biochemistry 39:4267-4275(2000).
RN   [11]
RP   FUNCTION.
RX   PubMed=11477421; DOI=10.1038/90476;
RA   Inagaki N., Chihara K., Arimura N., Menager C., Kawano Y., Matsuo N.,
RA   Nishimura T., Amano M., Kaibuchi K.;
RT   "CRMP-2 induces axons in cultured hippocampal neurons.";
RL   Nat. Neurosci. 4:781-782(2001).
RN   [12]
RP   FUNCTION, AND PHOSPHORYLATION AT SER-522.
RX   PubMed=15466863; DOI=10.1074/jbc.c400412200;
RA   Cole A.R., Knebel A., Morrice N.A., Robertson L.A., Irving A.J.,
RA   Connolly C.N., Sutherland C.;
RT   "GSK-3 phosphorylation of the Alzheimer epitope within collapsin response
RT   mediator proteins regulates axon elongation in primary neurons.";
RL   J. Biol. Chem. 279:50176-50180(2004).
RN   [13]
RP   INTERACTION WITH CYFIP1, AND MUTAGENESIS OF ASP-71.
RX   PubMed=16260607; DOI=10.1128/mcb.25.22.9920-9935.2005;
RA   Kawano Y., Yoshimura T., Tsuboi D., Kawabata S., Kaneko-Kawano T.,
RA   Shirataki H., Takenawa T., Kaibuchi K.;
RT   "CRMP-2 is involved in kinesin-1-dependent transport of the Sra-1/WAVE1
RT   complex and axon formation.";
RL   Mol. Cell. Biol. 25:9920-9935(2005).
RN   [14]
RP   INTERACTION WITH PLEXNA1, AND SUBUNIT.
RX   PubMed=14685275; DOI=10.1038/sj.emboj.7600021;
RA   Deo R.C., Schmidt E.F., Elhabazi A., Togashi H., Burley S.K.,
RA   Strittmatter S.M.;
RT   "Structural bases for CRMP function in plexin-dependent semaphorin3A
RT   signaling.";
RL   EMBO J. 23:9-22(2004).
RN   [15]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-509 AND SER-522, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=16964243; DOI=10.1038/nbt1240;
RA   Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT   "A probability-based approach for high-throughput protein phosphorylation
RT   analysis and site localization.";
RL   Nat. Biotechnol. 24:1285-1292(2006).
RN   [16]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-509, 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   [17]
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   [18]
RP   PHOSPHORYLATION AT TYR-32 BY FYN.
RX   PubMed=19652227; DOI=10.1074/jbc.m109.000240;
RA   Uchida Y., Ohshima T., Yamashita N., Ogawara M., Sasaki Y., Nakamura F.,
RA   Goshima Y.;
RT   "Semaphorin3A signaling mediated by Fyn-dependent tyrosine phosphorylation
RT   of collapsin response mediator protein 2 at tyrosine 32.";
RL   J. Biol. Chem. 284:27393-27401(2009).
RN   [19]
RP   INTERACTION WITH CLN6.
RX   PubMed=19235893; DOI=10.1002/jnr.22032;
RA   Benedict J.W., Getty A.L., Wishart T.M., Gillingwater T.H., Pearce D.A.;
RT   "Protein product of CLN6 gene responsible for variant late-onset infantile
RT   neuronal ceroid lipofuscinosis interacts with CRMP-2.";
RL   J. Neurosci. Res. 87:2157-2166(2009).
RN   [20]
RP   FUNCTION IN ENDOCYTOSIS, INTERACTION WITH MICALL1, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=20801876; DOI=10.1074/jbc.c110.166066;
RA   Rahajeng J., Giridharan S.S., Naslavsky N., Caplan S.;
RT   "Collapsin response mediator protein-2 (Crmp2) regulates trafficking by
RT   linking endocytic regulatory proteins to dynein motors.";
RL   J. Biol. Chem. 285:31918-31922(2010).
RN   [21]
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   [22]
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   [23]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-509; THR-514; SER-517;
RP   SER-518 AND SER-522, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   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   [24]
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   [25]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-509, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [26]
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   [27]
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   [28]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 12-490, AND SUBUNIT.
RX   PubMed=17250651; DOI=10.1111/j.1471-4159.2006.04401.x;
RA   Stenmark P., Ogg D., Flodin S., Flores A., Kotenyova T., Nyman T.,
RA   Nordlund P., Kursula P.;
RT   "The structure of human collapsin response mediator protein 2, a regulator
RT   of axonal growth.";
RL   J. Neurochem. 101:906-917(2007).
RN   [29]
RP   VARIANT [LARGE SCALE ANALYSIS] CYS-481.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
CC   -!- FUNCTION: Plays a role in neuronal development and polarity, as well as
CC       in axon growth and guidance, neuronal growth cone collapse and cell
CC       migration. Necessary for signaling by class 3 semaphorins and
CC       subsequent remodeling of the cytoskeleton. May play a role in
CC       endocytosis. {ECO:0000269|PubMed:11477421, ECO:0000269|PubMed:15466863,
CC       ECO:0000269|PubMed:20801876}.
CC   -!- SUBUNIT: Homotetramer, and heterotetramer with CRMP1, DPYSL3, DPYSL4 or
CC       DPYSL5. Interacts through its C-terminus with the C-terminus of
CC       CYFIP1/SRA1. Interacts with HTR4. Interacts with CLN6. Interacts with
CC       MICALL1. {ECO:0000269|PubMed:14685275, ECO:0000269|PubMed:16260607,
CC       ECO:0000269|PubMed:17250651, ECO:0000269|PubMed:19235893,
CC       ECO:0000269|PubMed:20801876}.
CC   -!- INTERACTION:
CC       Q16555; Q8NFD5: ARID1B; NbExp=2; IntAct=EBI-1104711, EBI-679921;
CC       Q16555; Q14194: CRMP1; NbExp=5; IntAct=EBI-1104711, EBI-473101;
CC       Q16555; Q16555: DPYSL2; NbExp=7; IntAct=EBI-1104711, EBI-1104711;
CC       Q16555; Q14195: DPYSL3; NbExp=7; IntAct=EBI-1104711, EBI-1104726;
CC       Q16555; Q14195-2: DPYSL3; NbExp=10; IntAct=EBI-1104711, EBI-10232496;
CC       Q16555; Q8IXW6: DPYSL3; NbExp=3; IntAct=EBI-1104711, EBI-10262612;
CC       Q16555; O14531: DPYSL4; NbExp=4; IntAct=EBI-1104711, EBI-719542;
CC       Q16555; Q9BPU6: DPYSL5; NbExp=17; IntAct=EBI-1104711, EBI-724653;
CC       Q16555; Q9H8Y8: GORASP2; NbExp=15; IntAct=EBI-1104711, EBI-739467;
CC       Q16555; P42858: HTT; NbExp=3; IntAct=EBI-1104711, EBI-466029;
CC       Q16555; Q9BYB0: SHANK3; NbExp=2; IntAct=EBI-1104711, EBI-1752330;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:20801876}.
CC       Cytoplasm, cytoskeleton {ECO:0000269|PubMed:20801876}. Membrane
CC       {ECO:0000269|PubMed:20801876}. Note=Tightly but non-covalently
CC       associated with membranes.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q16555-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q16555-2; Sequence=VSP_044941;
CC   -!- TISSUE SPECIFICITY: Ubiquitous.
CC   -!- PTM: 3F4, a monoclonal antibody which strongly stains neurofibrillary
CC       tangles in Alzheimer disease brains, specifically labels DPYSL2 when
CC       phosphorylated on Ser-518, Ser-522 and Thr-509.
CC       {ECO:0000269|PubMed:10757975, ECO:0000269|PubMed:15466863}.
CC   -!- PTM: Phosphorylation at Thr-514 by GSK3B abolishes tubulin-binding
CC       leading to destabilization of microtubule assembly in axons and
CC       neurodegeneration (By similarity). Phosphorylation by DYRK2 at Ser-522
CC       is required for subsequent phosphorylation by GSK3B. {ECO:0000250,
CC       ECO:0000269|PubMed:10757975, ECO:0000269|PubMed:15466863}.
CC   -!- SIMILARITY: Belongs to the metallo-dependent hydrolases superfamily.
CC       Hydantoinase/dihydropyrimidinase family. {ECO:0000305}.
CC   -!- CAUTION: Lacks most of the conserved residues that are essential for
CC       binding the metal cofactor and hence for dihydropyrimidinase activity.
CC       Its enzyme activity is therefore unsure. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; U17279; AAA93202.1; -; mRNA.
DR   EMBL; D78013; BAA11191.1; -; mRNA.
DR   EMBL; U97105; AAC05793.1; -; mRNA.
DR   EMBL; AB020777; BAA86991.1; -; Genomic_DNA.
DR   EMBL; AK291287; BAF83976.1; -; mRNA.
DR   EMBL; AK299077; BAG61143.1; -; mRNA.
DR   EMBL; AC015564; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC015743; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471080; EAW63573.1; -; Genomic_DNA.
DR   EMBL; CH471080; EAW63574.1; -; Genomic_DNA.
DR   EMBL; BC056408; AAH56408.1; -; mRNA.
DR   EMBL; BC067109; AAH67109.1; -; mRNA.
DR   CCDS; CCDS59096.1; -. [Q16555-2]
DR   CCDS; CCDS6051.1; -. [Q16555-1]
DR   PIR; JC5317; JC5317.
DR   RefSeq; NP_001184222.1; NM_001197293.2.
DR   RefSeq; NP_001231533.1; NM_001244604.2. [Q16555-2]
DR   RefSeq; NP_001377.1; NM_001386.6. [Q16555-1]
DR   PDB; 2GSE; X-ray; 2.40 A; A/B/C/D=13-490.
DR   PDB; 2VM8; X-ray; 1.90 A; A/B/C/D=13-490.
DR   PDB; 5LXX; X-ray; 1.25 A; A/B=13-490.
DR   PDB; 5MKV; X-ray; 1.80 A; A/B/C/D=13-516.
DR   PDB; 5MLE; X-ray; 2.48 A; A/C=13-516.
DR   PDB; 5X1A; X-ray; 1.82 A; A=1-525.
DR   PDB; 5X1C; X-ray; 2.10 A; A/B=13-490.
DR   PDB; 5X1D; X-ray; 2.20 A; A=1-525.
DR   PDB; 5YZ5; X-ray; 1.80 A; A=1-525.
DR   PDB; 5YZA; X-ray; 2.30 A; A=1-525.
DR   PDB; 5YZB; X-ray; 2.80 A; A=1-525.
DR   PDB; 6JV9; X-ray; 2.26 A; A/B/C/D=1-532.
DR   PDB; 6JVB; X-ray; 2.00 A; A/B/C/D=1-532.
DR   PDB; 7X68; X-ray; 1.80 A; A=1-525.
DR   PDB; 8DNM; EM; 2.76 A; A/B/C/D=1-572.
DR   PDBsum; 2GSE; -.
DR   PDBsum; 2VM8; -.
DR   PDBsum; 5LXX; -.
DR   PDBsum; 5MKV; -.
DR   PDBsum; 5MLE; -.
DR   PDBsum; 5X1A; -.
DR   PDBsum; 5X1C; -.
DR   PDBsum; 5X1D; -.
DR   PDBsum; 5YZ5; -.
DR   PDBsum; 5YZA; -.
DR   PDBsum; 5YZB; -.
DR   PDBsum; 6JV9; -.
DR   PDBsum; 6JVB; -.
DR   PDBsum; 7X68; -.
DR   PDBsum; 8DNM; -.
DR   AlphaFoldDB; Q16555; -.
DR   EMDB; EMD-27574; -.
DR   SMR; Q16555; -.
DR   BioGRID; 108142; 232.
DR   FunCoup; Q16555; 1360.
DR   IntAct; Q16555; 66.
DR   MINT; Q16555; -.
DR   STRING; 9606.ENSP00000427985; -.
DR   ChEMBL; CHEMBL4295834; -.
DR   DrugBank; DB11638; Artenimol.
DR   DrugBank; DB06218; Lacosamide.
DR   DrugCentral; Q16555; -.
DR   MEROPS; M38.975; -.
DR   TCDB; 8.A.228.1.1; the collapsin response mediator protein 2 (crmp2) family.
DR   GlyCosmos; Q16555; 6 sites, 1 glycan.
DR   GlyGen; Q16555; 13 sites, 4 N-linked glycans (3 sites), 1 O-linked glycan (8 sites).
DR   iPTMnet; Q16555; -.
DR   MetOSite; Q16555; -.
DR   PhosphoSitePlus; Q16555; -.
DR   SwissPalm; Q16555; -.
DR   BioMuta; DPYSL2; -.
DR   DMDM; 3122051; -.
DR   REPRODUCTION-2DPAGE; IPI00257508; -.
DR   REPRODUCTION-2DPAGE; Q16555; -.
DR   CPTAC; CPTAC-60; -.
DR   CPTAC; CPTAC-61; -.
DR   jPOST; Q16555; -.
DR   MassIVE; Q16555; -.
DR   PaxDb; 9606-ENSP00000309539; -.
DR   PeptideAtlas; Q16555; -.
DR   ProteomicsDB; 4921; -.
DR   ProteomicsDB; 60912; -. [Q16555-1]
DR   Pumba; Q16555; -.
DR   TopDownProteomics; Q16555-1; -. [Q16555-1]
DR   ABCD; Q16555; 1 sequenced antibody.
DR   Antibodypedia; 1039; 657 antibodies from 42 providers.
DR   DNASU; 1808; -.
DR   Ensembl; ENST00000311151.9; ENSP00000309539.5; ENSG00000092964.18. [Q16555-1]
DR   Ensembl; ENST00000523027.1; ENSP00000431117.1; ENSG00000092964.18. [Q16555-2]
DR   GeneID; 1808; -.
DR   KEGG; hsa:1808; -.
DR   UCSC; uc003xfb.3; human. [Q16555-1]
DR   AGR; HGNC:3014; -.
DR   ClinPGx; PA27472; -.
DR   CTD; 1808; -.
DR   DisGeNET; 1808; -.
DR   GeneCards; DPYSL2; -.
DR   HGNC; HGNC:3014; DPYSL2.
DR   HPA; ENSG00000092964; Tissue enhanced (brain).
DR   MalaCards; DPYSL2; -.
DR   MIM; 602463; gene.
DR   OpenTargets; ENSG00000092964; -.
DR   Orphanet; 178469; Autosomal dominant non-syndromic intellectual disability.
DR   VEuPathDB; HostDB:ENSG00000092964; -.
DR   eggNOG; KOG2584; Eukaryota.
DR   GeneTree; ENSGT01030000234527; -.
DR   HOGENOM; CLU_015572_2_2_1; -.
DR   InParanoid; Q16555; -.
DR   OrthoDB; 10258955at2759; -.
DR   PAN-GO; Q16555; 0 GO annotations based on evolutionary models.
DR   PhylomeDB; Q16555; -.
DR   PathwayCommons; Q16555; -.
DR   Reactome; R-HSA-399956; CRMPs in Sema3A signaling.
DR   Reactome; R-HSA-437239; Recycling pathway of L1.
DR   SignaLink; Q16555; -.
DR   SIGNOR; Q16555; -.
DR   Agora; ENSG00000092964; -.
DR   BioGRID-ORCS; 1808; 16 hits in 1153 CRISPR screens.
DR   CD-CODE; DEE660B4; Stress granule.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; DPYSL2; human.
DR   EvolutionaryTrace; Q16555; -.
DR   GeneWiki; DPYSL2; -.
DR   GenomeRNAi; 1808; -.
DR   Pharos; Q16555; Tbio.
DR   PRO; PR:Q16555; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; Q16555; protein.
DR   Bgee; ENSG00000092964; Expressed in inferior vagus X ganglion and 207 other cell types or tissues.
DR   ExpressionAtlas; Q16555; baseline and differential.
DR   GO; GO:0005929; C:cilium; IDA:HPA.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA.
DR   GO; GO:0072686; C:mitotic spindle; IDA:HPA.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0004157; F:dihydropyrimidinase activity; TAS:ProtInc.
DR   GO; GO:0016812; F:hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides; IBA:GO_Central.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR   GO; GO:0007010; P:cytoskeleton organization; ISS:UniProtKB.
DR   GO; GO:0006897; P:endocytosis; IMP:UniProtKB.
DR   GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR   GO; GO:0006139; P:nucleobase-containing compound metabolic process; TAS:ProtInc.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   CDD; cd01314; D-HYD; 1.
DR   FunFam; 2.30.40.10:FF:000021; Dihydropyrimidinase-related protein 2; 1.
DR   FunFam; 2.30.40.10:FF:000022; Dihydropyrimidinase-related protein 2; 1.
DR   FunFam; 3.20.20.140:FF:000174; Dihydropyrimidinase-related protein 2; 1.
DR   Gene3D; 3.20.20.140; Metal-dependent hydrolases; 1.
DR   Gene3D; 2.30.40.10; Urease, subunit C, domain 1; 1.
DR   InterPro; IPR006680; Amidohydro-rel.
DR   InterPro; IPR011778; Hydantoinase/dihydroPyrase.
DR   InterPro; IPR011059; Metal-dep_hydrolase_composite.
DR   InterPro; IPR032466; Metal_Hydrolase.
DR   InterPro; IPR050378; Metallo-dep_Hydrolases_sf.
DR   NCBIfam; TIGR02033; D-hydantoinase; 1.
DR   PANTHER; PTHR11647:SF56; DIHYDROPYRIMIDINASE-RELATED PROTEIN 2; 1.
DR   PANTHER; PTHR11647; HYDRANTOINASE/DIHYDROPYRIMIDINASE FAMILY MEMBER; 1.
DR   Pfam; PF01979; Amidohydro_1; 1.
DR   SUPFAM; SSF51338; Composite domain of metallo-dependent hydrolases; 2.
DR   SUPFAM; SSF51556; Metallo-dependent hydrolases; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cytoplasm; Cytoskeleton;
KW   Developmental protein; Differentiation; Direct protein sequencing;
KW   Membrane; Methylation; Neurogenesis; Phosphoprotein;
KW   Proteomics identification; Reference proteome; S-nitrosylation.
FT   CHAIN           1..572
FT                   /note="Dihydropyrimidinase-related protein 2"
FT                   /id="PRO_0000165913"
FT   REGION          512..537
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        512..525
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         32
FT                   /note="Phosphotyrosine; by FYN"
FT                   /evidence="ECO:0000269|PubMed:19652227"
FT   MOD_RES         258
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         259
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P47942"
FT   MOD_RES         431
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         465
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         499
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         504
FT                   /note="S-nitrosocysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P47942"
FT   MOD_RES         507
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         509
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:10757975,
FT                   ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT   MOD_RES         512
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         514
FT                   /note="Phosphothreonine; by GSK3-beta"
FT                   /evidence="ECO:0007744|PubMed:21406692"
FT   MOD_RES         517
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21406692"
FT   MOD_RES         518
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:10757975,
FT                   ECO:0007744|PubMed:21406692"
FT   MOD_RES         521
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         522
FT                   /note="Phosphoserine; by DYRK2"
FT                   /evidence="ECO:0000269|PubMed:10757975,
FT                   ECO:0000269|PubMed:15466863, ECO:0007744|PubMed:16964243,
FT                   ECO:0007744|PubMed:21406692"
FT   MOD_RES         537
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         540
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         542
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   MOD_RES         555
FT                   /note="Phosphothreonine; by ROCK2"
FT                   /evidence="ECO:0000250|UniProtKB:O02675"
FT   MOD_RES         565
FT                   /note="Asymmetric dimethylarginine"
FT                   /evidence="ECO:0000250|UniProtKB:O08553"
FT   VAR_SEQ         1..36
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_044941"
FT   VARIANT         118
FT                   /note="A -> T (in dbSNP:rs2228979)"
FT                   /id="VAR_022016"
FT   VARIANT         481
FT                   /note="R -> C (in a colorectal cancer sample; somatic
FT                   mutation; dbSNP:rs1337153084)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_036316"
FT   MUTAGEN         71
FT                   /note="D->N: Inhibits axon outgrowth formation in
FT                   hippocampal neurons and decreases binding to CYFIP1."
FT                   /evidence="ECO:0000269|PubMed:16260607"
FT   MUTAGEN         507
FT                   /note="S->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   MUTAGEN         509
FT                   /note="T->A: Greatly diminishes binding to 3F4 antibody."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   MUTAGEN         512
FT                   /note="T->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   MUTAGEN         514
FT                   /note="T->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   MUTAGEN         517
FT                   /note="S->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   MUTAGEN         518
FT                   /note="S->A: Greatly diminishes binding to 3F4 antibody."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   MUTAGEN         521
FT                   /note="T->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   MUTAGEN         522
FT                   /note="S->A: Greatly diminishes binding to 3F4 antibody."
FT                   /evidence="ECO:0000269|PubMed:10757975"
FT   STRAND          17..21
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          23..25
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          30..32
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          34..38
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          41..48
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          53..55
FT                   /evidence="ECO:0007829|PDB:2VM8"
FT   STRAND          56..59
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          64..67
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          69..72
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           89..98
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          101..108
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           116..130
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          132..140
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           148..159
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          163..168
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   TURN            171..173
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           178..191
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          194..198
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           202..214
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           220..226
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           229..246
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          250..255
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           258..269
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          274..279
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           280..284
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           287..291
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           295..300
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           313..322
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          324..326
FT                   /evidence="ECO:0007829|PDB:8DNM"
FT   HELIX           338..341
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           342..344
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           348..350
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   TURN            358..360
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           361..369
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   TURN            370..373
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           377..384
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           386..391
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   TURN            395..397
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          409..419
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   TURN            422..424
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          425..428
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   TURN            433..436
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          438..448
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   STRAND          451..455
FT                   /evidence="ECO:0007829|PDB:5LXX"
FT   HELIX           476..486
FT                   /evidence="ECO:0007829|PDB:5LXX"
SQ   SEQUENCE   572 AA;  62294 MW;  5CDB6CF7F5C308AD CRC64;
     MSYQGKKNIP RITSDRLLIK GGKIVNDDQS FYADIYMEDG LIKQIGENLI VPGGVKTIEA
     HSRMVIPGGI DVHTRFQMPD QGMTSADDFF QGTKAALAGG TTMIIDHVVP EPGTSLLAAF
     DQWREWADSK SCCDYSLHVD ISEWHKGIQE EMEALVKDHG VNSFLVYMAF KDRFQLTDCQ
     IYEVLSVIRD IGAIAQVHAE NGDIIAEEQQ RILDLGITGP EGHVLSRPEE VEAEAVNRAI
     TIANQTNCPL YITKVMSKSS AEVIAQARKK GTVVYGEPIT ASLGTDGSHY WSKNWAKAAA
     FVTSPPLSPD PTTPDFLNSL LSCGDLQVTG SAHCTFNTAQ KAVGKDNFTL IPEGTNGTEE
     RMSVIWDKAV VTGKMDENQF VAVTSTNAAK VFNLYPRKGR IAVGSDADLV IWDPDSVKTI
     SAKTHNSSLE YNIFEGMECR GSPLVVISQG KIVLEDGTLH VTEGSGRYIP RKPFPDFVYK
     RIKARSRLAE LRGVPRGLYD GPVCEVSVTP KTVTPASSAK TSPAKQQAPP VRNLHQSGFS
     LSGAQIDDNI PRRTTQRIVA PPGGRANITS LG
//
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";
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; X01677; CAA25833.1; -; mRNA.
DR   EMBL; M17851; AAA86283.1; -; mRNA.
DR   EMBL; M33197; AAA52518.1; -; mRNA.
DR   EMBL; J02642; AAA52496.1; -; mRNA.
DR   EMBL; J04038; AAA53191.1; -; Genomic_DNA.
DR   EMBL; X53778; CAA37794.1; -; mRNA.
DR   EMBL; AF261085; AAF99678.1; -; mRNA.
DR   EMBL; AY007133; AAG01996.1; -; mRNA.
DR   EMBL; AB062273; BAB93466.1; -; mRNA.
DR   EMBL; BT006893; AAP35539.1; -; mRNA.
DR   EMBL; AY340484; AAP88932.1; -; Genomic_DNA.
DR   EMBL; CR407671; CAG28599.1; -; mRNA.
DR   EMBL; AC006064; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471116; EAW88787.1; -; Genomic_DNA.
DR   EMBL; BC001601; AAH01601.1; -; mRNA.
DR   EMBL; BC004109; AAH04109.1; -; mRNA.
DR   EMBL; BC009081; AAH09081.1; -; mRNA.
DR   EMBL; BC013310; AAH13310.1; -; mRNA.
DR   EMBL; BC023632; AAH23632.1; -; mRNA.
DR   EMBL; BC025925; AAH25925.1; -; mRNA.
DR   EMBL; BC026907; AAH26907.1; -; mRNA.
DR   EMBL; BC029618; AAH29618.1; -; mRNA.
DR   EMBL; BC083511; AAH83511.1; -; mRNA.
DR   CCDS; CCDS58201.1; -. [P04406-2]
DR   CCDS; CCDS8549.1; -. [P04406-1]
DR   PIR; A31988; DEHUG3.
DR   RefSeq; NP_001243728.1; NM_001256799.3. [P04406-2]
DR   RefSeq; NP_001276674.1; NM_001289745.3. [P04406-1]
DR   RefSeq; NP_001276675.1; NM_001289746.2. [P04406-1]
DR   RefSeq; NP_002037.2; NM_002046.5. [P04406-1]
DR   PDB; 1U8F; X-ray; 1.75 A; O/P/Q/R=1-335.
DR   PDB; 1ZNQ; X-ray; 2.50 A; O/P/Q/R=1-335.
DR   PDB; 3GPD; X-ray; 3.50 A; G/R=2-335.
DR   PDB; 4WNC; X-ray; 1.99 A; A/B/C/D/E/F/G/O=1-335.
DR   PDB; 4WNI; X-ray; 2.30 A; A/B/C/O=1-335.
DR   PDB; 6ADE; X-ray; 3.15 A; A/B/C=1-335.
DR   PDB; 6IQ6; X-ray; 2.29 A; A/B/C/D/E/F/G/H=1-335.
DR   PDB; 6M61; X-ray; 1.82 A; O/P/Q/R=1-335.
DR   PDB; 6YND; X-ray; 1.52 A; A/B/C/D/E/F/G/H=1-335.
DR   PDB; 6YNE; X-ray; 1.85 A; A/B/C/D=1-335.
DR   PDB; 6YNF; X-ray; 2.39 A; A/B/C/D/E/F/G/H=2-335.
DR   PDB; 6YNH; X-ray; 2.62 A; B/D/F/G=1-335.
DR   PDB; 8DNS; EM; 3.22 A; O/P/Q/R=1-335.
DR   PDB; 8G12; EM; 2.17 A; A/B/C/D=2-335.
DR   PDB; 8G13; EM; 2.30 A; A/B/C/D=2-335.
DR   PDB; 8G14; EM; 2.30 A; A/B/C/D=2-335.
DR   PDB; 8G15; EM; 2.07 A; A/B/C/D=2-335.
DR   PDB; 8G16; EM; 2.07 A; A/B/C/D=2-335.
DR   PDB; 8G17; EM; 1.98 A; A/B/C/D=2-335.
DR   PDB; 8P5F; X-ray; 1.82 A; AAA/DDD/EEE/GGG=1-335.
DR   PDB; 9L3E; X-ray; 1.77 A; O/P/Q/R=1-335.
DR   PDBsum; 1U8F; -.
DR   PDBsum; 1ZNQ; -.
DR   PDBsum; 3GPD; -.
DR   PDBsum; 4WNC; -.
DR   PDBsum; 4WNI; -.
DR   PDBsum; 6ADE; -.
DR   PDBsum; 6IQ6; -.
DR   PDBsum; 6M61; -.
DR   PDBsum; 6YND; -.
DR   PDBsum; 6YNE; -.
DR   PDBsum; 6YNF; -.
DR   PDBsum; 6YNH; -.
DR   PDBsum; 8DNS; -.
DR   PDBsum; 8G12; -.
DR   PDBsum; 8G13; -.
DR   PDBsum; 8G14; -.
DR   PDBsum; 8G15; -.
DR   PDBsum; 8G16; -.
DR   PDBsum; 8G17; -.
DR   PDBsum; 8P5F; -.
DR   PDBsum; 9L3E; -.
DR   AlphaFoldDB; P04406; -.
DR   EMDB; EMD-27579; -.
DR   EMDB; EMD-29659; -.
DR   EMDB; EMD-29660; -.
DR   EMDB; EMD-29661; -.
DR   EMDB; EMD-29662; -.
DR   EMDB; EMD-29663; -.
DR   EMDB; EMD-29664; -.
DR   EMDB; EMD-32162; -.
DR   SMR; P04406; -.
DR   BioGRID; 108868; 748.
DR   ComplexPortal; CPX-2476; GAIT complex.
DR   CORUM; P04406; -.
DR   DIP; DIP-32521N; -.
DR   FunCoup; P04406; 1599.
DR   IntAct; P04406; 269.
DR   MINT; P04406; -.
DR   STRING; 9606.ENSP00000380070; -.
DR   BindingDB; P04406; -.
DR   ChEMBL; CHEMBL2284; -.
DR   DrugBank; DB07347; 4-(2-Aminoethyl)Benzenesulfonyl Fluoride.
DR   DrugBank; DB02059; Adenosine-5-Diphosphoribose.
DR   DrugBank; DB11638; Artenimol.
DR   DrugBank; DB09130; Copper.
DR   DrugBank; DB00157; NADH.
DR   DrugBank; DB12879; Omigapil.
DR   DrugBank; DB03893; Thionicotinamide-Adenine-Dinucleotide.
DR   DrugBank; DB09092; Xanthinol.
DR   DrugCentral; P04406; -.
DR   MoonDB; P04406; Curated.
DR   MoonProt; P04406; -.
DR   GlyConnect; 1941; 7 N-Linked glycans (2 sites).
DR   GlyCosmos; P04406; 6 sites, 9 glycans.
DR   GlyGen; P04406; 4 sites, 18 N-linked glycans (2 sites), 2 O-linked glycans (2 sites).
DR   iPTMnet; P04406; -.
DR   MetOSite; P04406; -.
DR   PhosphoSitePlus; P04406; -.
DR   SwissPalm; P04406; -.
DR   BioMuta; GAPDH; -.
DR   DMDM; 120649; -.
DR   OGP; P04406; -.
DR   REPRODUCTION-2DPAGE; IPI00219018; -.
DR   REPRODUCTION-2DPAGE; P04406; -.
DR   CPTAC; CPTAC-2733; -.
DR   CPTAC; CPTAC-5855; -.
DR   CPTAC; CPTAC-5880; -.
DR   CPTAC; CPTAC-5942; -.
DR   jPOST; P04406; -.
DR   MassIVE; P04406; -.
DR   PaxDb; 9606-ENSP00000229239; -.
DR   PeptideAtlas; P04406; -.
DR   PRIDE; P04406; -.
DR   ProteomicsDB; 18491; -.
DR   ProteomicsDB; 51703; -. [P04406-1]
DR   Pumba; P04406; -.
DR   TopDownProteomics; P04406-1; -. [P04406-1]
DR   ABCD; P04406; 1 sequenced antibody.
DR   Antibodypedia; 3923; 2690 antibodies from 59 providers.
DR   CPTC; P04406; 1 antibody.
DR   DNASU; 2597; -.
DR   Ensembl; ENST00000229239.10; ENSP00000229239.5; ENSG00000111640.16. [P04406-1]
DR   Ensembl; ENST00000396858.5; ENSP00000380067.1; ENSG00000111640.16. [P04406-2]
DR   Ensembl; ENST00000396859.5; ENSP00000380068.1; ENSG00000111640.16. [P04406-1]
DR   Ensembl; ENST00000396861.5; ENSP00000380070.1; ENSG00000111640.16. [P04406-1]
DR   Ensembl; ENST00000619601.1; ENSP00000478864.1; ENSG00000111640.16. [P04406-2]
DR   GeneID; 2597; -.
DR   KEGG; hsa:2597; -.
DR   MANE-Select; ENST00000229239.10; ENSP00000229239.5; NM_002046.7; NP_002037.2.
DR   UCSC; uc031qfw.3; human. [P04406-1]
DR   AGR; HGNC:4141; -.
DR   ClinPGx; PA28554; -.
DR   CTD; 2597; -.
DR   DisGeNET; 2597; -.
DR   GeneCards; GAPDH; -.
DR   HGNC; HGNC:4141; GAPDH.
DR   HPA; ENSG00000111640; Group enriched (skeletal muscle, tongue).
DR   MalaCards; GAPDH; -.
DR   MIM; 138400; gene.
DR   OpenTargets; ENSG00000111640; -.
DR   VEuPathDB; HostDB:ENSG00000111640; -.
DR   eggNOG; KOG0657; Eukaryota.
DR   GeneTree; ENSGT00940000153298; -.
DR   HOGENOM; CLU_030140_0_3_1; -.
DR   InParanoid; P04406; -.
DR   OMA; YGYTCNM; -.
DR   OrthoDB; 9528699at2759; -.
DR   PAN-GO; P04406; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P04406; -.
DR   BioCyc; MetaCyc:HS03433-MONOMER; -.
DR   BRENDA; 1.2.1.12; 2681.
DR   PathwayCommons; P04406; -.
DR   Reactome; R-HSA-70171; Glycolysis.
DR   Reactome; R-HSA-70263; Gluconeogenesis.
DR   SABIO-RK; P04406; -.
DR   SignaLink; P04406; -.
DR   SIGNOR; P04406; -.
DR   UniPathway; UPA00109; UER00184.
DR   Agora; ENSG00000111640; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 2597; 626 hits in 1149 CRISPR screens.
DR   CD-CODE; 232F8A39; P-body.
DR   CD-CODE; 91857CE7; Nucleolus.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; GAPDH; human.
DR   EvolutionaryTrace; P04406; -.
DR   GeneWiki; Glyceraldehyde_3-phosphate_dehydrogenase; -.
DR   GenomeRNAi; 2597; -.
DR   Pharos; P04406; Tchem.
DR   PRO; PR:P04406; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; P04406; protein.
DR   Bgee; ENSG00000111640; Expressed in frontal pole and 218 other cell types or tissues.
DR   ExpressionAtlas; P04406; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0097452; C:GAIT complex; IDA:UniProtKB.
DR   GO; GO:0005811; C:lipid droplet; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0015630; C:microtubule cytoskeleton; ISS:UniProtKB.
DR   GO; GO:0031965; C:nuclear membrane; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:CACAO.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:1990904; C:ribonucleoprotein complex; IDA:UniProtKB.
DR   GO; GO:0031982; C:vesicle; HDA:UniProtKB.
DR   GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR   GO; GO:0097718; F:disordered domain specific binding; IPI:CAFA.
DR   GO; GO:0004365; F:glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity; ISS:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0008017; F:microtubule binding; ISS:UniProtKB.
DR   GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR   GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR   GO; GO:0035605; F:peptidyl-cysteine S-nitrosylase activity; ISS:UniProtKB.
DR   GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IDA:UniProtKB.
DR   GO; GO:0061621; P:canonical glycolysis; IDA:UniProt.
DR   GO; GO:0071346; P:cellular response to type II interferon; IDA:UniProtKB.
DR   GO; GO:0050832; P:defense response to fungus; IDA:UniProtKB.
DR   GO; GO:0006096; P:glycolytic process; IBA:GO_Central.
DR   GO; GO:0051873; P:killing by host of symbiont cells; IDA:UniProtKB.
DR   GO; GO:0031640; P:killing of cells of another organism; IDA:UniProtKB.
DR   GO; GO:0000226; P:microtubule cytoskeleton organization; ISS:UniProtKB.
DR   GO; GO:0010951; P:negative regulation of endopeptidase activity; IDA:UniProtKB.
DR   GO; GO:0017148; P:negative regulation of translation; IDA:UniProtKB.
DR   GO; GO:0051402; P:neuron apoptotic process; ISS:UniProtKB.
DR   GO; GO:0035606; P:peptidyl-cysteine S-trans-nitrosylation; ISS:UniProtKB.
DR   GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:UniProtKB.
DR   GO; GO:0001819; P:positive regulation of cytokine production; IDA:UniProtKB.
DR   GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProtKB.
DR   GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR   GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR   CDD; cd18126; GAPDH_I_C; 1.
DR   CDD; cd05214; GAPDH_I_N; 1.
DR   FunFam; 3.30.360.10:FF:000001; Glyceraldehyde-3-phosphate dehydrogenase; 1.
DR   FunFam; 3.40.50.720:FF:001161; Glyceraldehyde-3-phosphate dehydrogenase; 1.
DR   Gene3D; 3.30.360.10; Dihydrodipicolinate Reductase, domain 2; 1.
DR   Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR   InterPro; IPR020831; GlycerAld/Erythrose_P_DH.
DR   InterPro; IPR020830; GlycerAld_3-P_DH_AS.
DR   InterPro; IPR020829; GlycerAld_3-P_DH_cat.
DR   InterPro; IPR020828; GlycerAld_3-P_DH_NAD(P)-bd.
DR   InterPro; IPR006424; Glyceraldehyde-3-P_DH_1.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   NCBIfam; TIGR01534; GAPDH-I; 1.
DR   PANTHER; PTHR10836; GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE; 1.
DR   PANTHER; PTHR10836:SF111; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; 1.
DR   Pfam; PF02800; Gp_dh_C; 1.
DR   Pfam; PF00044; Gp_dh_N; 1.
DR   PIRSF; PIRSF000149; GAP_DH; 1.
DR   PRINTS; PR00078; G3PDHDRGNASE.
DR   SMART; SM00846; Gp_dh_N; 1.
DR   SUPFAM; SSF55347; Glyceraldehyde-3-phosphate dehydrogenase-like, C-terminal domain; 1.
DR   SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR   PROSITE; PS00071; GAPDH; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; ADP-ribosylation; Alternative splicing;
KW   Apoptosis; Cytoplasm; Cytoskeleton; Direct protein sequencing; Glycolysis;
KW   Glycoprotein; Immunity; Innate immunity; Isopeptide bond; Membrane;
KW   Methylation; NAD; Nucleus; Oxidation; Oxidoreductase; Phosphoprotein;
KW   Proteomics identification; Reference proteome; S-nitrosylation;
KW   Transferase; Translation regulation; Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:12665801, ECO:0000269|Ref.19"
FT   CHAIN           2..335
FT                   /note="Glyceraldehyde-3-phosphate dehydrogenase"
FT                   /id="PRO_0000145486"
FT   REGION          2..148
FT                   /note="Interaction with WARS1"
FT                   /evidence="ECO:0000269|PubMed:15628863"
FT   MOTIF           245..250
FT                   /note="[IL]-x-C-x-x-[DE] motif"
FT                   /evidence="ECO:0000305|PubMed:25417112"
FT   ACT_SITE        152
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   BINDING         13..14
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         35
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         80
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         122
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   BINDING         151..153
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         182
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         211..212
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         234
FT                   /ligand="D-glyceraldehyde 3-phosphate"
FT                   /ligand_id="ChEBI:CHEBI:59776"
FT                   /evidence="ECO:0000250|UniProtKB:P22513"
FT   BINDING         316
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16239728,
FT                   ECO:0000269|PubMed:16510976"
FT   SITE            179
FT                   /note="Activates thiol group during catalysis"
FT                   /evidence="ECO:0000305|PubMed:16239728,
FT                   ECO:0000305|PubMed:16510976"
FT   MOD_RES         5
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         9
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         42
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0007744|PubMed:15592455"
FT   MOD_RES         46
FT                   /note="Methionine sulfoxide; in vitro"
FT                   /evidence="ECO:0000305|PubMed:25086035"
FT   MOD_RES         61
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         64
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         66
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         70
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         75
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:18183946,
FT                   ECO:0007744|PubMed:20068231"
FT   MOD_RES         83
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17081983,
FT                   ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT   MOD_RES         122
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         148
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         149
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         151
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         152
FT                   /note="ADP-ribosylcysteine; by autocatalysis; in
FT                   irreversibly inhibited form"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         152
FT                   /note="Cysteine persulfide"
FT                   /evidence="ECO:0000250|UniProtKB:P16858"
FT   MOD_RES         152
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         152
FT                   /note="S-nitrosocysteine; in reversibly inhibited form"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         153
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         155
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         177
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         182
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         184
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:24275569"
FT   MOD_RES         194
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         194
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         194
FT                   /note="N6-malonyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:21908771"
FT   MOD_RES         211
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         215
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         215
FT                   /note="N6-malonyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:21908771"
FT   MOD_RES         219
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         225
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         227
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         227
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         229
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:18183946,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         237
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         241
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:24275569"
FT   MOD_RES         247
FT                   /note="S-(2-succinyl)cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P04797"
FT   MOD_RES         247
FT                   /note="S-nitrosocysteine"
FT                   /evidence="ECO:0000269|PubMed:22771119,
FT                   ECO:0000269|PubMed:25417112"
FT   MOD_RES         254
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         260
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         263
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         312
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:18183946,
FT                   ECO:0007744|PubMed:19690332"
FT   MOD_RES         316
FT                   /note="Deamidated asparagine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   MOD_RES         333
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         334
FT                   /note="N6,N6-dimethyllysine"
FT                   /evidence="ECO:0000269|PubMed:18183946"
FT   CARBOHYD        197
FT                   /note="(Microbial infection) N-beta-linked (GlcNAc)
FT                   arginine"
FT                   /evidence="ECO:0000269|PubMed:28522607"
FT   CARBOHYD        200
FT                   /note="(Microbial infection) N-beta-linked (GlcNAc)
FT                   arginine"
FT                   /evidence="ECO:0000269|PubMed:28522607"
FT   CROSSLNK        186
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2)"
FT                   /evidence="ECO:0007744|PubMed:28112733"
FT   VAR_SEQ         1..42
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_047289"
FT   VARIANT         22
FT                   /note="A -> G (in dbSNP:rs45541435)"
FT                   /evidence="ECO:0000269|Ref.12"
FT                   /id="VAR_018889"
FT   VARIANT         251
FT                   /note="K -> N (in dbSNP:rs1062429)"
FT                   /id="VAR_049218"
FT   MUTAGEN         46
FT                   /note="M->L: Drastic reduction of the extent and
FT                   significant prolongation of the lag phase of free radical-
FT                   induced aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         105
FT                   /note="M->L: Increased resistance to free radical-induced
FT                   aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         152
FT                   /note="C->S: Markedly reduced glycolytic activity; when
FT                   associated with S-156 and S-247. Forms free radical-induced
FT                   aggregates, but to a lesser extent than wild-type protein;
FT                   when associated with S-156 and S-247. Abolished interaction
FT                   with TRAF2 and TRAF3."
FT                   /evidence="ECO:0000269|PubMed:23332158,
FT                   ECO:0000269|PubMed:25086035, ECO:0000269|PubMed:27387501"
FT   MUTAGEN         156
FT                   /note="C->S: Markedly reduced glycolytic activity; when
FT                   associated with S-152 and S-247. Forms free radical-induced
FT                   aggregates, but to a lesser extent than wild-type protein;
FT                   when associated with S-156 and S-247."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         196
FT                   /note="W->F: Increased free radical-induced aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         211
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         229
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         241
FT                   /note="S->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         245
FT                   /note="L->M: Inhibits S-nitrosylation of Cys-247; when
FT                   associated with M-250."
FT                   /evidence="ECO:0000269|PubMed:25417112"
FT   MUTAGEN         246
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         247
FT                   /note="C->S: Markedly reduced glycolytic activity; when
FT                   associated with S-152 and S-156. Forms free radical-induced
FT                   aggregates, but to a lesser extent than wild-type protein;
FT                   when associated with S-156 and S-247."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   MUTAGEN         250
FT                   /note="E->M: Inhibits S-nitrosylation of Cys-247; when
FT                   associated with M-245."
FT                   /evidence="ECO:0000269|PubMed:25417112"
FT   MUTAGEN         277
FT                   /note="T->A: Does not affect glycosylation by C.rodentium
FT                   protein NleB."
FT                   /evidence="ECO:0000269|PubMed:23332158"
FT   MUTAGEN         320
FT                   /note="Y->F: No effect on free radical-induced
FT                   aggregation."
FT                   /evidence="ECO:0000269|PubMed:25086035"
FT   CONFLICT        225
FT                   /note="N -> D (in Ref. 2; CAA25833)"
FT                   /evidence="ECO:0000305"
FT   STRAND          5..9
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           13..25
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          27..34
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          36..38
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           40..48
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            51..53
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          60..63
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          66..69
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          72..77
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           82..84
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           88..90
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          94..97
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          99..101
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           105..108
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           110..113
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          117..123
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          126..128
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            133..135
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           137..139
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          146..148
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           152..168
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          170..179
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          185..189
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           196..199
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            202..204
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          207..210
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           213..220
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           222..224
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          227..234
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          241..251
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           255..267
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            268..273
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          274..277
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           283..286
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          292..296
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   TURN            297..299
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          301..304
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   STRAND          307..314
FT                   /evidence="ECO:0007829|PDB:6YND"
FT   HELIX           318..333
FT                   /evidence="ECO:0007829|PDB:6YND"
SQ   SEQUENCE   335 AA;  36053 MW;  C9C135E8AE3E8744 CRC64;
     MGKVKVGVNG FGRIGRLVTR AAFNSGKVDI VAINDPFIDL NYMVYMFQYD STHGKFHGTV
     KAENGKLVIN GNPITIFQER DPSKIKWGDA GAEYVVESTG VFTTMEKAGA HLQGGAKRVI
     ISAPSADAPM FVMGVNHEKY DNSLKIISNA SCTTNCLAPL AKVIHDNFGI VEGLMTTVHA
     ITATQKTVDG PSGKLWRDGR GALQNIIPAS TGAAKAVGKV IPELNGKLTG MAFRVPTANV
     SVVDLTCRLE KPAKYDDIKK VVKQASEGPL KGILGYTEHQ VVSSDFNSDT HSSTFDAGAG
     IALNDHFVKL ISWYDNEFGY SNRVVDLMAH MASKE
//
ID   GSK3A_HUMAN             Reviewed;         483 AA.
AC   P49840; O14959;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-2000, sequence version 2.
DT   28-JAN-2026, entry version 227.
DE   RecName: Full=Glycogen synthase kinase-3 alpha;
DE            Short=GSK-3 alpha;
DE            EC=2.7.11.26;
DE   AltName: Full=Serine/threonine-protein kinase GSK3A;
DE            EC=2.7.11.1 {ECO:0000269|PubMed:22539723, ECO:0000269|PubMed:25897075};
GN   Name=GSK3A;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Foreskin;
RA   He X., Saint-Jeannet J.P., Woodgett J.R., Varmus H.E., Dawid I.B.;
RT   "Glycogen synthase kinase 3 and dorsoventral patterning in Xenopus
RT   embryos.";
RL   Submitted (MAR-1995) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Brain;
RA   Hoshino T., Kondo K., Ishiguro K., Takashima A., Imahori K.;
RT   "Isolation of cDNA clones for human glycogen synthase kinase 3alpha.";
RL   Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA   Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA   Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA   Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA   Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA   Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA   Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA   Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA   Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA   McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA   Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA   Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA   She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA   Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA   Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Eye, and Pancreas;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   FUNCTION, AND ASSOCIATION WITH DIABETES MELLITUS.
RX   PubMed=10868943; DOI=10.2337/diabetes.49.2.263;
RA   Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L.,
RA   Henry R.R.;
RT   "Potential role of glycogen synthase kinase-3 in skeletal muscle insulin
RT   resistance of type 2 diabetes.";
RL   Diabetes 49:263-271(2000).
RN   [6]
RP   ASSOCIATION WITH ALZHEIMER DISEASE, AND FUNCTION.
RX   PubMed=12761548; DOI=10.1038/nature01640;
RA   Phiel C.J., Wilson C.A., Lee V.M., Klein P.S.;
RT   "GSK-3alpha regulates production of Alzheimer's disease amyloid-beta
RT   peptides.";
RL   Nature 423:435-439(2003).
RN   [7]
RP   FUNCTION IN WNT SIGNALING, AND INTERACTION WITH AXIN1 AND
RP   CTNNB1/BETA-CATENIN.
RX   PubMed=17229088; DOI=10.1111/j.1460-9568.2006.05243.x;
RA   Asuni A.A., Hooper C., Reynolds C.H., Lovestone S., Anderton B.H.,
RA   Killick R.;
RT   "GSK3alpha exhibits beta-catenin and tau directed kinase activities that
RT   are modulated by Wnt.";
RL   Eur. J. Neurosci. 24:3387-3392(2006).
RN   [8]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=11749387; DOI=10.1021/cr000110o;
RA   Ali A., Hoeflich K.P., Woodgett J.R.;
RT   "Glycogen synthase kinase-3: properties, functions, and regulation.";
RL   Chem. Rev. 101:2527-2540(2001).
RN   [9]
RP   REVIEW ON FUNCTION.
RX   PubMed=17478001; DOI=10.1016/j.diabres.2007.01.033;
RA   Lee J., Kim M.S.;
RT   "The role of GSK3 in glucose homeostasis and the development of insulin
RT   resistance.";
RL   Diabetes Res. Clin. Pract. 77:S49-S57(2007).
RN   [10]
RP   INTERACTION WITH DDX3X AND TNFRSF10B.
RX   PubMed=18846110; DOI=10.1038/cdd.2008.124;
RA   Sun M., Song L., Li Y., Zhou T., Jope R.S.;
RT   "Identification of an antiapoptotic protein complex at death receptors.";
RL   Cell Death Differ. 15:1887-1900(2008).
RN   [11]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-72, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [13]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [14]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=19366350; DOI=10.1111/j.1476-5381.2008.00085.x;
RA   Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A.;
RT   "Glycogen synthase kinase 3: more than a namesake.";
RL   Br. J. Pharmacol. 156:885-898(2009).
RN   [15]
RP   INTERACTION WITH CTNND2.
RX   PubMed=19706605; DOI=10.1074/jbc.m109.002659;
RA   Oh M., Kim H., Yang I., Park J.H., Cong W.T., Baek M.C., Bareiss S., Ki H.,
RA   Lu Q., No J., Kwon I., Choi J.K., Kim K.;
RT   "GSK-3 phosphorylates delta-catenin and negatively regulates its stability
RT   via ubiquitination/proteosome-mediated proteolysis.";
RL   J. Biol. Chem. 284:28579-28589(2009).
RN   [16]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE
RP   ANALYSIS] AT SER-2; SER-77 AND SER-97, CLEAVAGE OF INITIATOR METHIONINE
RP   [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE
RP   SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [17]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [18]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [19]
RP   CATALYTIC ACTIVITY.
RX   PubMed=22539723; DOI=10.1126/science.1217032;
RA   Lin S.Y., Li T.Y., Liu Q., Zhang C., Li X., Chen Y., Zhang S.M., Lian G.,
RA   Liu Q., Ruan K., Wang Z., Zhang C.S., Chien K.Y., Wu J., Li Q., Han J.,
RA   Lin S.C.;
RT   "GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to
RT   autophagy.";
RL   Science 336:477-481(2012).
RN   [20]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [21]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [22]
RP   INTERACTION WITH MYCOBACTERIUM TUBERCULOSIS PTPA, AND DEPHOSPHORYLATION
RP   (MICROBIAL INFECTION).
RX   PubMed=25187516; DOI=10.1074/jbc.m114.582502;
RA   Poirier V., Bach H., Av-Gay Y.;
RT   "Mycobacterium tuberculosis promotes anti-apoptotic activity of the
RT   macrophage by PtpA protein-dependent dephosphorylation of host GSK3alpha.";
RL   J. Biol. Chem. 289:29376-29385(2014).
RN   [23]
RP   FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH RICTOR.
RX   PubMed=25897075; DOI=10.1074/jbc.m114.633057;
RA   Koo J., Wu X., Mao Z., Khuri F.R., Sun S.Y.;
RT   "Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-
RT   mediated Ubiquitination and Proteasomal Degradation.";
RL   J. Biol. Chem. 290:14120-14129(2015).
RN   [24]
RP   FUNCTION.
RX   PubMed=30704899; DOI=10.1016/j.molcel.2018.12.017;
RA   Cheng X., Ma X., Zhu Q., Song D., Ding X., Li L., Jiang X., Wang X.,
RA   Tian R., Su H., Shen Z., Chen S., Liu T., Gong W., Liu W., Sun Q.;
RT   "Pacer is a mediator of mTORC1 and GSK3-TIP60 signaling in regulation of
RT   autophagosome maturation and lipid metabolism.";
RL   Mol. Cell 73:1-15(2019).
RN   [25]
RP   INTERACTION WITH LMBR1L.
RX   PubMed=31073040; DOI=10.1126/science.aau0812;
RA   Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J.,
RA   Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M.,
RA   Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y.,
RA   Beutler B.;
RT   "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling.";
RL   Science 364:0-0(2019).
RN   [26]
RP   VARIANT [LARGE SCALE ANALYSIS] PHE-461.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
CC   -!- FUNCTION: Constitutively active protein kinase that acts as a negative
CC       regulator in the hormonal control of glucose homeostasis, Wnt signaling
CC       and regulation of transcription factors and microtubules, by
CC       phosphorylating and inactivating glycogen synthase (GYS1 or GYS2),
CC       CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001,
CC       PubMed:19366350). Requires primed phosphorylation of the majority of
CC       its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350).
CC       Contributes to insulin regulation of glycogen synthesis by
CC       phosphorylating and inhibiting GYS1 activity and hence glycogen
CC       synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350).
CC       Regulates glycogen metabolism in liver, but not in muscle (By
CC       similarity). May also mediate the development of insulin resistance by
CC       regulating activation of transcription factors (PubMed:10868943,
CC       PubMed:17478001). In Wnt signaling, regulates the level and
CC       transcriptional activity of nuclear CTNNB1/beta-catenin
CC       (PubMed:17229088). Facilitates amyloid precursor protein (APP)
CC       processing and the generation of APP-derived amyloid plaques found in
CC       Alzheimer disease (PubMed:12761548). May be involved in the regulation
CC       of replication in pancreatic beta-cells (By similarity). Is necessary
CC       for the establishment of neuronal polarity and axon outgrowth (By
CC       similarity). Through phosphorylation of the anti-apoptotic protein
CC       MCL1, may control cell apoptosis in response to growth factors
CC       deprivation (By similarity). Acts as a regulator of autophagy by
CC       mediating phosphorylation of KAT5/TIP60 under starvation conditions
CC       which activates KAT5/TIP60 acetyltransferase activity and promotes
CC       acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer
CC       (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling
CC       pathway via death domain receptors. Promotes the formation of an anti-
CC       apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors,
CC       including TNFRSF10B. The anti-apoptotic function is most effective with
CC       weak apoptotic signals and can be overcome by stronger stimulation (By
CC       similarity). Phosphorylates mTORC2 complex component RICTOR at 'Thr-
CC       1695' which facilitates FBXW7-mediated ubiquitination and subsequent
CC       degradation of RICTOR (PubMed:25897075). {ECO:0000250|UniProtKB:P18265,
CC       ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q2NL51,
CC       ECO:0000269|PubMed:10868943, ECO:0000269|PubMed:12761548,
CC       ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:25897075,
CC       ECO:0000269|PubMed:30704899, ECO:0000303|PubMed:11749387,
CC       ECO:0000303|PubMed:17478001, ECO:0000303|PubMed:19366350}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein]
CC         + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC         COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau
CC         protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC         Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.26;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:22539723};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:25897075};
CC   -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-279. In
CC       response to insulin, inhibited by phosphorylation at Ser-21 by
CC       PKB/AKT1; phosphorylation at this site causes a conformational change,
CC       preventing access of substrates to the active site. Inhibited by
CC       lithium. {ECO:0000269|PubMed:11749387, ECO:0000269|PubMed:19366350}.
CC   -!- SUBUNIT: Monomer. Interacts with ARRB2 (By similarity). Interacts with
CC       AXIN1 and CTNNB1/beta-catenin (PubMed:17229088). Interacts with CTNND2
CC       (PubMed:19706605). Interacts with LMBR1L (PubMed:31073040). Interacts
CC       with DDX3X (PubMed:18846110). Interacts with TNFRSF10B
CC       (PubMed:18846110). Interacts with RICTOR; the interaction results in
CC       phosphorylation of RICTOR at 'Thr-1695' by GSK3A which facilitates
CC       FBXW7-mediated ubiquitination and subsequent degradation of RICTOR
CC       (PubMed:25897075). {ECO:0000250|UniProtKB:Q2NL51,
CC       ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:18846110,
CC       ECO:0000269|PubMed:19706605, ECO:0000269|PubMed:25897075,
CC       ECO:0000305|PubMed:31073040}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with M.tuberculosis PtpA.
CC       {ECO:0000269|PubMed:25187516}.
CC   -!- INTERACTION:
CC       P49840; PRO_0000000093 [P05067]: APP; NbExp=3; IntAct=EBI-1044067, EBI-2431589;
CC       P49840; O15169: AXIN1; NbExp=6; IntAct=EBI-1044067, EBI-710484;
CC       P49840; Q9Y2T1: AXIN2; NbExp=4; IntAct=EBI-1044067, EBI-4400025;
CC       P49840; P15056: BRAF; NbExp=6; IntAct=EBI-1044067, EBI-365980;
CC       P49840; O75398: DEAF1; NbExp=3; IntAct=EBI-1044067, EBI-718185;
CC       P49840; Q6P3S6: FBXO42; NbExp=3; IntAct=EBI-1044067, EBI-2506081;
CC       P49840; Q92837: FRAT1; NbExp=5; IntAct=EBI-1044067, EBI-3934879;
CC       P49840; Q9P0R6: GSKIP; NbExp=6; IntAct=EBI-1044067, EBI-1052580;
CC       P49840; P08238: HSP90AB1; NbExp=3; IntAct=EBI-1044067, EBI-352572;
CC       P49840; P42858: HTT; NbExp=6; IntAct=EBI-1044067, EBI-466029;
CC       P49840; O75581: LRP6; NbExp=3; IntAct=EBI-1044067, EBI-910915;
CC       P49840; P10636-8: MAPT; NbExp=2; IntAct=EBI-1044067, EBI-366233;
CC       P49840; Q14596: NBR1; NbExp=7; IntAct=EBI-1044067, EBI-742698;
CC       P49840; P62258: YWHAE; NbExp=3; IntAct=EBI-1044067, EBI-356498;
CC       P49840; P61981: YWHAG; NbExp=5; IntAct=EBI-1044067, EBI-359832;
CC       P49840; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-1044067, EBI-524753;
CC   -!- PTM: Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling,
CC       the activated PKB/AKT1 protein kinase phosphorylates and deactivates
CC       GSK3A, resulting in the dephosphorylation and activation of GYS1.
CC       Activated by phosphorylation at Tyr-279.
CC   -!- PTM: (Microbial infection) Dephosphorylated at Tyr-279 by
CC       M.tuberculosis PtpA, which leads to prevention of apoptosis during
CC       early stages of microbial infection. {ECO:0000269|PubMed:25187516}.
CC   -!- MISCELLANEOUS: Higher expression and activity of GSK3A are found in the
CC       skeletal muscle (vastus lateralis) of patients with type 2 diabetes
CC       (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors
CC       have been identified and characterized in preclinical models for
CC       treatments of type 2 diabetes (PubMed:19366350).
CC       {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. GSK-3 subfamily. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; L40027; AAA62432.1; -; mRNA.
DR   EMBL; D63424; BAA23608.1; -; mRNA.
DR   EMBL; AC006486; AAD11986.1; -; Genomic_DNA.
DR   EMBL; BC027984; AAH27984.1; -; mRNA.
DR   EMBL; BC051865; AAH51865.1; -; mRNA.
DR   CCDS; CCDS12599.1; -.
DR   RefSeq; NP_063937.2; NM_019884.2.
DR   PDB; 7SXF; X-ray; 1.94 A; A=101-444.
DR   PDB; 7SXG; X-ray; 2.40 A; A=103-445.
DR   PDBsum; 7SXF; -.
DR   PDBsum; 7SXG; -.
DR   AlphaFoldDB; P49840; -.
DR   SMR; P49840; -.
DR   BioGRID; 109186; 479.
DR   ComplexPortal; CPX-107; Beta-catenin destruction core complex, APC-AXIN1-GSK3A variant.
DR   ComplexPortal; CPX-441; Beta-catenin destruction core complex, APC-AXIN2-GSK3A variant.
DR   ComplexPortal; CPX-442; Beta-catenin destruction core complex, APC2-AXIN1-GSK3A variant.
DR   ComplexPortal; CPX-443; Beta-catenin destruction core complex, APC2-AXIN2-GSK3A variant.
DR   ELM; P49840; -.
DR   FunCoup; P49840; 1731.
DR   IntAct; P49840; 171.
DR   MINT; P49840; -.
DR   STRING; 9606.ENSP00000222330; -.
DR   BindingDB; P49840; -.
DR   ChEMBL; CHEMBL2850; -.
DR   DrugBank; DB01950; AR-AO-14418.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugBank; DB16607; Lithium chloride.
DR   DrugBank; DB11913; LY-2090314.
DR   DrugBank; DB00313; Valproic acid.
DR   DrugCentral; P49840; -.
DR   GuidetoPHARMACOLOGY; 2029; -.
DR   GlyCosmos; P49840; 1 site, 1 glycan.
DR   GlyGen; P49840; 3 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; P49840; -.
DR   PhosphoSitePlus; P49840; -.
DR   SwissPalm; P49840; -.
DR   BioMuta; GSK3A; -.
DR   DMDM; 12644292; -.
DR   CPTAC; CPTAC-3040; -.
DR   jPOST; P49840; -.
DR   MassIVE; P49840; -.
DR   PaxDb; 9606-ENSP00000222330; -.
DR   PeptideAtlas; P49840; -.
DR   ProteomicsDB; 56150; -.
DR   Pumba; P49840; -.
DR   Antibodypedia; 3833; 1208 antibodies from 49 providers.
DR   DNASU; 2931; -.
DR   Ensembl; ENST00000222330.8; ENSP00000222330.3; ENSG00000105723.13.
DR   Ensembl; ENST00000453535.1; ENSP00000412663.1; ENSG00000105723.13.
DR   GeneID; 2931; -.
DR   KEGG; hsa:2931; -.
DR   MANE-Select; ENST00000222330.8; ENSP00000222330.3; NM_019884.3; NP_063937.2.
DR   UCSC; uc002otb.2; human.
DR   AGR; HGNC:4616; -.
DR   ClinPGx; PA29008; -.
DR   CTD; 2931; -.
DR   DisGeNET; 2931; -.
DR   GeneCards; GSK3A; -.
DR   HGNC; HGNC:4616; GSK3A.
DR   HPA; ENSG00000105723; Low tissue specificity.
DR   MIM; 606784; gene.
DR   OpenTargets; ENSG00000105723; -.
DR   VEuPathDB; HostDB:ENSG00000105723; -.
DR   eggNOG; KOG0658; Eukaryota.
DR   GeneTree; ENSGT00520000055635; -.
DR   InParanoid; P49840; -.
DR   OMA; CLHAFFD; -.
DR   OrthoDB; 272141at2759; -.
DR   PAN-GO; P49840; 10 GO annotations based on evolutionary models.
DR   PhylomeDB; P49840; -.
DR   BRENDA; 2.7.11.26; 2681.
DR   PathwayCommons; P49840; -.
DR   Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
DR   Reactome; R-HSA-381038; XBP1(S) activates chaperone genes.
DR   Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR   Reactome; R-HSA-9635465; Suppression of apoptosis.
DR   Reactome; R-HSA-9683610; Maturation of nucleoprotein.
DR   Reactome; R-HSA-9694631; Maturation of nucleoprotein.
DR   SignaLink; P49840; -.
DR   SIGNOR; P49840; -.
DR   Agora; ENSG00000105723; -.
DR   BioGRID-ORCS; 2931; 21 hits in 1191 CRISPR screens.
DR   CD-CODE; 7FF4107C; Beta-Catenin Destruction Complex.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   ChiTaRS; GSK3A; human.
DR   GeneWiki; GSK3A; -.
DR   GenomeRNAi; 2931; -.
DR   Pharos; P49840; Tclin.
DR   PRO; PR:P49840; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; P49840; protein.
DR   Bgee; ENSG00000105723; Expressed in cortical plate and 213 other cell types or tissues.
DR   ExpressionAtlas; P49840; baseline and differential.
DR   GO; GO:0097440; C:apical dendrite; NAS:ARUK-UCL.
DR   GO; GO:0030424; C:axon; IBA:GO_Central.
DR   GO; GO:0030877; C:beta-catenin destruction complex; TAS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR   GO; GO:0043025; C:neuronal cell body; NAS:ARUK-UCL.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0098794; C:postsynapse; IEA:GOC.
DR   GO; GO:1990635; C:proximal dendrite; NAS:ARUK-UCL.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:BHF-UCL.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:Ensembl.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:ARUK-UCL.
DR   GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR   GO; GO:0050321; F:tau-protein kinase activity; TAS:UniProtKB.
DR   GO; GO:0141068; P:autosome genomic imprinting; IEA:Ensembl.
DR   GO; GO:0160213; P:beta-arrestin-dependent dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0003214; P:cardiac left ventricle morphogenesis; ISS:BHF-UCL.
DR   GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR   GO; GO:0016477; P:cell migration; IEA:Ensembl.
DR   GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IEA:Ensembl.
DR   GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
DR   GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR   GO; GO:0071285; P:cellular response to lithium ion; IEA:Ensembl.
DR   GO; GO:0060079; P:excitatory postsynaptic potential; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB.
DR   GO; GO:0005977; P:glycogen metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
DR   GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR   GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IBA:GO_Central.
DR   GO; GO:0061052; P:negative regulation of cell growth involved in cardiac muscle cell development; ISS:BHF-UCL.
DR   GO; GO:0046325; P:negative regulation of D-glucose import; IMP:BHF-UCL.
DR   GO; GO:2000466; P:negative regulation of glycogen (starch) synthase activity; TAS:UniProtKB.
DR   GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; TAS:UniProtKB.
DR   GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:BHF-UCL.
DR   GO; GO:0032007; P:negative regulation of TOR signaling; ISS:BHF-UCL.
DR   GO; GO:2000077; P:negative regulation of type B pancreatic cell development; TAS:UniProtKB.
DR   GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR   GO; GO:0071879; P:positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway; ISS:BHF-UCL.
DR   GO; GO:0106071; P:positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISS:BHF-UCL.
DR   GO; GO:1902004; P:positive regulation of amyloid-beta formation; IMP:ARUK-UCL.
DR   GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; ISS:ARUK-UCL.
DR   GO; GO:0045823; P:positive regulation of heart contraction; ISS:BHF-UCL.
DR   GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; ISS:UniProtKB.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:ARUK-UCL.
DR   GO; GO:0045732; P:positive regulation of protein catabolic process; NAS:BHF-UCL.
DR   GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0031398; P:positive regulation of protein ubiquitination; IMP:ARUK-UCL.
DR   GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; IEA:Ensembl.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IBA:GO_Central.
DR   GO; GO:1901524; P:regulation of mitophagy; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0010975; P:regulation of neuron projection development; IBA:GO_Central.
DR   GO; GO:0003073; P:regulation of systemic arterial blood pressure; ISS:BHF-UCL.
DR   GO; GO:0019082; P:viral protein processing; TAS:Reactome.
DR   GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR   CDD; cd14137; STKc_GSK3; 1.
DR   FunFam; 1.10.510.10:FF:000055; Glycogen synthase kinase-3 beta; 1.
DR   FunFam; 3.30.200.20:FF:000009; Glycogen synthase kinase-3 beta; 1.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR050591; GSK-3.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR039192; STKc_GSK3.
DR   PANTHER; PTHR24057; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1.
DR   PANTHER; PTHR24057:SF14; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alzheimer disease; ATP-binding;
KW   Carbohydrate metabolism; Diabetes mellitus; Glycogen metabolism; Kinase;
KW   Neurogenesis; Nucleotide-binding; Phosphoprotein;
KW   Proteomics identification; Reference proteome;
KW   Serine/threonine-protein kinase; Signal transduction inhibitor;
KW   Transferase; Wnt signaling pathway.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:19369195,
FT                   ECO:0007744|PubMed:19413330"
FT   CHAIN           2..483
FT                   /note="Glycogen synthase kinase-3 alpha"
FT                   /id="PRO_0000085978"
FT   DOMAIN          119..403
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..96
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          449..483
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..15
FT                   /note="Gly residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        25..82
FT                   /note="Gly residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        244
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         125..133
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         148
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         2
FT                   /note="N-acetylserine"
FT                   /evidence="ECO:0007744|PubMed:19369195,
FT                   ECO:0007744|PubMed:19413330"
FT   MOD_RES         2
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976,
FT                   ECO:0007744|PubMed:19369195"
FT   MOD_RES         21
FT                   /note="Phosphoserine; by PKB/AKT1"
FT                   /evidence="ECO:0000250|UniProtKB:Q2NL51"
FT   MOD_RES         72
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976"
FT   MOD_RES         77
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19369195"
FT   MOD_RES         97
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19369195"
FT   MOD_RES         279
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P18265"
FT   VARIANT         109
FT                   /note="Q -> E (in dbSNP:rs35978177)"
FT                   /id="VAR_051625"
FT   VARIANT         461
FT                   /note="L -> F (in dbSNP:rs35454502)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040539"
FT   CONFLICT        449
FT                   /note="A -> S (in Ref. 1; AAA62432)"
FT                   /evidence="ECO:0000305"
FT   STRAND          102..112
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          114..118
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          120..126
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          132..137
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          144..152
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           159..166
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          175..182
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          189..196
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          199..201
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           202..211
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           218..237
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           247..249
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          250..252
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   TURN            254..256
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   STRAND          259..261
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           264..266
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           283..285
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           288..291
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           300..315
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           325..336
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           341..347
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           349..351
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           364..366
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           374..383
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           388..390
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           394..398
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           401..403
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           404..407
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   TURN            414..416
FT                   /evidence="ECO:0007829|PDB:7SXG"
FT   HELIX           429..431
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           434..436
FT                   /evidence="ECO:0007829|PDB:7SXF"
FT   HELIX           437..440
FT                   /evidence="ECO:0007829|PDB:7SXF"
SQ   SEQUENCE   483 AA;  50981 MW;  F18C012C03B7D786 CRC64;
     MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK ASVGAMGGGV
     GASSSGGGPG GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV TTVVATLGQG PERSQEVAYT
     DIKVIGNGSF GVVYQARLAE TRELVAIKKV LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY
     SSGEKKDELY LNLVLEYVPE TVYRVARHFT KAKLTIPILY VKVYMYQLFR SLAYIHSQGV
     CHRDIKPQNL LVDPDTAVLK LCDFGSAKQL VRGEPNVSYI CSRYYRAPEL IFGATDYTSS
     IDVWSAGCVL AELLLGQPIF PGDSGVDQLV EIIKVLGTPT REQIREMNPN YTEFKFPQIK
     AHPWTKVFKS RTPPEAIALC SSLLEYTPSS RLSPLEACAH SFFDELRCLG TQLPNNRPLP
     PLFNFSAGEL SIQPSLNAIL IPPHLRSPAG TTTLTPSSQA LTETPTSSDW QSTDATPTLT
     NSS
//
ID   GSK3B_HUMAN             Reviewed;         420 AA.
AC   P49841; D3DN89; Q9BWH3; Q9UL47;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   02-MAY-2002, sequence version 2.
DT   28-JAN-2026, entry version 273.
DE   RecName: Full=Glycogen synthase kinase-3 beta {ECO:0000305};
DE            Short=GSK-3 beta;
DE            EC=2.7.11.26 {ECO:0000269|PubMed:14690523};
DE   AltName: Full=Serine/threonine-protein kinase GSK3B;
DE            EC=2.7.11.1 {ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942, ECO:0000269|PubMed:21343617, ECO:0000269|PubMed:22539723, ECO:0000269|PubMed:25827072, ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:29059170};
GN   Name=GSK3B {ECO:0000312|HGNC:HGNC:4617};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND MUTAGENESIS OF SER-9.
RX   PubMed=7980435; DOI=10.1042/bj3030701;
RA   Stambolic V., Woodgett J.R.;
RT   "Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells
RT   via serine 9 phosphorylation.";
RL   Biochem. J. 303:701-704(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Eye, and Placenta;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-28.
RX   PubMed=10486203; DOI=10.1006/geno.1999.5875;
RA   Lau K.F., Miller C.C.J., Anderton B.H., Shaw P.C.;
RT   "Molecular cloning and characterization of the human glycogen synthase
RT   kinase-3beta promoter.";
RL   Genomics 60:121-128(1999).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 185-202.
RX   PubMed=10523816; DOI=10.1038/sj.mp.4000538;
RA   Rhoads A.R., Karkera J.D., Detera-Wadleigh S.D.;
RT   "Radiation hybrid mapping of genes in the lithium-sensitive wnt signaling
RT   pathway.";
RL   Mol. Psychiatry 4:437-442(1999).
RN   [6]
RP   FUNCTION IN PHOSPHORYLATION OF JUN.
RX   PubMed=1846781; DOI=10.1016/0092-8674(91)90241-p;
RA   Boyle W.J., Smeal T., Defize L.H., Angel P., Woodgett J.R., Karin M.,
RA   Hunter T.;
RT   "Activation of protein kinase C decreases phosphorylation of c-Jun at sites
RT   that negatively regulate its DNA-binding activity.";
RL   Cell 64:573-584(1991).
RN   [7]
RP   FUNCTION IN PHOSPHORYLATION OF EIF2BE/EIF2B5.
RX   PubMed=8397507; DOI=10.1042/bj2940625;
RA   Welsh G.I., Proud C.G.;
RT   "Glycogen synthase kinase-3 is rapidly inactivated in response to insulin
RT   and phosphorylates eukaryotic initiation factor eIF-2B.";
RL   Biochem. J. 294:625-629(1993).
RN   [8]
RP   PHOSPHORYLATION AT SER-9.
RX   PubMed=8250835; DOI=10.1042/bj2960015;
RA   Sutherland C., Leighton I.A., Cohen P.;
RT   "Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new
RT   kinase connections in insulin and growth-factor signalling.";
RL   Biochem. J. 296:15-19(1993).
RN   [9]
RP   ACTIVITY REGULATION BY AKT1.
RX   PubMed=8524413; DOI=10.1038/378785a0;
RA   Cross D.A., Alessi D.R., Cohen P., Andjelkovich M., Hemmings B.A.;
RT   "Inhibition of glycogen synthase kinase-3 by insulin mediated by protein
RT   kinase B.";
RL   Nature 378:785-789(1995).
RN   [10]
RP   FUNCTION IN PHOSPHORYLATION OF NFATC1/NFATC.
RX   PubMed=9072970; DOI=10.1126/science.275.5308.1930;
RA   Beals C.R., Sheridan C.M., Turck C.W., Gardner P., Crabtree G.R.;
RT   "Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3.";
RL   Science 275:1930-1934(1997).
RN   [11]
RP   INTERACTION WITH DNM1L.
RC   TISSUE=Liver;
RX   PubMed=9731200; DOI=10.1006/bbrc.1998.9253;
RA   Hong Y.-R., Chen C.-H., Cheng D.-S., Howng S.-L., Chow C.-C.;
RT   "Human dynamin-like protein interacts with the glycogen synthase kinase
RT   3beta.";
RL   Biochem. Biophys. Res. Commun. 249:697-703(1998).
RN   [12]
RP   INTERACTION WITH MUC1, AND FUNCTION.
RX   PubMed=9819408; DOI=10.1128/mcb.18.12.7216;
RA   Li Y., Bharti A., Chen D., Gong J., Kufe D.;
RT   "Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-
RT   associated antigen and beta-catenin.";
RL   Mol. Cell. Biol. 18:7216-7224(1998).
RN   [13]
RP   CHARACTERIZATION.
RX   PubMed=9736715; DOI=10.1073/pnas.95.19.11211;
RA   Delcommenne M., Tan C., Gray V., Rue L., Woodgett J.R., Dedhar S.;
RT   "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase
RT   kinase 3 and protein kinase B/AKT by the integrin-linked kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:11211-11216(1998).
RN   [14]
RP   INTERACTION WITH NIN.
RX   PubMed=11004522; DOI=10.1016/s0167-4781(00)00127-5;
RA   Hong Y.-R., Chen C.-H., Chang J.-H., Wang S.-K., Sy W.-D., Chou C.-K.,
RA   Howng S.-L.;
RT   "Cloning and characterization of a novel human ninein protein that
RT   interacts with the glycogen synthase kinase 3beta.";
RL   Biochim. Biophys. Acta 1492:513-516(2000).
RN   [15]
RP   ASSOCIATION WITH DIABETES MELLITUS.
RX   PubMed=10868943; DOI=10.2337/diabetes.49.2.263;
RA   Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L.,
RA   Henry R.R.;
RT   "Potential role of glycogen synthase kinase-3 in skeletal muscle insulin
RT   resistance of type 2 diabetes.";
RL   Diabetes 49:263-271(2000).
RN   [16]
RP   FUNCTION, AND MUTAGENESIS OF ARG-96 AND LEU-128.
RX   PubMed=11430833; DOI=10.1016/s1097-2765(01)00253-2;
RA   Frame S., Cohen P., Biondi R.M.;
RT   "A common phosphate binding site explains the unique substrate specificity
RT   of GSK3 and its inactivation by phosphorylation.";
RL   Mol. Cell 7:1321-1327(2001).
RN   [17]
RP   PHOSPHORYLATION AT SER-9 BY SGK3, AND INTERACTION WITH SGK3.
RX   PubMed=12054501; DOI=10.1016/s0006-291x(02)00349-2;
RA   Dai F., Yu L., He H., Chen Y., Yu J., Yang Y., Xu Y., Ling W., Zhao S.;
RT   "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL)
RT   phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9
RT   through direct interaction.";
RL   Biochem. Biophys. Res. Commun. 293:1191-1196(2002).
RN   [18]
RP   FUNCTION IN PHOSPHORYLATION OF MAPT/TAU.
RX   PubMed=14690523; DOI=10.1111/j.1471-4159.2004.02155.x;
RA   Cho J.H., Johnson G.V.;
RT   "Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta
RT   (GSK3beta) plays a critical role in regulating tau's ability to bind and
RT   stabilize microtubules.";
RL   J. Neurochem. 88:349-358(2004).
RN   [19]
RP   FUNCTION, INTERACTION WITH SNAI1, AND SUBCELLULAR LOCATION.
RX   PubMed=15448698; DOI=10.1038/ncb1173;
RA   Zhou B.P., Deng J., Xia W., Xu J., Li Y.M., Gunduz M., Hung M.C.;
RT   "Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control
RT   of epithelial-mesenchymal transition.";
RL   Nat. Cell Biol. 6:931-940(2004).
RN   [20]
RP   INTERACTION WITH CABYR.
RX   PubMed=15752768; DOI=10.1016/j.bbrc.2005.02.089;
RA   Hsu H.-C., Lee Y.-L., Cheng T.-S., Howng S.-L., Chang L.-K., Lu P.-J.,
RA   Hong Y.-R.;
RT   "Characterization of two non-testis-specific CABYR variants that bind to
RT   GSK3beta with a proline-rich extensin-like domain.";
RL   Biochem. Biophys. Res. Commun. 329:1108-1117(2005).
RN   [21]
RP   FUNCTION, AND INTERACTION WITH SNAI1.
RX   PubMed=15647282; DOI=10.1074/jbc.m413878200;
RA   Yook J.I., Li X.Y., Ota I., Fearon E.R., Weiss S.J.;
RT   "Wnt-dependent regulation of the E-cadherin repressor snail.";
RL   J. Biol. Chem. 280:11740-11748(2005).
RN   [22]
RP   INTERACTION WITH GSKIP.
RX   PubMed=16981698; DOI=10.1021/bi061147r;
RA   Chou H.-Y., Howng S.-L., Cheng T.-S., Hsiao Y.-L., Lieu A.-S., Loh J.-K.,
RA   Hwang S.-L., Lin C.-C., Hsu C.-M., Wang C., Lee C.-I., Lu P.-J.,
RA   Chou C.-K., Huang C.-Y., Hong Y.-R.;
RT   "GSKIP is homologous to the axin GSK3beta interaction domain and functions
RT   as a negative regulator of GSK3beta.";
RL   Biochemistry 45:11379-11389(2006).
RN   [23]
RP   INTERACTION WITH PRUNE1.
RX   PubMed=16428445; DOI=10.1128/mcb.26.3.898-911.2006;
RA   Kobayashi T., Hino S., Oue N., Asahara T., Zollo M., Yasui W., Kikuchi A.;
RT   "Glycogen synthase kinase 3 and h-prune regulate cell migration by
RT   modulating focal adhesions.";
RL   Mol. Cell. Biol. 26:898-911(2006).
RN   [24]
RP   FUNCTION, AND PHOSPHORYLATION AT SER-9.
RX   PubMed=16484495; DOI=10.1126/science.1121613;
RA   Yin L., Wang J., Klein P.S., Lazar M.A.;
RT   "Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of
RT   the circadian clock.";
RL   Science 311:1002-1005(2006).
RN   [25]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-9 AND 85-LYS-LYS-86.
RX   PubMed=17050006; DOI=10.1016/j.bbamcr.2006.09.015;
RA   Garcia-Alvarez G., Ventura V., Ros O., Aligue R., Gil J., Tauler A.;
RT   "Glycogen synthase kinase-3beta binds to E2F1 and regulates its
RT   transcriptional activity.";
RL   Biochim. Biophys. Acta 1773:375-382(2007).
RN   [26]
RP   INTERACTION WITH AXIN1.
RX   PubMed=17318175; DOI=10.1038/sj.emboj.7601607;
RA   Luo W., Peterson A., Garcia B.A., Coombs G., Kofahl B., Heinrich R.,
RA   Shabanowitz J., Hunt D.F., Yost H.J., Virshup D.M.;
RT   "Protein phosphatase 1 regulates assembly and function of the beta-catenin
RT   degradation complex.";
RL   EMBO J. 26:1511-1521(2007).
RN   [27]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=17681942; DOI=10.1074/jbc.m703948200;
RA   Higgins M.J., Graves P.R., Graves L.M.;
RT   "Regulation of human cytidine triphosphate synthetase 1 by glycogen
RT   synthase kinase 3.";
RL   J. Biol. Chem. 282:29493-29503(2007).
RN   [28]
RP   FUNCTION, AND INTERACTION WITH BIRC2; DDX3X AND TNFRSF10B.
RX   PubMed=18846110; DOI=10.1038/cdd.2008.124;
RA   Sun M., Song L., Li Y., Zhou T., Jope R.S.;
RT   "Identification of an antiapoptotic protein complex at death receptors.";
RL   Cell Death Differ. 15:1887-1900(2008).
RN   [29]
RP   FUNCTION IN PHOSPHORYLATION OF SIK1.
RX   PubMed=18348280; DOI=10.1002/jcb.21737;
RA   Hashimoto Y.K., Satoh T., Okamoto M., Takemori H.;
RT   "Importance of autophosphorylation at Ser186 in the A-loop of salt
RT   inducible kinase 1 for its sustained kinase activity.";
RL   J. Cell. Biochem. 104:1724-1739(2008).
RN   [30]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-402, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [31]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-390, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [32]
RP   INTERACTION WITH MMP2.
RX   PubMed=19493954; DOI=10.1093/cvr/cvp175;
RA   Kandasamy A.D., Schulz R.;
RT   "Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2
RT   mediated proteolysis in cardiomyoblasts.";
RL   Cardiovasc. Res. 83:698-706(2009).
RN   [33]
RP   FUNCTION, AND INTERACTION WITH CLOCK-BMAL1.
RX   PubMed=19946213; DOI=10.4161/cc.8.24.10273;
RA   Spengler M.L., Kuropatwinski K.K., Schumer M., Antoch M.P.;
RT   "A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and
RT   degradation.";
RL   Cell Cycle 8:4138-4146(2009).
RN   [34]
RP   INTERACTION WITH CTNND2.
RX   PubMed=19706605; DOI=10.1074/jbc.m109.002659;
RA   Oh M., Kim H., Yang I., Park J.H., Cong W.T., Baek M.C., Bareiss S., Ki H.,
RA   Lu Q., No J., Kwon I., Choi J.K., Kim K.;
RT   "GSK-3 phosphorylates delta-catenin and negatively regulates its stability
RT   via ubiquitination/proteosome-mediated proteolysis.";
RL   J. Biol. Chem. 284:28579-28589(2009).
RN   [35]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [36]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [37]
RP   FUNCTION, AND ALTERNATIVE SPLICING.
RX   PubMed=20067585; DOI=10.1111/j.1471-4159.2010.06581.x;
RA   Castano Z., Gordon-Weeks P.R., Kypta R.M.;
RT   "The neuron-specific isoform of glycogen synthase kinase-3beta is required
RT   for axon growth.";
RL   J. Neurochem. 113:117-130(2010).
RN   [38]
RP   FUNCTION.
RX   PubMed=20932480; DOI=10.1016/j.molcel.2010.09.013;
RA   Heyd F., Lynch K.W.;
RT   "Phosphorylation-dependent regulation of PSF by GSK3 controls CD45
RT   alternative splicing.";
RL   Mol. Cell 40:126-137(2010).
RN   [39]
RP   INTERACTION WITH DAB2IP AND PPP2CA.
RX   PubMed=20080667; DOI=10.1073/pnas.0908133107;
RA   Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M., Kabbani W.,
RA   Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W., Hsieh J.T.;
RT   "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and
RT   prostate cancer metastasis.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010).
RN   [40]
RP   FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-9.
RX   PubMed=20937854; DOI=10.1073/pnas.1000975107;
RA   Zaoui K., Benseddik K., Daou P., Salaun D., Badache A.;
RT   "ErbB2 receptor controls microtubule capture by recruiting ACF7 to the
RT   plasma membrane of migrating cells.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010).
RN   [41]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=11749387; DOI=10.1021/cr000110o;
RA   Ali A., Hoeflich K.P., Woodgett J.R.;
RT   "Glycogen synthase kinase-3: properties, functions, and regulation.";
RL   Chem. Rev. 101:2527-2540(2001).
RN   [42]
RP   REVIEW ON FUNCTION.
RX   PubMed=17478001; DOI=10.1016/j.diabres.2007.01.033;
RA   Lee J., Kim M.S.;
RT   "The role of GSK3 in glucose homeostasis and the development of insulin
RT   resistance.";
RL   Diabetes Res. Clin. Pract. 77:S49-S57(2007).
RN   [43]
RP   REVIEW ON FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=19366350; DOI=10.1111/j.1476-5381.2008.00085.x;
RA   Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A.;
RT   "Glycogen synthase kinase 3: more than a namesake.";
RL   Br. J. Pharmacol. 156:885-898(2009).
RN   [44]
RP   INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2A AND GSKIP.
RX   PubMed=20007971; DOI=10.1074/jbc.m109.047944;
RA   Hundsrucker C., Skroblin P., Christian F., Zenn H.M., Popara V., Joshi M.,
RA   Eichhorst J., Wiesner B., Herberg F.W., Reif B., Rosenthal W.,
RA   Klussmann E.;
RT   "Glycogen synthase kinase 3beta interaction protein functions as an A-
RT   kinase anchoring protein.";
RL   J. Biol. Chem. 285:5507-5521(2010).
RN   [45]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [46]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [47]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
RX   PubMed=21029237; DOI=10.1111/j.1750-3639.2010.00437.x;
RA   Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F., Hugon J.;
RT   "Modulation of tau phosphorylation by the kinase PKR: implications in
RT   Alzheimer's disease.";
RL   Brain Pathol. 21:189-200(2011).
RN   [48]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=21343617; DOI=10.1126/scisignal.2001731;
RA   Chen C.H., Shaikenov T., Peterson T.R., Aimbetov R., Bissenbaev A.K.,
RA   Lee S.W., Wu J., Lin H.K., Sarbassov D.D.;
RT   "ER stress inhibits mTORC2 and Akt signaling through GSK-3beta-mediated
RT   phosphorylation of rictor.";
RL   Sci. Signal. 4:ra10-ra10(2011).
RN   [49]
RP   FUNCTION.
RX   PubMed=22514281; DOI=10.1074/jbc.m111.306373;
RA   Sun L., Lv F., Guo X., Gao G.;
RT   "Glycogen synthase kinase 3? (GSK3?) modulates antiviral activity of zinc-
RT   finger antiviral protein (ZAP).";
RL   J. Biol. Chem. 287:22882-22888(2012).
RN   [50]
RP   CATALYTIC ACTIVITY.
RX   PubMed=22539723; DOI=10.1126/science.1217032;
RA   Lin S.Y., Li T.Y., Liu Q., Zhang C., Li X., Chen Y., Zhang S.M., Lian G.,
RA   Liu Q., Ruan K., Wang Z., Zhang C.S., Chien K.Y., Wu J., Li Q., Han J.,
RA   Lin S.C.;
RT   "GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to
RT   autophagy.";
RL   Science 336:477-481(2012).
RN   [51]
RP   ADP-RIBOSYLATION BY PARP10.
RX   PubMed=23332125; DOI=10.1186/1478-811x-11-5;
RA   Feijs K.L., Kleine H., Braczynski A., Forst A.H., Herzog N., Verheugd P.,
RA   Linzen U., Kremmer E., Luscher B.;
RT   "ARTD10 substrate identification on protein microarrays: regulation of
RT   GSK3beta by mono-ADP-ribosylation.";
RL   Cell Commun. Signal. 11:5-5(2013).
RN   [52]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-390, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [53]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [54]
RP   FUNCTION, INTERACTION WITH NCYM, AND PHOSPHORYLATION AT SER-9.
RX   PubMed=24391509; DOI=10.1371/journal.pgen.1003996;
RA   Suenaga Y., Islam S.M., Alagu J., Kaneko Y., Kato M., Tanaka Y., Kawana H.,
RA   Hossain S., Matsumoto D., Yamamoto M., Shoji W., Itami M., Shibata T.,
RA   Nakamura Y., Ohira M., Haraguchi S., Takatori A., Nakagawara A.;
RT   "NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that
RT   inhibits GSK3beta resulting in the stabilization of MYCN in human
RT   neuroblastomas.";
RL   PLoS Genet. 10:E1003996-E1003996(2014).
RN   [55]
RP   PHOSPHORYLATION AT SER-9 AND TYR-216, INTERACTION WITH JPT1, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=25169422; DOI=10.1002/jcb.24956;
RA   Varisli L., Ozturk B.E., Akyuz G.K., Korkmaz K.S.;
RT   "HN1 negatively influences the beta-catenin/E-cadherin interaction, and
RT   contributes to migration in prostate cells.";
RL   J. Cell. Biochem. 116:170-178(2015).
RN   [56]
RP   INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2B AND GSKIP.
RX   PubMed=25920809; DOI=10.1016/j.bbamcr.2015.04.013;
RA   Loh J.K., Lin C.C., Yang M.C., Chou C.H., Chen W.S., Hong M.C., Cho C.L.,
RA   Hsu C.M., Cheng J.T., Chou A.K., Chang C.H., Tseng C.N., Wang C.H.,
RA   Lieu A.S., Howng S.L., Hong Y.R.;
RT   "GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis
RT   signaling in the regulation of mitochondrial elongation.";
RL   Biochim. Biophys. Acta 1853:1796-1807(2015).
RN   [57]
RP   FUNCTION, AND INTERACTION WITH RICTOR.
RX   PubMed=25897075; DOI=10.1074/jbc.m114.633057;
RA   Koo J., Wu X., Mao Z., Khuri F.R., Sun S.Y.;
RT   "Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-
RT   mediated Ubiquitination and Proteasomal Degradation.";
RL   J. Biol. Chem. 290:14120-14129(2015).
RN   [58]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=25733715; DOI=10.1083/jcb.201406020;
RA   Albrecht L.V., Zhang L., Shabanowitz J., Purevjav E., Towbin J.A.,
RA   Hunt D.F., Green K.J.;
RT   "GSK3- and PRMT-1-dependent modifications of desmoplakin control
RT   desmoplakin-cytoskeleton dynamics.";
RL   J. Cell Biol. 208:597-612(2015).
RN   [59]
RP   INTERACTION WITH GSKIP, AND COMPLEX FORMATION WITH PRKAR2A AND GSKIP.
RX   PubMed=27484798; DOI=10.1074/jbc.m116.738047;
RA   Dema A., Schroeter M.F., Perets E., Skroblin P., Moutty M.C., Deak V.A.,
RA   Birchmeier W., Klussmann E.;
RT   "The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3beta
RT   Interaction Protein (GSKIP) Regulates beta-Catenin through Its Interactions
RT   with Both Protein Kinase A (PKA) and GSK3beta.";
RL   J. Biol. Chem. 291:19618-19630(2016).
RN   [60]
RP   INTERACTION WITH AXIN1 AND GID8.
RX   PubMed=28829046; DOI=10.1038/cr.2017.107;
RA   Lu Y., Xie S., Zhang W., Zhang C., Gao C., Sun Q., Cai Y., Xu Z., Xiao M.,
RA   Xu Y., Huang X., Wu X., Liu W., Wang F., Kang Y., Zhou T.;
RT   "Twa1/Gid8 is a beta-catenin nuclear retention factor in Wnt signaling and
RT   colorectal tumorigenesis.";
RL   Cell Res. 27:1422-1440(2017).
RN   [61]
RP   FUNCTION, AND INTERACTION WITH BMAL1.
RX   PubMed=28903391; DOI=10.18632/oncotarget.18973;
RA   Lu Y., Zheng X., Hu W., Bian S., Zhang Z., Tao D., Liu Y., Ma Y.;
RT   "Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating
RT   the stability and activity of BMAL1 and CLOCK.";
RL   Oncotarget 8:54913-54924(2017).
RN   [62]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-9.
RX   PubMed=28992046; DOI=10.1093/jmcb/mjx034;
RA   Wang D., Zhao J., Li S., Wei J., Nan L., Mallampalli R.K.,
RA   Weathington N.M., Ma H., Zhao Y.;
RT   "Phosphorylated E2F1 is stabilized by nuclear USP11 to drive Peg10 gene
RT   expression and activate lung epithelial cells.";
RL   J. Mol. Cell Biol. 10:60-73(2018).
RN   [63]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=25827072; DOI=10.1016/j.canlet.2015.03.037;
RA   Jin Y., Shenoy A.K., Doernberg S., Chen H., Luo H., Shen H., Lin T.,
RA   Tarrash M., Cai Q., Hu X., Fiske R., Chen T., Wu L., Mohammed K.A.,
RA   Rottiers V., Lee S.S., Lu J.;
RT   "FBXO11 promotes ubiquitination of the Snail family of transcription
RT   factors in cancer progression and epidermal development.";
RL   Cancer Lett. 362:70-82(2015).
RN   [64]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=29059170; DOI=10.1038/onc.2017.370;
RA   Liu Y., Zhou H., Zhu R., Ding F., Li Y., Cao X., Liu Z.;
RT   "SPSB3 targets SNAIL for degradation in GSK-3beta phosphorylation-dependent
RT   manner and regulates metastasis.";
RL   Oncogene 37:768-776(2018).
RN   [65]
RP   FUNCTION.
RX   PubMed=30704899; DOI=10.1016/j.molcel.2018.12.017;
RA   Cheng X., Ma X., Zhu Q., Song D., Ding X., Li L., Jiang X., Wang X.,
RA   Tian R., Su H., Shen Z., Chen S., Liu T., Gong W., Liu W., Sun Q.;
RT   "Pacer is a mediator of mTORC1 and GSK3-TIP60 signaling in regulation of
RT   autophagosome maturation and lipid metabolism.";
RL   Mol. Cell 73:1-15(2019).
RN   [66]
RP   INTERACTION WITH LMBR1L.
RX   PubMed=31073040; DOI=10.1126/science.aau0812;
RA   Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J.,
RA   Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M.,
RA   Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y.,
RA   Beutler B.;
RT   "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling.";
RL   Science 364:0-0(2019).
RN   [67]
RP   INTERACTION WITH PKP3.
RX   PubMed=34058472; DOI=10.1016/j.bbrc.2021.05.043;
RA   Hong J.Y., Zapata J., Blackburn A., Baumert R., Bae S.M., Ji H., Nam H.J.,
RA   Miller R.K., McCrea P.D.;
RT   "A catenin of the plakophilin-subfamily, Pkp3, responds to canonical-Wnt
RT   pathway components and signals.";
RL   Biochem. Biophys. Res. Commun. 563:31-39(2021).
RN   [68]
RP   PHOSPHORYLATION AT SER-9, MUTAGENESIS OF CYS-14, SUBCELLULAR LOCATION, AND
RP   PALMITOYLATION AT CYS-14.
RX   PubMed=35606353; DOI=10.1038/s41389-022-00402-w;
RA   Zhao C., Yu H., Fan X., Niu W., Fan J., Sun S., Gong M., Zhao B., Fang Z.,
RA   Chen X.;
RT   "GSK3beta palmitoylation mediated by ZDHHC4 promotes tumorigenicity of
RT   glioblastoma stem cells in temozolomide-resistant glioblastoma through the
RT   EZH2-STAT3 axis.";
RL   Oncogenesis 11:28-28(2022).
RN   [69]
RP   PHOSPHORYLATION AT SER-9.
RX   PubMed=34764205; DOI=10.1158/0008-5472.can-21-1020;
RA   Ren X., Rong Z., Liu X., Gao J., Xu X., Zi Y., Mu Y., Guan Y., Cao Z.,
RA   Zhang Y., Zeng Z., Fan Q., Wang X., Pei Q., Wang X., Xin H., Li Z., Nie Y.,
RA   Qiu Z., Li N., Sun L., Deng Y.;
RT   "The Protein Kinase Activity of NME7 Activates Wnt/beta-Catenin Signaling
RT   to Promote One-Carbon Metabolism in Hepatocellular Carcinoma.";
RL   Cancer Res. 82:60-74(2022).
RN   [70]
RP   X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 35-386.
RX   PubMed=11440715; DOI=10.1016/s0092-8674(01)00374-9;
RA   Dajani R., Fraser E., Roe S.M., Young N., Good V., Dale T.C., Pearl L.H.;
RT   "Crystal structure of glycogen synthase kinase 3 beta: structural basis for
RT   phosphate-primed substrate specificity and autoinhibition.";
RL   Cell 105:721-732(2001).
RN   [71]
RP   X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 27-393 OF PHOSPHORYLATED GSK3B.
RX   PubMed=11738041; DOI=10.1016/s0969-2126(01)00679-7;
RA   Bax B., Carter P.S., Lewis C., Guy A.R., Bridges A., Tanner R., Pettman G.,
RA   Mannix C., Culbert A.A., Brown M.J.B., Smith D.G., Reith A.D.;
RT   "The structure of phosphorylated GSK-3beta complexed with a peptide,
RT   FRATtide, that inhibits beta-catenin phosphorylation.";
RL   Structure 9:1143-1152(2001).
RN   [72]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 35-384 IN COMPLEX WITH AXIN1,
RP   INTERACTION WITH AXIN1 AND FRAT1, FUNCTION, ACTIVITY REGULATION, AND
RP   PHOSPHORYLATION AT TYR-216.
RX   PubMed=12554650; DOI=10.1093/emboj/cdg068;
RA   Dajani R., Fraser E., Roe S.M., Yeo M., Good V.M., Thompson V., Dale T.C.,
RA   Pearl L.H.;
RT   "Structural basis for recruitment of glycogen synthase kinase 3beta to the
RT   axin-APC scaffold complex.";
RL   EMBO J. 22:494-501(2003).
CC   -!- FUNCTION: Constitutively active protein kinase that acts as a negative
CC       regulator in the hormonal control of glucose homeostasis, Wnt signaling
CC       and regulation of transcription factors and microtubules, by
CC       phosphorylating and inactivating glycogen synthase (GYS1 or GYS2),
CC       EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN,
CC       NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:11430833, PubMed:12554650,
CC       PubMed:14690523, PubMed:16484495, PubMed:1846781, PubMed:20937854,
CC       PubMed:9072970). Requires primed phosphorylation of the majority of its
CC       substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle,
CC       contributes to insulin regulation of glycogen synthesis by
CC       phosphorylating and inhibiting GYS1 activity and hence glycogen
CC       synthesis (PubMed:8397507). May also mediate the development of insulin
CC       resistance by regulating activation of transcription factors
CC       (PubMed:8397507). Regulates protein synthesis by controlling the
CC       activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as
CC       glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a
CC       multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and
CC       phosphorylates the N-terminus of CTNNB1 leading to its degradation
CC       mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN
CC       at sites proximal to its DNA-binding domain, thereby reducing its
CC       affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on
CC       conserved serine residues promoting NFATC1/NFATC nuclear export,
CC       shutting off NFATC1/NFATC gene regulation, and thereby opposing the
CC       action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on
CC       'Thr-548', decreasing significantly MAPT/TAU ability to bind and
CC       stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal
CC       component of neurofibrillary tangles in Alzheimer disease
CC       (PubMed:14690523). Plays an important role in ERBB2-dependent
CC       stabilization of microtubules at the cell cortex (PubMed:20937854).
CC       Phosphorylates MACF1, inhibiting its binding to microtubules which is
CC       critical for its role in bulge stem cell migration and skin wound
CC       repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the
CC       transcriptional level and is required for the NF-kappa-B-mediated anti-
CC       apoptotic response to TNF (TNF/TNFA) (By similarity). Negatively
CC       regulates replication in pancreatic beta-cells, resulting in apoptosis,
CC       loss of beta-cells and diabetes (By similarity). Through
CC       phosphorylation of the anti-apoptotic protein MCL1, may control cell
CC       apoptosis in response to growth factors deprivation (By similarity).
CC       Phosphorylates MUC1 in breast cancer cells, decreasing the interaction
CC       of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the
CC       establishment of neuronal polarity and axon outgrowth
CC       (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its
CC       activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to
CC       sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1
CC       which enhances its antiviral activity (PubMed:22514281). Phosphorylates
CC       SNAI1, leading to its ubiquitination and proteasomal degradation
CC       (PubMed:15448698, PubMed:15647282, PubMed:25827072, PubMed:29059170).
CC       Phosphorylates SFPQ at 'Thr-687' upon T-cell activation
CC       (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and
CC       stabilizes it by protecting it from proteasomal degradation. Regulates
CC       the circadian clock via phosphorylation of the major clock components
CC       including BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391).
CC       Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by
CC       the SCF(FBXO3) complex and proteasomal degradation (By similarity).
CC       Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal
CC       degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and
CC       'Ser-21' and primes it for ubiquitination and proteasomal degradation
CC       (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which
CC       positively regulates its activity. Phosphorylates MYCN in neuroblastoma
CC       cells which may promote its degradation (PubMed:24391509). Regulates
CC       the circadian rhythmicity of hippocampal long-term potentiation and
CC       BMAL1 and PER2 expression (By similarity). Acts as a regulator of
CC       autophagy by mediating phosphorylation of KAT5/TIP60 under starvation
CC       conditions, activating KAT5/TIP60 acetyltransferase activity and
CC       promoting acetylation of key autophagy regulators, such as ULK1 and
CC       RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic
CC       apoptotic signaling pathway via death domain receptors. Promotes the
CC       formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B,
CC       at death receptors, including TNFRSF10B. The anti-apoptotic function is
CC       most effective with weak apoptotic signals and can be overcome by
CC       stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting
CC       the interaction between E2F1 and USP11, stabilizing E2F1 and promoting
CC       its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2
CC       complex component RICTOR at 'Ser-1235' in response to endoplasmic
CC       stress, inhibiting mTORC2 (PubMed:21343617). Phosphorylates mTORC2
CC       complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated
CC       ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
CC       Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4)
CC       complex and FXR1 degradation by the proteasome (By similarity).
CC       Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its
CC       proteasomal degradation (By similarity). Phosphorylates and inhibits
CC       the CTP synthase and protein-asparagine deamidase activities of CTPS1
CC       (PubMed:17681942). Phosphorylates DSP at multiple sequential serine
CC       residues in the C-terminus tail, promoting its recruitment to
CC       developing desmosome cell-cell junctions (PubMed:25733715).
CC       {ECO:0000250|UniProtKB:P18266, ECO:0000250|UniProtKB:Q9WV60,
CC       ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650,
CC       ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698,
CC       ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495,
CC       ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942,
CC       ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781,
CC       ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19946213,
CC       ECO:0000269|PubMed:20067585, ECO:0000269|PubMed:20932480,
CC       ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21343617,
CC       ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509,
CC       ECO:0000269|PubMed:25733715, ECO:0000269|PubMed:25827072,
CC       ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:28903391,
CC       ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:29059170,
CC       ECO:0000269|PubMed:30704899, ECO:0000269|PubMed:8397507,
CC       ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein]
CC         + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC         COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC         Evidence={ECO:0000269|PubMed:14690523};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau
CC         protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC         Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.26; Evidence={ECO:0000269|PubMed:14690523};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942,
CC         ECO:0000269|PubMed:21343617, ECO:0000269|PubMed:22539723,
CC         ECO:0000269|PubMed:25827072, ECO:0000269|PubMed:28992046,
CC         ECO:0000269|PubMed:29059170};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:17050006};
CC   -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-216. In
CC       response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1
CC       and RPS6KA3; phosphorylation at this site causes a conformational
CC       change, preventing access of substrates to the active site. Inhibited
CC       by IL22 treatment which also triggers phosphorylation at Ser-9,
CC       promoting inactivation (By similarity). Inhibited by lithium.
CC       {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11749387,
CC       ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:19366350,
CC       ECO:0000269|PubMed:8524413}.
CC   -!- SUBUNIT: Monomer. Interacts with ARRB2, DISC1 and ZBED3 (By
CC       similarity). Interacts with CABYR, MMP2, MUC1, NIN and PRUNE1.
CC       Interacts with AXIN1; the interaction mediates hyperphosphorylation of
CC       CTNNB1 leading to its ubiquitination and destruction. Interacts with
CC       and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal
CC       domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and
CC       GSK3B (By similarity). Interacts with SGK3. Interacts with DAB2IP (via
CC       C2 domain); the interaction stimulates GSK3B kinase activation.
CC       Interacts (via C2 domain) with PPP2CA. Interacts with the CLOCK-BMAL1
CC       heterodimer (PubMed:19946213). Interacts with the BMAL1
CC       (PubMed:28903391). Interacts with CTNND2 (PubMed:19706605). Interacts
CC       with NCYM (PubMed:24391509). The complex composed, at least, of APC,
CC       CTNNB1 and GSK3B interacts with JPT1; the interaction requires the
CC       inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422).
CC       Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through
CC       GSKIP interaction; facilitates PKA-induced phosphorylation and
CC       regulates GSK3B activity (PubMed:20007971, PubMed:25920809,
CC       PubMed:27484798). Interacts with GSKIP (PubMed:16981698). Interacts
CC       with GID8 (PubMed:28829046). Interacts with PIWIL2 (By similarity).
CC       Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X
CC       (PubMed:18846110). Interacts with BIRC2 (PubMed:18846110). Interacts
CC       with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity
CC       (PubMed:18846110). Interacts with RICTOR; the interaction results in
CC       phosphorylation of RICTOR at 'Thr-1695' by GSK3B which facilitates
CC       FBXW7-mediated ubiquitination and subsequent degradation of RICTOR
CC       (PubMed:25897075). Found in a complex with SLC39A6, SLC39A10 and with
CC       GSK3B that controls NCAM1 phosphorylation (By similarity). Interacts
CC       with PKP3 (via ARM repeats); the interaction may be involved in PKP3
CC       protein degradation (PubMed:34058472). {ECO:0000250|UniProtKB:P18266,
CC       ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11004522,
CC       ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12554650,
CC       ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282,
CC       ECO:0000269|PubMed:15752768, ECO:0000269|PubMed:16428445,
CC       ECO:0000269|PubMed:16981698, ECO:0000269|PubMed:17318175,
CC       ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19493954,
CC       ECO:0000269|PubMed:19706605, ECO:0000269|PubMed:19946213,
CC       ECO:0000269|PubMed:20007971, ECO:0000269|PubMed:20080667,
CC       ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25169422,
CC       ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:25920809,
CC       ECO:0000269|PubMed:27484798, ECO:0000269|PubMed:28829046,
CC       ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:31073040,
CC       ECO:0000269|PubMed:34058472, ECO:0000269|PubMed:9731200,
CC       ECO:0000269|PubMed:9819408}.
CC   -!- INTERACTION:
CC       P49841; P31749: AKT1; NbExp=5; IntAct=EBI-373586, EBI-296087;
CC       P49841; P31751: AKT2; NbExp=2; IntAct=EBI-373586, EBI-296058;
CC       P49841; PRO_0000000093 [P05067]: APP; NbExp=2; IntAct=EBI-373586, EBI-2431589;
CC       P49841; O15169: AXIN1; NbExp=52; IntAct=EBI-373586, EBI-710484;
CC       P49841; Q9Y2T1: AXIN2; NbExp=6; IntAct=EBI-373586, EBI-4400025;
CC       P49841; Q96G01: BICD1; NbExp=7; IntAct=EBI-373586, EBI-1104509;
CC       P49841; O75952-3: CABYR; NbExp=3; IntAct=EBI-373586, EBI-10900795;
CC       P49841; O75952-5: CABYR; NbExp=3; IntAct=EBI-373586, EBI-10898671;
CC       P49841; P35222: CTNNB1; NbExp=20; IntAct=EBI-373586, EBI-491549;
CC       P49841; Q5VWQ8: DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-2871881;
CC       P49841; Q5VWQ8-2: DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-9543020;
CC       P49841; Q9NYF0: DACT1; NbExp=3; IntAct=EBI-373586, EBI-3951744;
CC       P49841; O75398: DEAF1; NbExp=2; IntAct=EBI-373586, EBI-718185;
CC       P49841; Q13144: EIF2B5; NbExp=2; IntAct=EBI-373586, EBI-4401110;
CC       P49841; Q92837: FRAT1; NbExp=5; IntAct=EBI-373586, EBI-3934879;
CC       P49841; Q9P0R6: GSKIP; NbExp=10; IntAct=EBI-373586, EBI-1052580;
CC       P49841; P13807: GYS1; NbExp=4; IntAct=EBI-373586, EBI-740553;
CC       P49841; O75581: LRP6; NbExp=4; IntAct=EBI-373586, EBI-910915;
CC       P49841; Q5S007: LRRK2; NbExp=7; IntAct=EBI-373586, EBI-5323863;
CC       P49841; P10636: MAPT; NbExp=4; IntAct=EBI-373586, EBI-366182;
CC       P49841; P10636-8: MAPT; NbExp=12; IntAct=EBI-373586, EBI-366233;
CC       P49841; Q14596: NBR1; NbExp=4; IntAct=EBI-373586, EBI-742698;
CC       P49841; Q8N4C6: NIN; NbExp=3; IntAct=EBI-373586, EBI-1164022;
CC       P49841; P17612: PRKACA; NbExp=7; IntAct=EBI-373586, EBI-476586;
CC       P49841; Q01201: RELB; NbExp=4; IntAct=EBI-373586, EBI-357837;
CC       P49841; Q13485: SMAD4; NbExp=5; IntAct=EBI-373586, EBI-347263;
CC       P49841; Q9NRG4: SMYD2; NbExp=2; IntAct=EBI-373586, EBI-1055671;
CC       P49841; O95863: SNAI1; NbExp=5; IntAct=EBI-373586, EBI-1045459;
CC       P49841; P37840: SNCA; NbExp=2; IntAct=EBI-373586, EBI-985879;
CC       P49841; Q6J9G0: STYK1; NbExp=2; IntAct=EBI-373586, EBI-6424915;
CC       P49841; P04637: TP53; NbExp=3; IntAct=EBI-373586, EBI-366083;
CC       P49841; Q14134: TRIM29; NbExp=2; IntAct=EBI-373586, EBI-702370;
CC       P49841; O95071: UBR5; NbExp=8; IntAct=EBI-373586, EBI-358329;
CC       P49841; P67809: YBX1; NbExp=2; IntAct=EBI-373586, EBI-354065;
CC       P49841; P16989: YBX3; NbExp=2; IntAct=EBI-373586, EBI-358193;
CC       P49841; P63104: YWHAZ; NbExp=4; IntAct=EBI-373586, EBI-347088;
CC       P49841; Q8IX07: ZFPM1; NbExp=2; IntAct=EBI-373586, EBI-3942619;
CC       P49841; O35625: Axin1; Xeno; NbExp=5; IntAct=EBI-373586, EBI-2365912;
CC       P49841; Q14DJ8: Axin1; Xeno; NbExp=2; IntAct=EBI-373586, EBI-4312125;
CC       P49841; Q02248: Ctnnb1; Xeno; NbExp=3; IntAct=EBI-373586, EBI-397872;
CC       P49841; Q811T9: Disc1; Xeno; NbExp=4; IntAct=EBI-373586, EBI-2298259;
CC       P49841; P63085: Mapk1; Xeno; NbExp=2; IntAct=EBI-373586, EBI-397697;
CC       P49841; P0DTC9: N; Xeno; NbExp=3; IntAct=EBI-373586, EBI-25475856;
CC       P49841-2; P05067: APP; NbExp=3; IntAct=EBI-15870655, EBI-77613;
CC       P49841-2; P35637: FUS; NbExp=3; IntAct=EBI-15870655, EBI-400434;
CC       P49841-2; P01106: MYC; NbExp=3; IntAct=EBI-15870655, EBI-447544;
CC       P49841-2; Q8BMD2-1: Dzip1; Xeno; NbExp=3; IntAct=EBI-15870655, EBI-16153101;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21029237,
CC       ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:25733715,
CC       ECO:0000269|PubMed:35606353}. Nucleus {ECO:0000269|PubMed:15448698,
CC       ECO:0000269|PubMed:21029237}. Cell membrane
CC       {ECO:0000269|PubMed:20937854}. Note=The phosphorylated form shows
CC       localization to cytoplasm and cell membrane (PubMed:20937854). The
CC       MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the
CC       phosphorylated form to the cell membrane (PubMed:20937854).
CC       {ECO:0000269|PubMed:20937854}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1; Synonyms=GSK-3beta1;
CC         IsoId=P49841-1; Sequence=Displayed;
CC       Name=2; Synonyms=GSK-3beta2, neuron-specific;
CC         IsoId=P49841-2; Sequence=VSP_004790;
CC   -!- TISSUE SPECIFICITY: Expressed in testis, thymus, prostate and ovary and
CC       weakly expressed in lung, brain and kidney. Colocalizes with
CC       EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain.
CC       {ECO:0000269|PubMed:21029237}.
CC   -!- PTM: Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling,
CC       the activated PKB/AKT1 protein kinase phosphorylates and deactivates
CC       GSK3B, resulting in the dephosphorylation and activation of GYS1.
CC       Activated by phosphorylation at Tyr-216 (PubMed:25169422). Inactivated
CC       by phosphorylation at Ser-9 (Probable). Phosphorylated in a circadian
CC       manner in the hippocampus (By similarity).
CC       {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:12054501,
CC       ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:16484495,
CC       ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21029237,
CC       ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:8250835,
CC       ECO:0000305|PubMed:25169422}.
CC   -!- PTM: Mono-ADP-ribosylation by PARP10 negatively regulates kinase
CC       activity. {ECO:0000269|PubMed:23332125}.
CC   -!- PTM: Palmitoylated. Palmitoylation by ZDHHC4 prevents AKT1-mediated
CC       phosphorylation. {ECO:0000269|PubMed:35606353}.
CC   -!- MISCELLANEOUS: Higher expression and activity of GSK3B are found in the
CC       skeletal muscle (vastus lateralis) of patients with type 2 diabetes
CC       (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors
CC       have been identified and characterized in preclinical models for
CC       treatments of type 2 diabetes (PubMed:19366350).
CC       {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}.
CC   -!- MISCELLANEOUS: [Isoform 2]: May play a specific role in axon growth and
CC       neurite outgrowth. Reduced binding to AXIN1, reduced ability to
CC       phosphorylate MAPT/TAU. {ECO:0000269|PubMed:20067585}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. GSK-3 subfamily. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/40761/GSK3B";
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; L33801; AAA66475.1; -; mRNA.
DR   EMBL; CH471052; EAW79533.1; -; Genomic_DNA.
DR   EMBL; CH471052; EAW79536.1; -; Genomic_DNA.
DR   EMBL; BC000251; AAH00251.1; -; mRNA.
DR   EMBL; BC012760; AAH12760.1; -; mRNA.
DR   EMBL; AF074333; AAD48517.1; -; Genomic_DNA.
DR   EMBL; AF098789; AAC69340.1; -; Genomic_DNA.
DR   CCDS; CCDS2996.1; -. [P49841-2]
DR   CCDS; CCDS54628.1; -. [P49841-1]
DR   PIR; S53324; S53324.
DR   RefSeq; NP_001139628.1; NM_001146156.2. [P49841-1]
DR   RefSeq; NP_002084.2; NM_002093.3. [P49841-2]
DR   PDB; 1GNG; X-ray; 2.60 A; A/B=27-393.
DR   PDB; 1H8F; X-ray; 2.80 A; A/B=35-386.
DR   PDB; 1I09; X-ray; 2.70 A; A/B=1-420.
DR   PDB; 1J1B; X-ray; 1.80 A; A/B=1-420.
DR   PDB; 1J1C; X-ray; 2.10 A; A/B=1-420.
DR   PDB; 1O6K; X-ray; 1.70 A; C=3-12.
DR   PDB; 1O6L; X-ray; 1.60 A; C=3-12.
DR   PDB; 1O9U; X-ray; 2.40 A; A=35-384.
DR   PDB; 1PYX; X-ray; 2.40 A; A/B=1-420.
DR   PDB; 1Q3D; X-ray; 2.20 A; A/B=2-420.
DR   PDB; 1Q3W; X-ray; 2.30 A; A/B=2-420.
DR   PDB; 1Q41; X-ray; 2.10 A; A/B=2-420.
DR   PDB; 1Q4L; X-ray; 2.77 A; A/B=2-420.
DR   PDB; 1Q5K; X-ray; 1.94 A; A/B=7-420.
DR   PDB; 1R0E; X-ray; 2.25 A; A/B=35-420.
DR   PDB; 1UV5; X-ray; 2.80 A; A=35-384.
DR   PDB; 2JDO; X-ray; 1.80 A; C=3-12.
DR   PDB; 2JDR; X-ray; 2.30 A; C=3-12.
DR   PDB; 2JLD; X-ray; 2.35 A; A/B=1-420.
DR   PDB; 2O5K; X-ray; 3.20 A; A=29-393.
DR   PDB; 2OW3; X-ray; 2.80 A; A/B=35-386.
DR   PDB; 2UW9; X-ray; 2.10 A; C=3-12.
DR   PDB; 2X39; X-ray; 1.93 A; C=3-12.
DR   PDB; 2XH5; X-ray; 2.72 A; C=3-12.
DR   PDB; 3CQU; X-ray; 2.20 A; C=3-12.
DR   PDB; 3CQW; X-ray; 2.00 A; C=3-12.
DR   PDB; 3DU8; X-ray; 2.20 A; A/B=1-420.
DR   PDB; 3E87; X-ray; 2.30 A; C/D=3-12.
DR   PDB; 3E88; X-ray; 2.50 A; C/D=3-12.
DR   PDB; 3E8D; X-ray; 2.70 A; C/D=3-12.
DR   PDB; 3F7Z; X-ray; 2.40 A; A/B=35-383.
DR   PDB; 3F88; X-ray; 2.60 A; A/B=35-383.
DR   PDB; 3GB2; X-ray; 2.40 A; A=34-383.
DR   PDB; 3I4B; X-ray; 2.30 A; A/B=7-420.
DR   PDB; 3L1S; X-ray; 2.90 A; A/B=7-420.
DR   PDB; 3M1S; X-ray; 3.13 A; A/B=1-420.
DR   PDB; 3MV5; X-ray; 2.47 A; C=3-12.
DR   PDB; 3OW4; X-ray; 2.60 A; C/D=3-12.
DR   PDB; 3PUP; X-ray; 2.99 A; A/B=1-420.
DR   PDB; 3Q3B; X-ray; 2.70 A; A/B=2-420.
DR   PDB; 3QKK; X-ray; 2.30 A; C=3-12.
DR   PDB; 3QKL; X-ray; 1.90 A; C=3-12.
DR   PDB; 3SAY; X-ray; 2.23 A; A/B=1-420.
DR   PDB; 3SD0; X-ray; 2.70 A; A/B=35-384.
DR   PDB; 3ZDI; X-ray; 2.64 A; A=35-384.
DR   PDB; 3ZRK; X-ray; 2.37 A; A/B=23-393.
DR   PDB; 3ZRL; X-ray; 2.48 A; A/B=23-393.
DR   PDB; 3ZRM; X-ray; 2.49 A; A/B=23-393.
DR   PDB; 4ACC; X-ray; 2.21 A; A/B=1-420.
DR   PDB; 4ACD; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 4ACG; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 4ACH; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 4AFJ; X-ray; 1.98 A; A/B=27-393.
DR   PDB; 4B7T; X-ray; 2.77 A; A=35-384.
DR   PDB; 4DIT; X-ray; 2.60 A; A=27-393.
DR   PDB; 4EKK; X-ray; 2.80 A; C/D=3-12.
DR   PDB; 4IQ6; X-ray; 3.12 A; A/B=1-420.
DR   PDB; 4J1R; X-ray; 2.70 A; A/B/C/D=1-420.
DR   PDB; 4J71; X-ray; 2.31 A; A/B=1-420.
DR   PDB; 4NM0; X-ray; 2.50 A; A=1-383.
DR   PDB; 4NM3; X-ray; 2.10 A; A=1-383.
DR   PDB; 4NM5; X-ray; 2.30 A; A=13-383.
DR   PDB; 4NM7; X-ray; 2.30 A; A=13-383.
DR   PDB; 4PTC; X-ray; 2.71 A; A/B=1-420.
DR   PDB; 4PTE; X-ray; 2.03 A; A/B=1-420.
DR   PDB; 4PTG; X-ray; 2.36 A; A/B=1-420.
DR   PDB; 5F94; X-ray; 2.51 A; A/B=36-385.
DR   PDB; 5F95; X-ray; 2.52 A; A/B=36-385.
DR   PDB; 5HLN; X-ray; 3.10 A; A/B=1-420.
DR   PDB; 5HLP; X-ray; 2.45 A; A/B=1-420.
DR   PDB; 5K5N; X-ray; 2.20 A; A/B=28-384.
DR   PDB; 5KPK; X-ray; 2.40 A; A/B=1-420.
DR   PDB; 5KPL; X-ray; 2.60 A; A/B=1-420.
DR   PDB; 5KPM; X-ray; 2.69 A; A/B=1-420.
DR   PDB; 5OY4; X-ray; 3.20 A; A/B=1-420.
DR   PDB; 5T31; X-ray; 2.85 A; A/B=1-420.
DR   PDB; 6B8J; X-ray; 2.60 A; A=1-420.
DR   PDB; 6BUU; X-ray; 2.40 A; F/G=3-12.
DR   PDB; 6GJO; X-ray; 2.91 A; A/B=7-420.
DR   PDB; 6GN1; X-ray; 2.60 A; A/B=27-393.
DR   PDB; 6H0U; X-ray; 2.30 A; A/B=1-420.
DR   PDB; 6HK3; X-ray; 2.35 A; A/B=35-384.
DR   PDB; 6HK4; X-ray; 2.50 A; A/B=35-384.
DR   PDB; 6HK7; X-ray; 3.20 A; A=36-382.
DR   PDB; 6NPZ; X-ray; 2.12 A; F/G=3-12.
DR   PDB; 6TCU; X-ray; 2.14 A; A=35-386.
DR   PDB; 6V6L; X-ray; 2.19 A; A=1-420.
DR   PDB; 6Y9R; X-ray; 2.08 A; A=35-384.
DR   PDB; 6Y9S; X-ray; 2.03 A; A/B=35-384.
DR   PDB; 7B6F; X-ray; 2.05 A; A=26-383.
DR   PDB; 7OY5; X-ray; 2.57 A; A/B=35-385.
DR   PDB; 7SXH; X-ray; 2.09 A; A=37-383.
DR   PDB; 7SXJ; X-ray; 1.85 A; A=34-383.
DR   PDB; 7U2Z; X-ray; 2.21 A; A/B=35-382.
DR   PDB; 7U31; X-ray; 2.38 A; A/B=36-385.
DR   PDB; 7U33; X-ray; 2.60 A; A/B=35-385.
DR   PDB; 7U36; X-ray; 2.75 A; A/B=35-385.
DR   PDB; 7Z1F; X-ray; 3.00 A; A/B=26-383.
DR   PDB; 7Z1G; X-ray; 2.85 A; A=26-383.
DR   PDB; 8AUZ; X-ray; 2.66 A; A/B=26-383.
DR   PDB; 8AV1; X-ray; 2.15 A; A/B=26-383.
DR   PDB; 8DJC; X-ray; 2.46 A; A/B=1-420.
DR   PDB; 8DJD; X-ray; 2.21 A; A/B=1-420.
DR   PDB; 8DJE; X-ray; 2.37 A; A/B=1-420.
DR   PDB; 8FF8; X-ray; 2.33 A; A/B=1-420.
DR   PDB; 8QJI; X-ray; 3.02 A; A=26-383.
DR   PDB; 8XN6; X-ray; 2.40 A; A/B=2-420.
DR   PDB; 9HUK; X-ray; 3.50 A; A/B=2-420.
DR   PDB; 9HUL; X-ray; 2.90 A; A/B=2-420.
DR   PDB; 9HV3; X-ray; 2.90 A; A/B=2-420.
DR   PDBsum; 1GNG; -.
DR   PDBsum; 1H8F; -.
DR   PDBsum; 1I09; -.
DR   PDBsum; 1J1B; -.
DR   PDBsum; 1J1C; -.
DR   PDBsum; 1O6K; -.
DR   PDBsum; 1O6L; -.
DR   PDBsum; 1O9U; -.
DR   PDBsum; 1PYX; -.
DR   PDBsum; 1Q3D; -.
DR   PDBsum; 1Q3W; -.
DR   PDBsum; 1Q41; -.
DR   PDBsum; 1Q4L; -.
DR   PDBsum; 1Q5K; -.
DR   PDBsum; 1R0E; -.
DR   PDBsum; 1UV5; -.
DR   PDBsum; 2JDO; -.
DR   PDBsum; 2JDR; -.
DR   PDBsum; 2JLD; -.
DR   PDBsum; 2O5K; -.
DR   PDBsum; 2OW3; -.
DR   PDBsum; 2UW9; -.
DR   PDBsum; 2X39; -.
DR   PDBsum; 2XH5; -.
DR   PDBsum; 3CQU; -.
DR   PDBsum; 3CQW; -.
DR   PDBsum; 3DU8; -.
DR   PDBsum; 3E87; -.
DR   PDBsum; 3E88; -.
DR   PDBsum; 3E8D; -.
DR   PDBsum; 3F7Z; -.
DR   PDBsum; 3F88; -.
DR   PDBsum; 3GB2; -.
DR   PDBsum; 3I4B; -.
DR   PDBsum; 3L1S; -.
DR   PDBsum; 3M1S; -.
DR   PDBsum; 3MV5; -.
DR   PDBsum; 3OW4; -.
DR   PDBsum; 3PUP; -.
DR   PDBsum; 3Q3B; -.
DR   PDBsum; 3QKK; -.
DR   PDBsum; 3QKL; -.
DR   PDBsum; 3SAY; -.
DR   PDBsum; 3SD0; -.
DR   PDBsum; 3ZDI; -.
DR   PDBsum; 3ZRK; -.
DR   PDBsum; 3ZRL; -.
DR   PDBsum; 3ZRM; -.
DR   PDBsum; 4ACC; -.
DR   PDBsum; 4ACD; -.
DR   PDBsum; 4ACG; -.
DR   PDBsum; 4ACH; -.
DR   PDBsum; 4AFJ; -.
DR   PDBsum; 4B7T; -.
DR   PDBsum; 4DIT; -.
DR   PDBsum; 4EKK; -.
DR   PDBsum; 4IQ6; -.
DR   PDBsum; 4J1R; -.
DR   PDBsum; 4J71; -.
DR   PDBsum; 4NM0; -.
DR   PDBsum; 4NM3; -.
DR   PDBsum; 4NM5; -.
DR   PDBsum; 4NM7; -.
DR   PDBsum; 4PTC; -.
DR   PDBsum; 4PTE; -.
DR   PDBsum; 4PTG; -.
DR   PDBsum; 5F94; -.
DR   PDBsum; 5F95; -.
DR   PDBsum; 5HLN; -.
DR   PDBsum; 5HLP; -.
DR   PDBsum; 5K5N; -.
DR   PDBsum; 5KPK; -.
DR   PDBsum; 5KPL; -.
DR   PDBsum; 5KPM; -.
DR   PDBsum; 5OY4; -.
DR   PDBsum; 5T31; -.
DR   PDBsum; 6B8J; -.
DR   PDBsum; 6BUU; -.
DR   PDBsum; 6GJO; -.
DR   PDBsum; 6GN1; -.
DR   PDBsum; 6H0U; -.
DR   PDBsum; 6HK3; -.
DR   PDBsum; 6HK4; -.
DR   PDBsum; 6HK7; -.
DR   PDBsum; 6NPZ; -.
DR   PDBsum; 6TCU; -.
DR   PDBsum; 6V6L; -.
DR   PDBsum; 6Y9R; -.
DR   PDBsum; 6Y9S; -.
DR   PDBsum; 7B6F; -.
DR   PDBsum; 7OY5; -.
DR   PDBsum; 7SXH; -.
DR   PDBsum; 7SXJ; -.
DR   PDBsum; 7U2Z; -.
DR   PDBsum; 7U31; -.
DR   PDBsum; 7U33; -.
DR   PDBsum; 7U36; -.
DR   PDBsum; 7Z1F; -.
DR   PDBsum; 7Z1G; -.
DR   PDBsum; 8AUZ; -.
DR   PDBsum; 8AV1; -.
DR   PDBsum; 8DJC; -.
DR   PDBsum; 8DJD; -.
DR   PDBsum; 8DJE; -.
DR   PDBsum; 8FF8; -.
DR   PDBsum; 8QJI; -.
DR   PDBsum; 8XN6; -.
DR   PDBsum; 9HUK; -.
DR   PDBsum; 9HUL; -.
DR   PDBsum; 9HV3; -.
DR   AlphaFoldDB; P49841; -.
DR   SMR; P49841; -.
DR   BioGRID; 109187; 867.
DR   ComplexPortal; CPX-109; Beta-catenin destruction core complex, APC-AXIN1-GSK3B variant.
DR   ComplexPortal; CPX-439; Beta-catenin destruction core complex, APC-AXIN2-GSK3B variant.
DR   ComplexPortal; CPX-440; Beta-catenin destruction core complex, APC2-AXIN2-GSK3B variant.
DR   ComplexPortal; CPX-459; Nuclear export complex FRAT1-GSK3B.
DR   ComplexPortal; CPX-462; Nuclear export complex FRAT2-GSK3B.
DR   ComplexPortal; CPX-99; Beta-catenin destruction core complex, APC2-AXIN1-GSK3B variant.
DR   CORUM; P49841; -.
DR   DIP; DIP-878N; -.
DR   ELM; P49841; -.
DR   FunCoup; P49841; 3788.
DR   IntAct; P49841; 399.
DR   MINT; P49841; -.
DR   STRING; 9606.ENSP00000324806; -.
DR   BindingDB; P49841; -.
DR   ChEMBL; CHEMBL262; -.
DR   DrugBank; DB08073; (2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE.
DR   DrugBank; DB07149; (7S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoroethyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one.
DR   DrugBank; DB07014; 2-(1,3-benzodioxol-5-yl)-5-[(3-fluoro-4-methoxybenzyl)sulfanyl]-1,3,4-oxadiazole.
DR   DrugBank; DB07676; 3-({[(3S)-3,4-dihydroxybutyl]oxy}amino)-1H,2'H-2,3'-biindol-2'-one.
DR   DrugBank; DB01772; 3-[3-(2,3-Dihydroxy-Propylamino)-Phenyl]-4-(5-Fluoro-1-Methyl-1h-Indol-3-Yl)-Pyrrole-2,5-Dione.
DR   DrugBank; DB07859; 4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE.
DR   DrugBank; DB07585; 5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine.
DR   DrugBank; DB07058; 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2(3H)-thione.
DR   DrugBank; DB03444; 6-bromoindirubin-3'-oxime.
DR   DrugBank; DB04014; Alsterpaullone.
DR   DrugBank; DB01950; AR-AO-14418.
DR   DrugBank; DB03777; Bisindolylmaleimide I.
DR   DrugBank; DB12429; CI-1040.
DR   DrugBank; DB08846; Ellagic acid.
DR   DrugBank; DB16047; Elraglusib.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugBank; DB02052; Indirubin-3'-monoxime.
DR   DrugBank; DB07947; ISOQUINOLINE-5-SULFONIC ACID (2-(2-(4-CHLOROBENZYLOXY)ETHYLAMINO)ETHYL)AMIDE.
DR   DrugBank; DB14509; Lithium carbonate.
DR   DrugBank; DB01356; Lithium cation.
DR   DrugBank; DB14507; Lithium citrate.
DR   DrugBank; DB14508; Lithium succinate.
DR   DrugBank; DB11913; LY-2090314.
DR   DrugBank; DB08454; N-(5-METHYL-1H-PYRAZOL-3-YL)-2-PHENYLQUINAZOLIN-4-AMINE.
DR   DrugBank; DB07812; N-[(1S)-2-amino-1-phenylethyl]-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide.
DR   DrugBank; DB07584; N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
DR   DrugBank; DB07126; O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINE.
DR   DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester.
DR   DrugBank; DB01793; SB-409513.
DR   DrugBank; DB02010; Staurosporine.
DR   DrugBank; DB04462; Tetrabromo-2-Benzotriazole.
DR   DrugBank; DB12129; Tideglusib.
DR   DrugCentral; P49841; -.
DR   GuidetoPHARMACOLOGY; 2030; -.
DR   GlyCosmos; P49841; 3 sites, 1 glycan.
DR   GlyGen; P49841; 24 sites, 1 O-linked glycan (24 sites).
DR   iPTMnet; P49841; -.
DR   PhosphoSitePlus; P49841; -.
DR   SwissPalm; P49841; -.
DR   BioMuta; GSK3B; -.
DR   DMDM; 20455502; -.
DR   CPTAC; CPTAC-3038; -.
DR   CPTAC; CPTAC-3039; -.
DR   CPTAC; CPTAC-5749; -.
DR   CPTAC; CPTAC-5750; -.
DR   CPTAC; CPTAC-5751; -.
DR   CPTAC; CPTAC-5790; -.
DR   CPTAC; CPTAC-5791; -.
DR   CPTAC; CPTAC-804; -.
DR   CPTAC; non-CPTAC-5401; -.
DR   CPTAC; non-CPTAC-5403; -.
DR   CPTAC; non-CPTAC-5404; -.
DR   CPTAC; non-CPTAC-5554; -.
DR   CPTAC; non-CPTAC-5556; -.
DR   CPTAC; non-CPTAC-5705; -.
DR   jPOST; P49841; -.
DR   MassIVE; P49841; -.
DR   PaxDb; 9606-ENSP00000324806; -.
DR   PeptideAtlas; P49841; -.
DR   ProteomicsDB; 56151; -. [P49841-1]
DR   ProteomicsDB; 56152; -. [P49841-2]
DR   Pumba; P49841; -.
DR   Antibodypedia; 4266; 1367 antibodies from 55 providers.
DR   CPTC; P49841; 10 antibodies.
DR   DNASU; 2932; -.
DR   Ensembl; ENST00000264235.13; ENSP00000264235.9; ENSG00000082701.18. [P49841-1]
DR   Ensembl; ENST00000316626.6; ENSP00000324806.5; ENSG00000082701.18. [P49841-2]
DR   GeneID; 2932; -.
DR   KEGG; hsa:2932; -.
DR   MANE-Select; ENST00000264235.13; ENSP00000264235.9; NM_001146156.2; NP_001139628.1.
DR   UCSC; uc003edn.4; human. [P49841-1]
DR   AGR; HGNC:4617; -.
DR   ClinPGx; PA29009; -.
DR   CTD; 2932; -.
DR   DisGeNET; 2932; -.
DR   GeneCards; GSK3B; -.
DR   HGNC; HGNC:4617; GSK3B.
DR   HPA; ENSG00000082701; Low tissue specificity.
DR   MalaCards; GSK3B; -.
DR   MIM; 605004; gene.
DR   OpenTargets; ENSG00000082701; -.
DR   VEuPathDB; HostDB:ENSG00000082701; -.
DR   eggNOG; KOG0658; Eukaryota.
DR   GeneTree; ENSGT00520000055635; -.
DR   HOGENOM; CLU_000288_181_20_1; -.
DR   InParanoid; P49841; -.
DR   OMA; MKTTMPM; -.
DR   OrthoDB; 272141at2759; -.
DR   PAN-GO; P49841; 14 GO annotations based on evolutionary models.
DR   PhylomeDB; P49841; -.
DR   BRENDA; 2.7.11.26; 2681.
DR   PathwayCommons; P49841; -.
DR   Reactome; R-HSA-195253; Degradation of beta-catenin by the destruction complex.
DR   Reactome; R-HSA-196299; Beta-catenin phosphorylation cascade.
DR   Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
DR   Reactome; R-HSA-3371453; Regulation of HSF1-mediated heat shock response.
DR   Reactome; R-HSA-399956; CRMPs in Sema3A signaling.
DR   Reactome; R-HSA-4641262; Disassembly of the destruction complex and recruitment of AXIN to the membrane.
DR   Reactome; R-HSA-5250924; B-WICH complex positively regulates rRNA expression.
DR   Reactome; R-HSA-5339716; Signaling by GSK3beta mutants.
DR   Reactome; R-HSA-5358747; CTNNB1 S33 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5358749; CTNNB1 S37 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5358751; CTNNB1 S45 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5358752; CTNNB1 T41 mutants aren't phosphorylated.
DR   Reactome; R-HSA-5467337; APC truncation mutants have impaired AXIN binding.
DR   Reactome; R-HSA-5467340; AXIN missense mutants destabilize the destruction complex.
DR   Reactome; R-HSA-5467348; Truncations of AMER1 destabilize the destruction complex.
DR   Reactome; R-HSA-5610783; Degradation of GLI2 by the proteasome.
DR   Reactome; R-HSA-5610785; GLI3 is processed to GLI3R by the proteasome.
DR   Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR   Reactome; R-HSA-75815; Ubiquitin-dependent degradation of Cyclin D.
DR   Reactome; R-HSA-8939902; Regulation of RUNX2 expression and activity.
DR   Reactome; R-HSA-9683610; Maturation of nucleoprotein.
DR   Reactome; R-HSA-9694631; Maturation of nucleoprotein.
DR   Reactome; R-HSA-9762114; GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2.
DR   Reactome; R-HSA-9856649; Transcriptional and post-translational regulation of MITF-M expression and activity.
DR   SignaLink; P49841; -.
DR   SIGNOR; P49841; -.
DR   Agora; ENSG00000082701; -.
DR   BioGRID-ORCS; 2932; 75 hits in 1226 CRISPR screens.
DR   CD-CODE; 804901D1; Nuclear speckle.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; GSK3B; human.
DR   EvolutionaryTrace; P49841; -.
DR   GeneWiki; GSK3B; -.
DR   GenomeRNAi; 2932; -.
DR   Pharos; P49841; Tclin.
DR   PRO; PR:P49841; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; P49841; protein.
DR   Bgee; ENSG00000082701; Expressed in calcaneal tendon and 197 other cell types or tissues.
DR   ExpressionAtlas; P49841; baseline and differential.
DR   GO; GO:0030424; C:axon; ISS:ARUK-UCL.
DR   GO; GO:0030877; C:beta-catenin destruction complex; IDA:UniProtKB.
DR   GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0030425; C:dendrite; ISS:ARUK-UCL.
DR   GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR   GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0098794; C:postsynapse; IEA:GOC.
DR   GO; GO:0098793; C:presynapse; IEA:GOC.
DR   GO; GO:1990909; C:Wnt signalosome; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0008013; F:beta-catenin binding; IPI:BHF-UCL.
DR   GO; GO:0034452; F:dynactin binding; IPI:ARUK-UCL.
DR   GO; GO:0016301; F:kinase activity; IDA:UniProtKB.
DR   GO; GO:0051059; F:NF-kappaB binding; IPI:UniProtKB.
DR   GO; GO:0002039; F:p53 binding; IDA:MGI.
DR   GO; GO:0002020; F:protease binding; IPI:ParkinsonsUK-UCL.
DR   GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:BHF-UCL.
DR   GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IGI:ARUK-UCL.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB.
DR   GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL.
DR   GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR   GO; GO:0050321; F:tau-protein kinase activity; IDA:UniProtKB.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL.
DR   GO; GO:0160213; P:beta-arrestin-dependent dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0060070; P:canonical Wnt signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR   GO; GO:1904646; P:cellular response to amyloid-beta; ISS:ARUK-UCL.
DR   GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR   GO; GO:0071300; P:cellular response to retinoic acid; IMP:ARUK-UCL.
DR   GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0001837; P:epithelial to mesenchymal transition; IMP:UniProtKB.
DR   GO; GO:0006983; P:ER overload response; IDA:MGI.
DR   GO; GO:0030010; P:establishment of cell polarity; ISS:ARUK-UCL.
DR   GO; GO:0060079; P:excitatory postsynaptic potential; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISS:ARUK-UCL.
DR   GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB.
DR   GO; GO:0005977; P:glycogen metabolic process; IDA:BHF-UCL.
DR   GO; GO:0003170; P:heart valve development; ISS:BHF-UCL.
DR   GO; GO:0021766; P:hippocampus development; IMP:BHF-UCL.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; IBA:GO_Central.
DR   GO; GO:0035556; P:intracellular signal transduction; IDA:MGI.
DR   GO; GO:0030011; P:maintenance of cell polarity; ISS:ARUK-UCL.
DR   GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IDA:MGI.
DR   GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; IMP:UniProtKB.
DR   GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:ARUK-UCL.
DR   GO; GO:0030336; P:negative regulation of cell migration; IDA:UniProt.
DR   GO; GO:1904339; P:negative regulation of dopaminergic neuron differentiation; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IDA:UniProtKB.
DR   GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IMP:UniProtKB.
DR   GO; GO:0010629; P:negative regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:2000466; P:negative regulation of glycogen (starch) synthase activity; TAS:UniProtKB.
DR   GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; TAS:UniProtKB.
DR   GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:ARUK-UCL.
DR   GO; GO:0045668; P:negative regulation of osteoblast differentiation; IMP:ARUK-UCL.
DR   GO; GO:1900181; P:negative regulation of protein localization to nucleus; ISS:BHF-UCL.
DR   GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IMP:BHF-UCL.
DR   GO; GO:0032007; P:negative regulation of TOR signaling; IBA:GO_Central.
DR   GO; GO:1903940; P:negative regulation of TORC2 signaling; IDA:UniProtKB.
DR   GO; GO:2000077; P:negative regulation of type B pancreatic cell development; TAS:UniProtKB.
DR   GO; GO:0031175; P:neuron projection development; IDA:UniProtKB.
DR   GO; GO:0106027; P:neuron projection organization; ISS:ARUK-UCL.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:MGI.
DR   GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR   GO; GO:0045597; P:positive regulation of cell differentiation; IMP:ARUK-UCL.
DR   GO; GO:0001954; P:positive regulation of cell-matrix adhesion; IMP:BHF-UCL.
DR   GO; GO:0045724; P:positive regulation of cilium assembly; ISS:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; ISS:UniProtKB.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:FlyBase.
DR   GO; GO:0032092; P:positive regulation of protein binding; ISS:UniProtKB.
DR   GO; GO:0045732; P:positive regulation of protein catabolic process; IC:BHF-UCL.
DR   GO; GO:0046827; P:positive regulation of protein export from nucleus; IDA:MGI.
DR   GO; GO:1904781; P:positive regulation of protein localization to centrosome; IMP:ARUK-UCL.
DR   GO; GO:1903566; P:positive regulation of protein localization to cilium; ISS:UniProtKB.
DR   GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProt.
DR   GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL.
DR   GO; GO:0032481; P:positive regulation of type I interferon production; ISS:UniProtKB.
DR   GO; GO:0099171; P:presynaptic modulation of chemical synaptic transmission; IDA:SynGO.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ComplexPortal.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:0030516; P:regulation of axon extension; ISS:ARUK-UCL.
DR   GO; GO:0050770; P:regulation of axonogenesis; ISS:ARUK-UCL.
DR   GO; GO:1900034; P:regulation of cellular response to heat; TAS:Reactome.
DR   GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:ARUK-UCL.
DR   GO; GO:1900271; P:regulation of long-term synaptic potentiation; ISS:UniProtKB.
DR   GO; GO:0150101; P:regulation of microtubule anchoring at centrosome; IMP:ARUK-UCL.
DR   GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:ARUK-UCL.
DR   GO; GO:0032886; P:regulation of microtubule-based process; IMP:UniProtKB.
DR   GO; GO:0010975; P:regulation of neuron projection development; IBA:GO_Central.
DR   GO; GO:0046825; P:regulation of protein export from nucleus; IDA:ComplexPortal.
DR   GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:UniProt.
DR   GO; GO:0071109; P:superior temporal gyrus development; IMP:BHF-UCL.
DR   GO; GO:0019082; P:viral protein processing; TAS:Reactome.
DR   GO; GO:0016055; P:Wnt signaling pathway; IMP:BHF-UCL.
DR   CDD; cd14137; STKc_GSK3; 1.
DR   DisProt; DP00385; -.
DR   FunFam; 1.10.510.10:FF:000055; Glycogen synthase kinase-3 beta; 1.
DR   FunFam; 3.30.200.20:FF:000009; Glycogen synthase kinase-3 beta; 1.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   IDEAL; IID00052; -.
DR   InterPro; IPR050591; GSK-3.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR039192; STKc_GSK3.
DR   PANTHER; PTHR24057; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1.
DR   PANTHER; PTHR24057:SF8; GLYCOGEN SYNTHASE KINASE-3 BETA; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; ADP-ribosylation; Alternative splicing; Alzheimer disease;
KW   ATP-binding; Biological rhythms; Carbohydrate metabolism; Cell membrane;
KW   Cytoplasm; Developmental protein; Diabetes mellitus; Differentiation;
KW   Glycogen metabolism; Kinase; Lipoprotein; Membrane; Neurogenesis;
KW   Nucleotide-binding; Nucleus; Palmitate; Phosphoprotein;
KW   Proteomics identification; Reference proteome;
KW   Serine/threonine-protein kinase; Signal transduction inhibitor;
KW   Transferase; Wnt signaling pathway.
FT   CHAIN           1..420
FT                   /note="Glycogen synthase kinase-3 beta"
FT                   /id="PRO_0000085980"
FT   DOMAIN          56..340
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..53
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          386..420
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..22
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        386..401
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        409..420
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        181
FT                   /note="Proton acceptor"
FT   BINDING         62..70
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         85
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000305|PubMed:17050006"
FT   MOD_RES         9
FT                   /note="Phosphoserine; by PKB/AKT1, RPS6KA3, SGK3 and NME7"
FT                   /evidence="ECO:0000269|PubMed:12054501,
FT                   ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:20937854,
FT                   ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25169422,
FT                   ECO:0000269|PubMed:34764205, ECO:0000269|PubMed:35606353,
FT                   ECO:0000269|PubMed:8250835"
FT   MOD_RES         216
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:12554650,
FT                   ECO:0000269|PubMed:25169422"
FT   MOD_RES         389
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9WV60"
FT   MOD_RES         390
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         402
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18691976"
FT   LIPID           14
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:35606353"
FT   VAR_SEQ         303
FT                   /note="K -> KDSSGTGHFTSGVR (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_004790"
FT   MUTAGEN         9
FT                   /note="S->A: Loss of phosphorylation; abolished inhibition
FT                   of activity, leading to constitutively active."
FT                   /evidence="ECO:0000269|PubMed:17050006,
FT                   ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:7980435"
FT   MUTAGEN         14
FT                   /note="C->A: Significantly reduced palmitoylation."
FT                   /evidence="ECO:0000269|PubMed:35606353"
FT   MUTAGEN         85..86
FT                   /note="KK->AA: Abolished serine/threonine-protein kinase
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:17050006"
FT   MUTAGEN         96
FT                   /note="R->A: Prevents the phosphorylation of phosphate-
FT                   primed glycogen synthase."
FT                   /evidence="ECO:0000269|PubMed:11430833"
FT   MUTAGEN         128
FT                   /note="L->A: Abolishes activity toward AXIN1."
FT                   /evidence="ECO:0000269|PubMed:11430833"
FT   CONFLICT        28
FT                   /note="V -> G (in Ref. 4; AAD48517)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        350
FT                   /note="L -> H (in Ref. 1; AAA66475)"
FT                   /evidence="ECO:0000305"
FT   STRAND          10..12
FT                   /evidence="ECO:0007829|PDB:2JDO"
FT   STRAND          26..30
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          32..34
FT                   /evidence="ECO:0007829|PDB:4NM5"
FT   STRAND          38..48
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          52..64
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          66..75
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            76..78
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          81..88
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          91..93
FT                   /evidence="ECO:0007829|PDB:1Q5K"
FT   HELIX           96..102
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          112..120
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            121..124
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          125..133
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          136..138
FT                   /evidence="ECO:0007829|PDB:7SXJ"
FT   HELIX           139..148
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           155..173
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            174..176
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           184..186
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          187..190
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            191..194
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          195..198
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           201..203
FT                   /evidence="ECO:0007829|PDB:7SXJ"
FT   STRAND          209..211
FT                   /evidence="ECO:0007829|PDB:6HK4"
FT   HELIX           220..222
FT                   /evidence="ECO:0007829|PDB:7SXJ"
FT   HELIX           225..228
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           237..252
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           262..273
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           278..284
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           286..288
FT                   /evidence="ECO:0007829|PDB:7B6F"
FT   STRAND          289..291
FT                   /evidence="ECO:0007829|PDB:4ACC"
FT   HELIX           301..304
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           311..320
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           325..327
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           331..335
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           338..344
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   STRAND          345..347
FT                   /evidence="ECO:0007829|PDB:1UV5"
FT   STRAND          353..355
FT                   /evidence="ECO:0007829|PDB:6HK4"
FT   HELIX           364..367
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           371..373
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   HELIX           374..377
FT                   /evidence="ECO:0007829|PDB:1J1B"
FT   TURN            380..383
FT                   /evidence="ECO:0007829|PDB:1J1B"
SQ   SEQUENCE   420 AA;  46744 MW;  4ACC24D00CDBB9C3 CRC64;
     MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK
     VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG
     EKKDEVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR
     DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDV
     WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP
     WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL PNGRDTPALF
     NFTTQELSSN PPLATILIPP HARIQAAAST PTNATAASDA NTGDRGQTNN AASASASNST
//
ID   KC1D_HUMAN              Reviewed;         415 AA.
AC   P48730; A2I2P2; Q96KZ6; Q9BTN5;
DT   01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT   27-JAN-2003, sequence version 2.
DT   28-JAN-2026, entry version 234.
DE   RecName: Full=Casein kinase I isoform delta;
DE            Short=CKI-delta;
DE            Short=CKId;
DE            EC=2.7.11.1 {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20637175, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092};
DE   AltName: Full=Tau-protein kinase CSNK1D;
DE            EC=2.7.11.26 {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:17562708};
GN   Name=CSNK1D; Synonyms=HCKID;
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;
RX   PubMed=8786104; DOI=10.1006/geno.1996.0091;
RA   Kusuda J., Hidari N., Hidari M., Hashimoto K.;
RT   "Sequence analysis of the cDNA for the human casein kinase I delta (CSNK1D)
RT   gene and its chromosomal localization.";
RL   Genomics 32:140-143(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC   TISSUE=Hematopoietic stem cell;
RX   PubMed=15070676; DOI=10.1182/blood-2003-08-2768;
RA   Okamura A., Iwata N., Nagata A., Tamekane A., Shimoyama M., Gomyo H.,
RA   Yakushijin K., Urahama N., Hamaguchi M., Fukui C., Chihara K., Ito M.,
RA   Matsui T.;
RT   "Involvement of casein kinase Iepsilon in cytokine-induced granulocytic
RT   differentiation.";
RL   Blood 103:2997-3004(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   NHLBI resequencing and genotyping service (RS&G);
RL   Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Placenta, and Spleen;
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   ACTIVITY REGULATION, AND AUTOPHOSPHORYLATION.
RX   PubMed=9632646; DOI=10.1074/jbc.273.26.15980;
RA   Rivers A., Gietzen K.F., Vielhaber E., Virshup D.M.;
RT   "Regulation of casein kinase I epsilon and casein kinase I delta by an in
RT   vivo futile phosphorylation cycle.";
RL   J. Biol. Chem. 273:15980-15984(1998).
RN   [7]
RP   FUNCTION AS TP53 KINASE, AND CATALYTIC ACTIVITY.
RX   PubMed=10606744; DOI=10.1016/s0014-5793(99)01647-6;
RA   Dumaz N., Milne D.M., Meek D.W.;
RT   "Protein kinase CK1 is a p53-threonine 18 kinase which requires prior
RT   phosphorylation of serine 15.";
RL   FEBS Lett. 463:312-316(1999).
RN   [8]
RP   INTERACTION WITH TUBULINS, AND SUBCELLULAR LOCATION.
RX   PubMed=10826492; DOI=10.1078/s0171-9335(04)70027-8;
RA   Behrend L., Stoeter M., Kurth M., Rutter G., Heukeshoven J., Deppert W.,
RA   Knippschild U.;
RT   "Interaction of casein kinase 1 delta (CK1delta) with post-Golgi
RT   structures, microtubules and the spindle apparatus.";
RL   Eur. J. Cell Biol. 79:240-251(2000).
RN   [9]
RP   SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-38 AND THR-176.
RX   PubMed=11161704; DOI=10.1006/excr.2000.5100;
RA   Milne D.M., Looby P., Meek D.W.;
RT   "Catalytic activity of protein kinase CK1 delta (casein kinase 1delta) is
RT   essential for its normal subcellular localization.";
RL   Exp. Cell Res. 263:43-54(2001).
RN   [10]
RP   INTERACTION WITH PER1 AND PER2.
RX   PubMed=11165242; DOI=10.1016/s0014-5793(00)02434-0;
RA   Camacho F., Cilio M., Guo Y., Virshup D.M., Patel K., Khorkova O.,
RA   Styren S., Morse B., Yao Z., Keesler G.A.;
RT   "Human casein kinase Idelta phosphorylation of human circadian clock
RT   proteins period 1 and 2.";
RL   FEBS Lett. 489:159-165(2001).
RN   [11]
RP   FUNCTION AS CONNEXIN-43/GJA1 KINASE, INTERACTION WITH CONNEXIN-43/GJA1, AND
RP   CATALYTIC ACTIVITY.
RX   PubMed=12270943; DOI=10.1074/jbc.m209427200;
RA   Cooper C.D., Lampe P.D.;
RT   "Casein kinase 1 regulates connexin-43 gap junction assembly.";
RL   J. Biol. Chem. 277:44962-44968(2002).
RN   [12]
RP   INTERACTION WITH AKAP9/AKAP450, AND SUBCELLULAR LOCATION.
RX   PubMed=12270714; DOI=10.1016/s0022-2836(02)00857-4;
RA   Sillibourne J.E., Milne D.M., Takahashi M., Ono Y., Meek D.W.;
RT   "Centrosomal anchoring of the protein kinase CK1delta mediated by
RT   attachment to the large, coiled-coil scaffolding protein CG-NAP/AKAP450.";
RL   J. Mol. Biol. 322:785-797(2002).
RN   [13]
RP   IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION [LARGE SCALE
RP   ANALYSIS].
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   [14]
RP   FUNCTION AS MAPT/TAU KINASE, ACTIVITY REGULATION, INTERACTION WITH
RP   MAPT/TAU, AND CATALYTIC ACTIVITY.
RX   PubMed=14761950; DOI=10.1074/jbc.m314116200;
RA   Li G., Yin H., Kuret J.;
RT   "Casein kinase 1 delta phosphorylates tau and disrupts its binding to
RT   microtubules.";
RL   J. Biol. Chem. 279:15938-15945(2004).
RN   [15]
RP   FUNCTION IN MITOTIC SPINDLE FORMATION, SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, DEVELOPMENTAL STAGE, AND ACTIVITY REGULATION.
RX   PubMed=16027726; DOI=10.1038/sj.onc.1208941;
RA   Stoeter M., Bamberger A.-M., Aslan B., Kurth M., Speidel D., Loening T.,
RA   Frank H.-G., Kaufmann P., Loehler J., Henne-Bruns D., Deppert W.,
RA   Knippschild U.;
RT   "Inhibition of casein kinase I delta alters mitotic spindle formation and
RT   induces apoptosis in trophoblast cells.";
RL   Oncogene 24:7964-7975(2005).
RN   [16]
RP   CATALYTIC ACTIVITY, AND INTERACTION WITH DBNDD2.
RX   PubMed=16618118; DOI=10.1021/bi052354e;
RA   Yin H., Laguna K.A., Li G., Kuret J.;
RT   "Dysbindin structural homologue CK1BP is an isoform-selective binding
RT   partner of human casein kinase-1.";
RL   Biochemistry 45:5297-5308(2006).
RN   [17]
RP   FUNCTION AS PKD2 KINASE, AND CATALYTIC ACTIVITY.
RX   PubMed=17962809; DOI=10.1038/sj.emboj.7601891;
RA   von Blume J., Knippschild U., Dequiedt F., Giamas G., Beck A., Auer A.,
RA   Van Lint J., Adler G., Seufferlein T.;
RT   "Phosphorylation at Ser244 by CK1 determines nuclear localization and
RT   substrate targeting of PKD2.";
RL   EMBO J. 26:4619-4633(2007).
RN   [18]
RP   FUNCTION AS MAPT/TAU KINASE, AND CATALYTIC ACTIVITY.
RX   PubMed=17562708; DOI=10.1074/jbc.m703269200;
RA   Hanger D.P., Byers H.L., Wray S., Leung K.-Y., Saxton M.J., Seereeram A.,
RA   Reynolds C.H., Ward M.A., Anderton B.H.;
RT   "Novel phosphorylation sites in tau from Alzheimer brain support a role for
RT   casein kinase 1 in disease pathogenesis.";
RL   J. Biol. Chem. 282:23645-23654(2007).
RN   [19]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18220336; DOI=10.1021/pr0705441;
RA   Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT   "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT   phosphoproteomic analysis.";
RL   J. Proteome Res. 7:1346-1351(2008).
RN   [20]
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   [21]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-331 AND SER-384, 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   [22]
RP   ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX   PubMed=19591487; DOI=10.1021/jm9005127;
RA   Peifer C., Abadleh M., Bischof J., Hauser D., Schattel V., Hirner H.,
RA   Knippschild U., Laufer S.;
RT   "3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of
RT   p38alpha mitogen activated protein kinase and casein kinase 1delta.";
RL   J. Med. Chem. 52:7618-7630(2009).
RN   [23]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-411, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [24]
RP   FUNCTION AS TOP2A KINASE, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX   PubMed=19043076; DOI=10.1093/nar/gkn934;
RA   Grozav A.G., Chikamori K., Kozuki T., Grabowski D.R., Bukowski R.M.,
RA   Willard B., Kinter M., Andersen A.H., Ganapathi R., Ganapathi M.K.;
RT   "Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at
RT   serine-1106 and modulates DNA cleavage activity.";
RL   Nucleic Acids Res. 37:382-392(2009).
RN   [25]
RP   RETRACTED PAPER.
RX   PubMed=19339517; DOI=10.1093/nar/gkp136;
RA   Giamas G., Castellano L., Feng Q., Knippschild U., Jacob J., Thomas R.S.,
RA   Coombes R.C., Smith C.L., Jiao L.R., Stebbing J.;
RT   "CK1delta modulates the transcriptional activity of ERalpha via AIB1 in an
RT   estrogen-dependent manner and regulates ERalpha-AIB1 interactions.";
RL   Nucleic Acids Res. 37:3110-3123(2009).
RN   [26]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, 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   [27]
RP   FUNCTION AS DCK KINASE, AND CATALYTIC ACTIVITY.
RX   PubMed=20637175; DOI=10.1016/j.abb.2010.07.009;
RA   Smal C., Vertommen D., Amsailale R., Arts A., Degand H., Morsomme P.,
RA   Rider M.H., Neste E.V., Bontemps F.;
RT   "Casein kinase 1delta activates human recombinant deoxycytidine kinase by
RT   Ser-74 phosphorylation, but is not involved in the in vivo regulation of
RT   its activity.";
RL   Arch. Biochem. Biophys. 502:44-52(2010).
RN   [28]
RP   FUNCTION AS P53/TP53 KINASE, GENE FAMILY, AND CATALYTIC ACTIVITY.
RX   PubMed=20041275; DOI=10.1007/s00018-009-0236-7;
RA   Venerando A., Marin O., Cozza G., Bustos V.H., Sarno S., Pinna L.A.;
RT   "Isoform specific phosphorylation of p53 by protein kinase CK1.";
RL   Cell. Mol. Life Sci. 67:1105-1118(2010).
RN   [29]
RP   FUNCTION AS YAP1 KINASE, AND CATALYTIC ACTIVITY.
RX   PubMed=20048001; DOI=10.1101/gad.1843810;
RA   Zhao B., Li L., Tumaneng K., Wang C.-Y., Guan K.-L.;
RT   "A coordinated phosphorylation by Lats and CK1 regulates YAP stability
RT   through SCF(beta-TRCP).";
RL   Genes Dev. 24:72-85(2010).
RN   [30]
RP   FUNCTION AS HIF1A KINASE, AND CATALYTIC ACTIVITY.
RX   PubMed=20699359; DOI=10.1242/jcs.068122;
RA   Kalousi A., Mylonis I., Politou A.S., Chachami G., Paraskeva E., Simos G.;
RT   "Casein kinase 1 regulates human hypoxia-inducible factor HIF-1.";
RL   J. Cell Sci. 123:2976-2986(2010).
RN   [31]
RP   FUNCTION IN CIRCADIAN RHYTHMS, AND ACTIVITY REGULATION.
RX   PubMed=20696890; DOI=10.1073/pnas.1005101107;
RA   Meng Q.-J., Maywood E.S., Bechtold D.A., Lu W.-Q., Li J., Gibbs J.E.,
RA   Dupre S.M., Chesham J.E., Rajamohan F., Knafels J., Sneed B.,
RA   Zawadzke L.E., Ohren J.F., Walton K.M., Wager T.T., Hastings M.H.,
RA   Loudon A.S.I.;
RT   "Entrainment of disrupted circadian behavior through inhibition of casein
RT   kinase 1 (CK1) enzymes.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:15240-15245(2010).
RN   [32]
RP   FUNCTION IN CIRCADIAN RHYTHMS, AND ACTIVITY REGULATION.
RX   PubMed=20407760; DOI=10.1007/s00213-010-1860-5;
RA   Sprouse J., Reynolds L., Kleiman R., Tate B., Swanson T.A., Pickard G.E.;
RT   "Chronic treatment with a selective inhibitor of casein kinase I
RT   delta/epsilon yields cumulative phase delays in circadian rhythms.";
RL   Psychopharmacology 210:569-576(2010).
RN   [33]
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   [34]
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   [35]
RP   FUNCTION AS EIF6 KINASE, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX   PubMed=21084295; DOI=10.1074/jbc.m110.188565;
RA   Biswas A., Mukherjee S., Das S., Shields D., Chow C.W., Maitra U.;
RT   "Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic
RT   shuttling of mammalian translation initiation factor eIF6.";
RL   J. Biol. Chem. 286:3129-3138(2011).
RN   [36]
RP   FUNCTION AS DVL2 AND DVL3 KINASE, ACTIVITY REGULATION, SUBCELLULAR
RP   LOCATION, AND CATALYTIC ACTIVITY.
RX   PubMed=21422228; DOI=10.1083/jcb.201011111;
RA   Greer Y.E., Rubin J.S.;
RT   "Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-
RT   dependent neurite outgrowth.";
RL   J. Cell Biol. 192:993-1004(2011).
RN   [37]
RP   ACTIVITY REGULATION, AND AUTOPHOSPHORYLATION.
RX   PubMed=21258417; DOI=10.1038/onc.2010.627;
RA   Cheong J.K., Nguyen T.H., Wang H., Tan P., Voorhoeve P.M., Lee S.H.,
RA   Virshup D.M.;
RT   "IC261 induces cell cycle arrest and apoptosis of human cancer cells via
RT   CK1delta/epsilon and Wnt/beta-catenin independent inhibition of mitotic
RT   spindle formation.";
RL   Oncogene 30:2558-2569(2011).
RN   [38]
RP   REVIEW ON CIRCADIAN RHYTHMS, AND GENE FAMILY.
RX   PubMed=21145983; DOI=10.1016/j.biocel.2010.12.004;
RA   Cheong J.K., Virshup D.M.;
RT   "Casein kinase 1: Complexity in the family.";
RL   Int. J. Biochem. Cell Biol. 43:465-469(2011).
RN   [39]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-328; SER-331; SER-382;
RP   SER-384 AND SER-407, 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   [40]
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   [41]
RP   INTERACTION WITH DDX3X.
RX   PubMed=29222110; DOI=10.1242/jcs.207316;
RA   Dolde C., Bischof J., Grueter S., Montada A., Halekotte J., Peifer C.,
RA   Kalbacher H., Baumann U., Knippschild U., Suter B.;
RT   "A CK1 FRET biosensor reveals that DDX3X is an essential activator of
RT   CK1epsilon.";
RL   J. Cell Sci. 131:0-0(2018).
RN   [42]
RP   INTERACTION WITH FAM83A; FAM83B; FAM83E AND FAM83H.
RX   PubMed=29789297; DOI=10.1126/scisignal.aao2341;
RA   Fulcher L.J., Bozatzi P., Tachie-Menson T., Wu K.Z.L., Cummins T.D.,
RA   Bufton J.C., Pinkas D.M., Dunbar K., Shrestha S., Wood N.T., Weidlich S.,
RA   Macartney T.J., Varghese J., Gourlay R., Campbell D.G., Dingwell K.S.,
RA   Smith J.C., Bullock A.N., Sapkota G.P.;
RT   "The DUF1669 domain of FAM83 family proteins anchor casein kinase 1
RT   isoforms.";
RL   Sci. Signal. 11:0-0(2018).
RN   [43]
RP   RETRACTION NOTICE OF PUBMED:19339517.
RX   PubMed=34718754; DOI=10.1093/nar/gkab845;
RA   Giamas G., Castellano L., Feng Q., Knippschild U., Jacob J., Thomas R.S.,
RA   Coombes R.C., Smith C.L., Jiao L.R., Stebbing J.;
RT   "Retraction of 'CK1delta modulates the transcriptional activity of ERalpha
RT   via AIB1 in an estrogen-dependent manner and regulates ERalpha-AIB1
RT   interactions'.";
RL   Nucleic Acids Res. 49:12006-12006(2021).
RN   [44]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
RX   PubMed=9761932; DOI=10.1107/s0907444997011724;
RA   Longenecker K.L., Roach P.J., Hurley T.D.;
RT   "Crystallographic studies of casein kinase I delta toward a structural
RT   understanding of auto-inhibition.";
RL   Acta Crystallogr. D 54:473-475(1998).
RN   [45]
RP   X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 1-294 IN COMPLEX WITH INHIBITOR,
RP   AND SUBUNIT.
RX   PubMed=22168824; DOI=10.1021/jm201387s;
RA   Long A., Zhao H., Huang X.;
RT   "Structural basis for the interaction between casein kinase 1 delta and a
RT   potent and selective inhibitor.";
RL   J. Med. Chem. 55:956-960(2012).
RN   [46]
RP   X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS) OF 1-294 IN COMPLEX WITH INHIBITOR,
RP   AND SUBUNIT.
RX   PubMed=23106386; DOI=10.1021/jm301336n;
RA   Long A.M., Zhao H., Huang X.;
RT   "Structural basis for the potent and selective inhibition of casein kinase
RT   1 epsilon.";
RL   J. Med. Chem. 55:10307-10311(2012).
RN   [47]
RP   VARIANT FASPS2 ALA-44.
RX   PubMed=15800623; DOI=10.1038/nature03453;
RA   Xu Y., Padiath Q.S., Shapiro R.E., Jones C.R., Wu S.C., Saigoh N.,
RA   Saigoh K., Ptacek L.J., Fu Y.H.;
RT   "Functional consequences of a CKIdelta mutation causing familial advanced
RT   sleep phase syndrome.";
RL   Nature 434:640-644(2005).
RN   [48]
RP   VARIANT [LARGE SCALE ANALYSIS] CYS-97.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
RN   [49]
RP   VARIANTS [LARGE SCALE ANALYSIS] CYS-97 AND ALA-401.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
RN   [50]
RP   VARIANTS FASPS2 ALA-44 AND ARG-46, CHARACTERIZATION OF VARIANTS FASPS2
RP   ALA-44 AND ARG-46, FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL
RP   PROPERTIES.
RX   PubMed=23636092; DOI=10.1126/scitranslmed.3005784;
RA   Brennan K.C., Bates E.A., Shapiro R.E., Zyuzin J., Hallows W.C., Huang Y.,
RA   Lee H.Y., Jones C.R., Fu Y.H., Charles A.C., Ptacek L.J.;
RT   "Casein kinase idelta mutations in familial migraine and advanced phase.";
RL   Sci. Transl. Med. 5:183ra56-183ra56(2013).
CC   -!- FUNCTION: Essential serine/threonine-protein kinase that regulates
CC       diverse cellular growth and survival processes including Wnt signaling,
CC       DNA repair and circadian rhythms. It can phosphorylate a large number
CC       of proteins. Casein kinases are operationally defined by their
CC       preferential utilization of acidic proteins such as caseins as
CC       substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU,
CC       TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1,
CC       PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In
CC       balance with PP1, determines the circadian period length through the
CC       regulation of the speed and rhythmicity of PER1 and PER2
CC       phosphorylation. Controls PER1 and PER2 nuclear transport and
CC       degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3
CC       ubiquitin ligase-mediated ubiquitination and subsequent degradation.
CC       DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation
CC       of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation.
CC       Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that
CC       controls neurite outgrowth. Phosphorylates NEDD9/HEF1 (By similarity).
CC       EIF6 phosphorylation promotes its nuclear export. Triggers down-
CC       regulation of dopamine receptors in the forebrain. Activates DCK in
CC       vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable
CC       complex formation. May regulate the formation of the mitotic spindle
CC       apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap
CC       junction assembly by phosphorylation. Probably involved in lymphocyte
CC       physiology. Regulates fast synaptic transmission mediated by glutamate.
CC       {ECO:0000250|UniProtKB:Q9DC28, ECO:0000269|PubMed:10606744,
CC       ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950,
CC       ECO:0000269|PubMed:16027726, ECO:0000269|PubMed:17562708,
CC       ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076,
CC       ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20048001,
CC       ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20637175,
CC       ECO:0000269|PubMed:20696890, ECO:0000269|PubMed:20699359,
CC       ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21422228,
CC       ECO:0000269|PubMed:23636092}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950,
CC         ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:17562708,
CC         ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076,
CC         ECO:0000269|PubMed:19591487, ECO:0000269|PubMed:20041275,
CC         ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:20637175,
CC         ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:21084295,
CC         ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC         Evidence={ECO:0000305|PubMed:20637175};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:10606744, ECO:0000269|PubMed:14761950,
CC         ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:19591487,
CC         ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20637175,
CC         ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609;
CC         Evidence={ECO:0000305|PubMed:20637175};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein]
CC         + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC         COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC         Evidence={ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16618118,
CC         ECO:0000269|PubMed:17562708};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12802;
CC         Evidence={ECO:0000305|PubMed:14761950};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau
CC         protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC         Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.26; Evidence={ECO:0000269|PubMed:14761950,
CC         ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:17562708};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53905;
CC         Evidence={ECO:0000305|PubMed:14761950};
CC   -!- ACTIVITY REGULATION: Exhibits substrate-dependent heparin activation.
CC       Drug-mediated inhibition leads to a delay of the oscillations with the
CC       magnitude of this effect dependent upon the timing of drug
CC       administration. Inhibited by phosphorylation. Repressed by 3-[(2,4,6-
CC       trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), N-(2-aminoethyl)-
CC       5-chloroisoquinoline-8-sulfonamide (CKI-7), 4-[4-(2,3-dihydro-
CC       benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide
CC       (D4476), 3,4-diaryl-isoxazoles and -imidazoles, and 4-(3-cyclohexyl-5-
CC       (4-fluoro-phenyl)-3H-imidazol-4-yl) pyrimidin-2-ylamine (PF670462,
CC       PF670). {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16027726,
CC       ECO:0000269|PubMed:19043076, ECO:0000269|PubMed:19591487,
CC       ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20696890,
CC       ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21258417,
CC       ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:9632646}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=36.5 uM for alpha-casein {ECO:0000269|PubMed:23636092};
CC         KM=635.8 uM for PER2 peptide {ECO:0000269|PubMed:23636092};
CC         KM=180.6 uM for ATP {ECO:0000269|PubMed:23636092};
CC         Note=Maximal velocity nearly identical for the reactions with alpha-
CC         casein and PER2 peptide.;
CC   -!- SUBUNIT: Monomer (PubMed:22168824, PubMed:23106386). Component of the
CC       circadian core oscillator, which includes the CRY proteins, CLOCK, or
CC       NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and
CC       the PER proteins (By similarity). Interacts with DNMT1 and MAP1A (By
CC       similarity). Interacts directly with PER1 and PER2 which may lead to
CC       their degradation (PubMed:11165242). Interacts with MAPT/TAU
CC       (PubMed:14761950). Interacts with SNAPIN (By similarity). Interacts
CC       with DBNDD2 (PubMed:16618118). Interacts with AKAP9/AKAP450; this
CC       interaction promotes centrosomal subcellular location
CC       (PubMed:12270714). Binds to tubulins in mitotic cells upon DNA damage
CC       (PubMed:10826492). Interacts with GJA1 (PubMed:12270943). Interacts
CC       with DDX3X; this interaction enhances CSNK1D kinase activity in vitro,
CC       but it is unclear whether this interaction is physiologically relevant
CC       (PubMed:29222110). Interacts with FAM83A, FAM83B, FAM83E and FAM83H
CC       (via DUF1669) (PubMed:29789297). {ECO:0000250|UniProtKB:Q06486,
CC       ECO:0000250|UniProtKB:Q9DC28, ECO:0000269|PubMed:10826492,
CC       ECO:0000269|PubMed:11165242, ECO:0000269|PubMed:12270714,
CC       ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950,
CC       ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:22168824,
CC       ECO:0000269|PubMed:23106386, ECO:0000269|PubMed:29222110,
CC       ECO:0000269|PubMed:29789297}.
CC   -!- INTERACTION:
CC       P48730; P05067: APP; NbExp=3; IntAct=EBI-751621, EBI-77613;
CC       P48730; Q49A88-3: CCDC14; NbExp=3; IntAct=EBI-751621, EBI-12105646;
CC       P48730; Q6PGQ1: DRICH1; NbExp=3; IntAct=EBI-751621, EBI-10253641;
CC       P48730; Q92997: DVL3; NbExp=4; IntAct=EBI-751621, EBI-739789;
CC       P48730; O60447: EVI5; NbExp=3; IntAct=EBI-751621, EBI-852291;
CC       P48730; Q14C86: GAPVD1; NbExp=5; IntAct=EBI-751621, EBI-1049788;
CC       P48730; Q9H2S9: IKZF4; NbExp=3; IntAct=EBI-751621, EBI-1640423;
CC       P48730; Q96LR2: LURAP1; NbExp=4; IntAct=EBI-751621, EBI-741355;
CC       P48730; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-751621, EBI-741037;
CC       P48730; P23508: MCC; NbExp=6; IntAct=EBI-751621, EBI-307531;
CC       P48730; Q00987: MDM2; NbExp=6; IntAct=EBI-751621, EBI-389668;
CC       P48730; Q9P286: PAK5; NbExp=3; IntAct=EBI-751621, EBI-741896;
CC       P48730; O15055: PER2; NbExp=7; IntAct=EBI-751621, EBI-1054296;
CC       P48730; O75382: TRIM3; NbExp=3; IntAct=EBI-751621, EBI-2129889;
CC       P48730; Q9C026: TRIM9; NbExp=3; IntAct=EBI-751621, EBI-720828;
CC       P48730; P62258: YWHAE; NbExp=2; IntAct=EBI-751621, EBI-356498;
CC       P48730; Q96BR9: ZBTB8A; NbExp=3; IntAct=EBI-751621, EBI-742740;
CC       P48730; Q5T7W0: ZNF618; NbExp=4; IntAct=EBI-751621, EBI-6255994;
CC       P48730; Q60838: Dvl2; Xeno; NbExp=2; IntAct=EBI-751621, EBI-641940;
CC       P48730-2; P05067: APP; NbExp=3; IntAct=EBI-9087876, EBI-77613;
CC       P48730-2; Q92624: APPBP2; NbExp=3; IntAct=EBI-9087876, EBI-743771;
CC       P48730-2; Q96GW7: BCAN; NbExp=3; IntAct=EBI-9087876, EBI-2690445;
CC       P48730-2; Q8IU99: CALHM1; NbExp=3; IntAct=EBI-9087876, EBI-1790341;
CC       P48730-2; Q03135: CAV1; NbExp=3; IntAct=EBI-9087876, EBI-603614;
CC       P48730-2; P45973: CBX5; NbExp=3; IntAct=EBI-9087876, EBI-78219;
CC       P48730-2; P06850: CRH; NbExp=3; IntAct=EBI-9087876, EBI-3870390;
CC       P48730-2; Q01658: DR1; NbExp=3; IntAct=EBI-9087876, EBI-750300;
CC       P48730-2; Q9BS26: ERP44; NbExp=3; IntAct=EBI-9087876, EBI-541644;
CC       P48730-2; P35637: FUS; NbExp=3; IntAct=EBI-9087876, EBI-400434;
CC       P48730-2; P17302: GJA1; NbExp=3; IntAct=EBI-9087876, EBI-1103439;
CC       P48730-2; Q9H8Y8: GORASP2; NbExp=3; IntAct=EBI-9087876, EBI-739467;
CC       P48730-2; P25098: GRK2; NbExp=3; IntAct=EBI-9087876, EBI-3904795;
CC       P48730-2; Q00403: GTF2B; NbExp=3; IntAct=EBI-9087876, EBI-389564;
CC       P48730-2; Q9Y5Q9: GTF3C3; NbExp=3; IntAct=EBI-9087876, EBI-1054873;
CC       P48730-2; P42858: HTT; NbExp=15; IntAct=EBI-9087876, EBI-466029;
CC       P48730-2; Q14114-3: LRP8; NbExp=3; IntAct=EBI-9087876, EBI-25832196;
CC       P48730-2; Q5S007: LRRK2; NbExp=3; IntAct=EBI-9087876, EBI-5323863;
CC       P48730-2; Q16539: MAPK14; NbExp=3; IntAct=EBI-9087876, EBI-73946;
CC       P48730-2; Q96L34: MARK4; NbExp=3; IntAct=EBI-9087876, EBI-302319;
CC       P48730-2; P35240-4: NF2; NbExp=3; IntAct=EBI-9087876, EBI-1014514;
CC       P48730-2; Q6ZW49: PAXIP1; NbExp=3; IntAct=EBI-9087876, EBI-743225;
CC       P48730-2; O14494: PLPP1; NbExp=3; IntAct=EBI-9087876, EBI-2865290;
CC       P48730-2; A0A6Q8PF08: PMP22; NbExp=3; IntAct=EBI-9087876, EBI-50433196;
CC       P48730-2; P17612: PRKACA; NbExp=3; IntAct=EBI-9087876, EBI-476586;
CC       P48730-2; P07602: PSAP; NbExp=3; IntAct=EBI-9087876, EBI-716699;
CC       P48730-2; P54725: RAD23A; NbExp=3; IntAct=EBI-9087876, EBI-746453;
CC       P48730-2; P04271: S100B; NbExp=3; IntAct=EBI-9087876, EBI-458391;
CC       P48730-2; Q8WTV0: SCARB1; NbExp=3; IntAct=EBI-9087876, EBI-78657;
CC       P48730-2; P50454: SERPINH1; NbExp=3; IntAct=EBI-9087876, EBI-350723;
CC       P48730-2; Q8IUQ4-2: SIAH1; NbExp=3; IntAct=EBI-9087876, EBI-11522811;
CC       P48730-2; P84022: SMAD3; NbExp=3; IntAct=EBI-9087876, EBI-347161;
CC       P48730-2; P37840: SNCA; NbExp=3; IntAct=EBI-9087876, EBI-985879;
CC       P48730-2; P00441: SOD1; NbExp=3; IntAct=EBI-9087876, EBI-990792;
CC       P48730-2; Q6NUL7: SPTLC1; NbExp=3; IntAct=EBI-9087876, EBI-25912847;
CC       P48730-2; Q13148: TARDBP; NbExp=6; IntAct=EBI-9087876, EBI-372899;
CC       P48730-2; P37173: TGFBR2; NbExp=3; IntAct=EBI-9087876, EBI-296151;
CC       P48730-2; Q9NRS4: TMPRSS4; NbExp=3; IntAct=EBI-9087876, EBI-10313040;
CC       P48730-2; Q9BVJ6: UTP14A; NbExp=3; IntAct=EBI-9087876, EBI-473284;
CC       P48730-2; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-9087876, EBI-11141397;
CC       P48730-2; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-9087876, EBI-524753;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cytoplasm, cytoskeleton,
CC       microtubule organizing center, centrosome
CC       {ECO:0000269|PubMed:14654843}. Cytoplasm, perinuclear region. Cell
CC       membrane. Cytoplasm, cytoskeleton, spindle. Golgi apparatus.
CC       Note=Localized at mitotic spindle microtubules, and at the centrosomes
CC       and interphase in interphase cells. Recruited to the spindle apparatus
CC       and the centrosomes in response to DNA-damage. Correct subcellular
CC       localization requires kinase activity.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P48730-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P48730-2; Sequence=VSP_010253;
CC   -!- TISSUE SPECIFICITY: Expressed in all tissues examined, including brain,
CC       heart, lung, liver, pancreas, kidney, placenta and skeletal muscle.
CC       However, kinase activity is not uniform, with highest kinase activity
CC       in splenocytes. In blood, highly expressed in hemopoietic cells and
CC       mature granulocytes. Also found in monocytes and lymphocytes.
CC       {ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:16027726}.
CC   -!- DEVELOPMENTAL STAGE: Highly present in extravillous trophoblast cells,
CC       which are present at the placenta implantation site and invade the
CC       decidua and decidual vessels. {ECO:0000269|PubMed:16027726}.
CC   -!- PTM: Autophosphorylated on serine and threonine residues; this
CC       autophosphorylation represses activity. Reactivated by phosphatase-
CC       mediated dephosphorylation. May be dephosphorylated by PP1.
CC   -!- DISEASE: Advanced sleep phase syndrome, familial, 2 (FASPS2)
CC       [MIM:615224]: An autosomal dominant disorder characterized by very
CC       early sleep onset and offset. Individuals are 'morning larks' with a 4
CC       hours advance of the sleep, temperature and melatonin rhythms.
CC       {ECO:0000269|PubMed:15800623, ECO:0000269|PubMed:23636092}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- MISCELLANEOUS: May be involved in Alzheimer disease by phosphorylating
CC       MAPT/TAU. {ECO:0000305|PubMed:17562708}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CK1 Ser/Thr
CC       protein kinase family. Casein kinase I subfamily. {ECO:0000305}.
CC   -!- CAUTION: Was shown to phosphorylate and activate DCK in vitro but
CC       probably not in vivo. {ECO:0000305|PubMed:20637175}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; U29171; AAC50807.1; -; mRNA.
DR   EMBL; U31285; AAC50808.1; -; mRNA.
DR   EMBL; AB091044; BAC10903.1; -; mRNA.
DR   EMBL; AK291758; BAF84447.1; -; mRNA.
DR   EMBL; EF015900; ABM64211.1; -; Genomic_DNA.
DR   EMBL; BC003558; AAH03558.1; -; mRNA.
DR   EMBL; BC015775; AAH15775.1; -; mRNA.
DR   CCDS; CCDS11805.1; -. [P48730-1]
DR   CCDS; CCDS11806.1; -. [P48730-2]
DR   PIR; G01876; G01876.
DR   RefSeq; NP_001884.2; NM_001893.4. [P48730-1]
DR   RefSeq; NP_620693.1; NM_139062.4. [P48730-2]
DR   PDB; 3UYS; X-ray; 2.30 A; A/B/C/D=1-294.
DR   PDB; 3UYT; X-ray; 2.00 A; A/B/C/D=1-294.
DR   PDB; 3UZP; X-ray; 1.94 A; A/B=1-294.
DR   PDB; 4HGT; X-ray; 1.80 A; A/B=1-294.
DR   PDB; 4HNF; X-ray; 2.07 A; A/B=1-294.
DR   PDB; 4KB8; X-ray; 1.95 A; A/B/C/D=3-317.
DR   PDB; 4KBA; X-ray; 1.98 A; A/B/C/D=3-317.
DR   PDB; 4KBC; X-ray; 1.98 A; A/B=1-317.
DR   PDB; 4KBK; X-ray; 2.10 A; A/B/C/D=3-317.
DR   PDB; 4TN6; X-ray; 2.41 A; A/B=1-301.
DR   PDB; 4TW9; X-ray; 2.40 A; A/B=1-295.
DR   PDB; 4TWC; X-ray; 1.70 A; A/B=1-295.
DR   PDB; 5IH4; X-ray; 1.90 A; A=1-294.
DR   PDB; 5IH5; X-ray; 2.25 A; A=1-294.
DR   PDB; 5IH6; X-ray; 2.30 A; A=1-294.
DR   PDB; 5MQV; X-ray; 2.15 A; A/B/C/D/E/F=1-294.
DR   PDB; 5OKT; X-ray; 2.13 A; A/B/C/D=1-294.
DR   PDB; 5W4W; X-ray; 1.99 A; A/B/C/D=3-317.
DR   PDB; 6F1W; X-ray; 1.86 A; A/B=1-294.
DR   PDB; 6F26; X-ray; 1.83 A; A/B=1-294.
DR   PDB; 6GZM; X-ray; 1.59 A; A/B=1-295.
DR   PDB; 6HMP; X-ray; 2.04 A; A/B=1-294.
DR   PDB; 6HMR; X-ray; 1.78 A; A/B=1-294.
DR   PDB; 6PXN; X-ray; 1.55 A; A/B=1-415.
DR   PDB; 6PXO; X-ray; 2.00 A; A/B=1-294.
DR   PDB; 6PXP; X-ray; 2.35 A; A/B=1-294.
DR   PDB; 6RCG; X-ray; 1.40 A; A=1-294.
DR   PDB; 6RCH; X-ray; 1.45 A; A/B=1-294.
DR   PDB; 6RU6; X-ray; 2.05 A; A/B=1-294.
DR   PDB; 6RU7; X-ray; 2.08 A; A/B=1-294.
DR   PDB; 6RU8; X-ray; 1.92 A; A/B/C/D=1-294.
DR   PDB; 7NZY; X-ray; 1.85 A; A/B/C/D=1-294.
DR   PDB; 7P7F; X-ray; 1.96 A; A/B/C/D=1-294.
DR   PDB; 7P7G; X-ray; 1.70 A; A/B=1-294.
DR   PDB; 7P7H; X-ray; 2.40 A; A/B=1-294.
DR   PDB; 7QR9; X-ray; 2.30 A; A/B/C/D=1-294.
DR   PDB; 7QRA; X-ray; 2.40 A; A/B/C/D=1-294.
DR   PDB; 7QRB; X-ray; 2.60 A; A/B/C/D=1-294.
DR   PDB; 8D7M; X-ray; 2.25 A; A/B=1-294.
DR   PDB; 8D7N; X-ray; 1.66 A; A/B=1-294.
DR   PDB; 8D7O; X-ray; 1.65 A; A/B=1-294.
DR   PDB; 8D7P; X-ray; 2.25 A; A/B=1-294.
DR   PDB; 8IZC; X-ray; 1.45 A; A/B=5-294.
DR   PDB; 8VXD; X-ray; 2.47 A; A/B=1-299.
DR   PDB; 8VXF; X-ray; 2.28 A; A/B=1-299.
DR   PDB; 9B3S; X-ray; 2.40 A; A/B=1-415.
DR   PDBsum; 3UYS; -.
DR   PDBsum; 3UYT; -.
DR   PDBsum; 3UZP; -.
DR   PDBsum; 4HGT; -.
DR   PDBsum; 4HNF; -.
DR   PDBsum; 4KB8; -.
DR   PDBsum; 4KBA; -.
DR   PDBsum; 4KBC; -.
DR   PDBsum; 4KBK; -.
DR   PDBsum; 4TN6; -.
DR   PDBsum; 4TW9; -.
DR   PDBsum; 4TWC; -.
DR   PDBsum; 5IH4; -.
DR   PDBsum; 5IH5; -.
DR   PDBsum; 5IH6; -.
DR   PDBsum; 5MQV; -.
DR   PDBsum; 5OKT; -.
DR   PDBsum; 5W4W; -.
DR   PDBsum; 6F1W; -.
DR   PDBsum; 6F26; -.
DR   PDBsum; 6GZM; -.
DR   PDBsum; 6HMP; -.
DR   PDBsum; 6HMR; -.
DR   PDBsum; 6PXN; -.
DR   PDBsum; 6PXO; -.
DR   PDBsum; 6PXP; -.
DR   PDBsum; 6RCG; -.
DR   PDBsum; 6RCH; -.
DR   PDBsum; 6RU6; -.
DR   PDBsum; 6RU7; -.
DR   PDBsum; 6RU8; -.
DR   PDBsum; 7NZY; -.
DR   PDBsum; 7P7F; -.
DR   PDBsum; 7P7G; -.
DR   PDBsum; 7P7H; -.
DR   PDBsum; 7QR9; -.
DR   PDBsum; 7QRA; -.
DR   PDBsum; 7QRB; -.
DR   PDBsum; 8D7M; -.
DR   PDBsum; 8D7N; -.
DR   PDBsum; 8D7O; -.
DR   PDBsum; 8D7P; -.
DR   PDBsum; 8IZC; -.
DR   PDBsum; 8VXD; -.
DR   PDBsum; 8VXF; -.
DR   PDBsum; 9B3S; -.
DR   AlphaFoldDB; P48730; -.
DR   SMR; P48730; -.
DR   BioGRID; 107837; 268.
DR   DIP; DIP-39735N; -.
DR   FunCoup; P48730; 4598.
DR   IntAct; P48730; 204.
DR   MINT; P48730; -.
DR   STRING; 9606.ENSP00000381531; -.
DR   BindingDB; P48730; -.
DR   ChEMBL; CHEMBL2828; -.
DR   DrugCentral; P48730; -.
DR   GuidetoPHARMACOLOGY; 1997; -.
DR   GlyGen; P48730; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P48730; -.
DR   PhosphoSitePlus; P48730; -.
DR   BioMuta; CSNK1D; -.
DR   DMDM; 27923980; -.
DR   CPTAC; CPTAC-3148; -.
DR   CPTAC; CPTAC-3149; -.
DR   jPOST; P48730; -.
DR   MassIVE; P48730; -.
DR   PaxDb; 9606-ENSP00000324464; -.
DR   PeptideAtlas; P48730; -.
DR   ProteomicsDB; 55930; -. [P48730-1]
DR   ProteomicsDB; 55931; -. [P48730-2]
DR   Pumba; P48730; -.
DR   TopDownProteomics; P48730-1; -. [P48730-1]
DR   Antibodypedia; 4210; 368 antibodies from 40 providers.
DR   DNASU; 1453; -.
DR   Ensembl; ENST00000314028.11; ENSP00000324464.6; ENSG00000141551.16. [P48730-1]
DR   Ensembl; ENST00000392334.7; ENSP00000376146.2; ENSG00000141551.16. [P48730-2]
DR   GeneID; 1453; -.
DR   KEGG; hsa:1453; -.
DR   MANE-Select; ENST00000314028.11; ENSP00000324464.6; NM_001893.6; NP_001884.2.
DR   UCSC; uc002kei.4; human. [P48730-1]
DR   AGR; HGNC:2452; -.
DR   ClinPGx; PA26952; -.
DR   CTD; 1453; -.
DR   DisGeNET; 1453; -.
DR   GeneCards; CSNK1D; -.
DR   HGNC; HGNC:2452; CSNK1D.
DR   HPA; ENSG00000141551; Low tissue specificity.
DR   MalaCards; CSNK1D; -.
DR   MIM; 600864; gene.
DR   MIM; 615224; phenotype.
DR   OpenTargets; ENSG00000141551; -.
DR   Orphanet; 164736; Familial advanced sleep-phase syndrome.
DR   VEuPathDB; HostDB:ENSG00000141551; -.
DR   eggNOG; KOG1164; Eukaryota.
DR   GeneTree; ENSGT00940000153536; -.
DR   HOGENOM; CLU_019279_2_2_1; -.
DR   InParanoid; P48730; -.
DR   OMA; IFDWTFL; -.
DR   OrthoDB; 5800476at2759; -.
DR   PAN-GO; P48730; 11 GO annotations based on evolutionary models.
DR   PhylomeDB; P48730; -.
DR   BRENDA; 2.7.11.1; 2681.
DR   BRENDA; 2.7.11.26; 2681.
DR   PathwayCommons; P48730; -.
DR   Reactome; R-HSA-204005; COPII-mediated vesicle transport.
DR   Reactome; R-HSA-2565942; Regulation of PLK1 Activity at G2/M Transition.
DR   Reactome; R-HSA-380259; Loss of Nlp from mitotic centrosomes.
DR   Reactome; R-HSA-380270; Recruitment of mitotic centrosome proteins and complexes.
DR   Reactome; R-HSA-380284; Loss of proteins required for interphase microtubule organization from the centrosome.
DR   Reactome; R-HSA-380320; Recruitment of NuMA to mitotic centrosomes.
DR   Reactome; R-HSA-5620912; Anchoring of the basal body to the plasma membrane.
DR   Reactome; R-HSA-6791226; Major pathway of rRNA processing in the nucleolus and cytosol.
DR   Reactome; R-HSA-8854518; AURKA Activation by TPX2.
DR   Reactome; R-HSA-9931521; The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex.
DR   Reactome; R-HSA-9931530; Phosphorylation and nuclear translocation of the CRY:PER:kinase complex.
DR   SABIO-RK; P48730; -.
DR   SignaLink; P48730; -.
DR   SIGNOR; P48730; -.
DR   Agora; ENSG00000141551; -.
DR   BioGRID-ORCS; 1453; 26 hits in 1201 CRISPR screens.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   CD-CODE; 91857CE7; Nucleolus.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; CSNK1D; human.
DR   EvolutionaryTrace; P48730; -.
DR   GeneWiki; CSNK1D; -.
DR   GenomeRNAi; 1453; -.
DR   Pharos; P48730; Tchem.
DR   PRO; PR:P48730; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; P48730; protein.
DR   Bgee; ENSG00000141551; Expressed in left testis and 205 other cell types or tissues.
DR   ExpressionAtlas; P48730; baseline and differential.
DR   GO; GO:0015629; C:actin cytoskeleton; IDA:HPA.
DR   GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR   GO; GO:0036064; C:ciliary basal body; IDA:GO_Central.
DR   GO; GO:0005929; C:cilium; IDA:HPA.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; TAS:Reactome.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0097229; C:sperm end piece; IDA:HPA.
DR   GO; GO:0097228; C:sperm principal piece; IDA:HPA.
DR   GO; GO:0005819; C:spindle; IDA:UniProtKB.
DR   GO; GO:0005876; C:spindle microtubule; IDA:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR   GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IDA:UniProtKB.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0050321; F:tau-protein kinase activity; IDA:UniProtKB.
DR   GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR   GO; GO:0048208; P:COPII vesicle coating; TAS:Reactome.
DR   GO; GO:0006897; P:endocytosis; IBA:GO_Central.
DR   GO; GO:0007030; P:Golgi organization; IMP:SYSCILIA_CCNET.
DR   GO; GO:0007020; P:microtubule nucleation; IMP:SYSCILIA_CCNET.
DR   GO; GO:1904948; P:midbrain dopaminergic neuron differentiation; ISS:ParkinsonsUK-UCL.
DR   GO; GO:1905515; P:non-motile cilium assembly; IMP:SYSCILIA_CCNET.
DR   GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:BHF-UCL.
DR   GO; GO:2000052; P:positive regulation of non-canonical Wnt signaling pathway; ISS:ParkinsonsUK-UCL.
DR   GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR   GO; GO:0071539; P:protein localization to centrosome; IMP:SYSCILIA_CCNET.
DR   GO; GO:0061512; P:protein localization to cilium; IMP:SYSCILIA_CCNET.
DR   GO; GO:0034067; P:protein localization to Golgi apparatus; IMP:SYSCILIA_CCNET.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR   GO; GO:0051225; P:spindle assembly; IDA:UniProtKB.
DR   GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR   CDD; cd14125; STKc_CK1_delta_epsilon; 1.
DR   FunFam; 1.10.510.10:FF:000194; Casein kinase I isoform delta; 1.
DR   FunFam; 3.30.200.20:FF:000538; Putative Casein kinase I; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR050235; CK1_Ser-Thr_kinase.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR11909; CASEIN KINASE-RELATED; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; ATP-binding; Biological rhythms;
KW   Cell membrane; Cytoplasm; Cytoskeleton; Disease variant; Golgi apparatus;
KW   Kinase; Membrane; Methylation; Nucleotide-binding; Nucleus; Phosphoprotein;
KW   Proteomics identification; Reference proteome;
KW   Serine/threonine-protein kinase; Transferase; Wnt signaling pathway.
FT   CHAIN           1..415
FT                   /note="Casein kinase I isoform delta"
FT                   /id="PRO_0000192833"
FT   DOMAIN          9..277
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          278..364
FT                   /note="Centrosomal localization signal (CLS)"
FT   REGION          301..415
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          317..342
FT                   /note="Autoinhibitory"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        301..315
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        347..358
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        380..400
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        128
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         15..23
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         38
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         328
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         331
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         370
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q06486"
FT   MOD_RES         375
FT                   /note="Omega-N-methylarginine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9DC28"
FT   MOD_RES         382
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         383
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         384
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         407
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         411
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19369195"
FT   VAR_SEQ         400..415
FT                   /note="IPGRVASSGLQSVVHR -> NSIPFEHHGK (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:15489334"
FT                   /id="VSP_010253"
FT   VARIANT         44
FT                   /note="T -> A (in FASPS2; strongly reduces kinase activity;
FT                   dbSNP:rs104894561)"
FT                   /evidence="ECO:0000269|PubMed:15800623,
FT                   ECO:0000269|PubMed:23636092"
FT                   /id="VAR_029075"
FT   VARIANT         46
FT                   /note="H -> R (in FASPS2; strongly reduces kinase activity;
FT                   dbSNP:rs397514693)"
FT                   /evidence="ECO:0000269|PubMed:23636092"
FT                   /id="VAR_069801"
FT   VARIANT         97
FT                   /note="S -> C (in breast cancer samples; infiltrating
FT                   ductal carcinoma; somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:16959974,
FT                   ECO:0000269|PubMed:17344846"
FT                   /id="VAR_036451"
FT   VARIANT         401
FT                   /note="P -> A (in dbSNP:rs56124628)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_042081"
FT   MUTAGEN         38
FT                   /note="K->M: Impaired kinase activity and abnormal
FT                   subcellular localization with exclusive accumulation to the
FT                   nucleus."
FT                   /evidence="ECO:0000269|PubMed:11161704"
FT   MUTAGEN         176
FT                   /note="T->I: Impaired kinase activity and abnormal
FT                   subcellular localization with exclusive accumulation to the
FT                   nucleus."
FT                   /evidence="ECO:0000269|PubMed:11161704"
FT   CONFLICT        330
FT                   /note="A -> D (in Ref. 1; AAC50807)"
FT                   /evidence="ECO:0000305"
FT   STRAND          3..5
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   TURN            6..8
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          9..18
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          21..28
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   TURN            29..32
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          33..41
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          44..46
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           49..59
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          68..74
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          77..83
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           89..95
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   TURN            96..98
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           102..121
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           131..133
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          134..136
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           139..141
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          145..147
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   STRAND          154..157
FT                   /evidence="ECO:0007829|PDB:8D7O"
FT   TURN            159..161
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           177..179
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           182..185
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           192..208
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   TURN            212..215
FT                   /evidence="ECO:0007829|PDB:6RCH"
FT   STRAND          217..219
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           221..233
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           237..240
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   TURN            241..243
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           247..257
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           266..279
FT                   /evidence="ECO:0007829|PDB:6RCG"
FT   HELIX           280..283
FT                   /evidence="ECO:0007829|PDB:6F1W"
FT   HELIX           289..292
FT                   /evidence="ECO:0007829|PDB:6RCG"
SQ   SEQUENCE   415 AA;  47330 MW;  B97F1717A52466D2 CRC64;
     MELRVGNRYR LGRKIGSGSF GDIYLGTDIA AGEEVAIKLE CVKTKHPQLH IESKIYKMMQ
     GGVGIPTIRW CGAEGDYNVM VMELLGPSLE DLFNFCSRKF SLKTVLLLAD QMISRIEYIH
     SKNFIHRDVK PDNFLMGLGK KGNLVYIIDF GLAKKYRDAR THQHIPYREN KNLTGTARYA
     SINTHLGIEQ SRRDDLESLG YVLMYFNLGS LPWQGLKAAT KRQKYERISE KKMSTPIEVL
     CKGYPSEFAT YLNFCRSLRF DDKPDYSYLR QLFRNLFHRQ GFSYDYVFDW NMLKFGASRA
     ADDAERERRD REERLRHSRN PATRGLPSTA SGRLRGTQEV APPTPLTPTS HTANTSPRPV
     SGMERERKVS MRLHRGAPVN ISSSDLTGRQ DTSRMSTSQI PGRVASSGLQ SVVHR
//
ID   LRP8_HUMAN              Reviewed;         963 AA.
AC   Q14114; B1AMT6; B1AMT7; B1AMT8; O14968; Q86V27; Q99876; Q9BR78;
DT   10-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT   22-SEP-2009, sequence version 4.
DT   28-JAN-2026, entry version 221.
DE   RecName: Full=Low-density lipoprotein receptor-related protein 8;
DE            Short=LRP-8;
DE   AltName: Full=Apolipoprotein E receptor 2;
DE   Flags: Precursor;
GN   Name=LRP8; Synonyms=APOER2;
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 VARIANTS ARG-25 AND GLU-46.
RC   TISSUE=Placenta;
RX   PubMed=8626535; DOI=10.1074/jbc.271.14.8373;
RA   Kim D.-H., Iijima H., Goto K., Sakai J., Ishii H., Kim H.-J., Suzuki H.,
RA   Kondo H., Saeki S., Yamamoto T.;
RT   "Human apolipoprotein E receptor 2. A novel lipoprotein receptor of the low
RT   density lipoprotein receptor family predominantly expressed in brain.";
RL   J. Biol. Chem. 271:8373-8380(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 4), AND VARIANTS ARG-25
RP   AND GLU-46.
RC   TISSUE=Peripheral blood;
RX   PubMed=9079678; DOI=10.1074/jbc.272.13.8498;
RA   Kim D.-H., Magoori K., Inoue T.R., Mao C.C., Kim H.-J., Suzuki H.,
RA   Fujita T., Endo Y., Saeki S., Yamamoto T.T.;
RT   "Exon/intron organization, chromosome localization, alternative splicing,
RT   and transcription units of the human apolipoprotein E receptor 2 gene.";
RL   J. Biol. Chem. 272:8498-8504(1997).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANTS ARG-25 AND GLU-46.
RC   TISSUE=Umbilical vein;
RX   PubMed=11152697; DOI=10.1074/jbc.m011795200;
RA   Korschineck I., Ziegler S., Breuss J., Lang I., Lorenz M., Kaun C.,
RA   Ambros P.F., Binder B.R.;
RT   "Identification of a novel exon in apolipoprotein E receptor 2 leading to
RT   alternatively spliced mRNAs found in cells of the vascular wall but not in
RT   neuronal tissue.";
RL   J. Biol. Chem. 276:13192-13197(2001).
RN   [4]
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   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), NUCLEOTIDE SEQUENCE
RP   [LARGE SCALE MRNA] OF 720-963 (ISOFORM 1), AND VARIANTS ARG-25 AND GLU-46.
RC   TISSUE=Eye, 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   [6]
RP   ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY.
RX   PubMed=10218790; DOI=10.1016/s0306-4522(98)00489-8;
RA   Clatworthy A.E., Stockinger W., Christie R.H., Schneider W.J., Nimpf J.,
RA   Hyman B.T., Rebeck G.W.;
RT   "Expression and alternate splicing of apolipoprotein E receptor 2 in
RT   brain.";
RL   Neuroscience 90:903-911(1999).
RN   [7]
RP   PHOSPHORYLATION AT TYROSINE RESIDUES.
RX   PubMed=12681505; DOI=10.1016/s0014-5793(03)00261-8;
RA   Sacre S.M., Stannard A.K., Owen J.S.;
RT   "Apolipoprotein E (apoE) isoforms differentially induce nitric oxide
RT   production in endothelial cells.";
RL   FEBS Lett. 540:181-187(2003).
RN   [8]
RP   CHARACTERIZATION, AND TISSUE SPECIFICITY.
RX   PubMed=10508213;
RA   Riddell D.R., Vinogradov D.V., Stannard A.K., Chadwick N., Owen J.S.;
RT   "Identification and characterization of LRP8 (apoER2) in human blood
RT   platelets.";
RL   J. Lipid Res. 40:1925-1930(1999).
RN   [9]
RP   FUNCTION AS A RECEPTOR FOR REELIN.
RX   PubMed=12899622; DOI=10.1021/bi034475p;
RA   Andersen O.M., Benhayon D., Curran T., Willnow T.E.;
RT   "Differential binding of ligands to the apolipoprotein E receptor 2.";
RL   Biochemistry 42:9355-9364(2003).
RN   [10]
RP   FUNCTION AS A RECEPTOR FOR APOE.
RX   PubMed=12950167; DOI=10.1021/bi027093c;
RA   Li X., Kypreos K., Zanni E.E., Zannis V.;
RT   "Domains of apoE required for binding to apoE receptor 2 and to
RT   phospholipids: implications for the functions of apoE in the brain.";
RL   Biochemistry 42:10406-10417(2003).
RN   [11]
RP   FUNCTION AS A RECEPTOR FOR BETA 2-GLYCOPROTEIN I.
RX   PubMed=12807892; DOI=10.1074/jbc.m212655200;
RA   Lutters B.C., Derksen R.H., Tekelenburg W.L., Lenting P.J., Arnout J.,
RA   de Groot P.G.;
RT   "Dimers of beta 2-glycoprotein I increase platelet deposition to collagen
RT   via interaction with phospholipids and the apolipoprotein E receptor 2'.";
RL   J. Biol. Chem. 278:33831-33838(2003).
RN   [12]
RP   INTERACTION WITH PCSK9.
RX   PubMed=18039658; DOI=10.1074/jbc.m708098200;
RA   Poirier S., Mayer G., Benjannet S., Bergeron E., Marcinkiewicz J.,
RA   Nassoury N., Mayer H., Nimpf J., Prat A., Seidah N.G.;
RT   "The proprotein convertase PCSK9 induces the degradation of low density
RT   lipoprotein receptor (LDLR) and its closest family members VLDLR and
RT   ApoER2.";
RL   J. Biol. Chem. 283:2363-2372(2008).
RN   [13]
RP   UBIQUITINATION.
RX   PubMed=20427281; DOI=10.1074/jbc.m110.123729;
RA   Hong C., Duit S., Jalonen P., Out R., Scheer L., Sorrentino V.,
RA   Boyadjian R., Rodenburg K.W., Foley E., Korhonen L., Lindholm D., Nimpf J.,
RA   van Berkel T.J., Tontonoz P., Zelcer N.;
RT   "The E3 ubiquitin ligase IDOL induces the degradation of the low density
RT   lipoprotein receptor family members VLDLR and ApoER2.";
RL   J. Biol. Chem. 285:19720-19726(2010).
RN   [14]
RP   INTERACTION WITH CLU.
RX   PubMed=24381170; DOI=10.1074/jbc.m113.529271;
RA   Leeb C., Eresheim C., Nimpf J.;
RT   "Clusterin is a ligand for apolipoprotein E receptor 2 (ApoER2) and very
RT   low density lipoprotein receptor (VLDLR) and signals via the Reelin-
RT   signaling pathway.";
RL   J. Biol. Chem. 289:4161-4172(2014).
RN   [15]
RP   FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND INTERACTION WITH VLDLR.
RX   PubMed=30873003; DOI=10.3389/fnmol.2019.00053;
RA   Dlugosz P., Tresky R., Nimpf J.;
RT   "Differential Action of Reelin on Oligomerization of ApoER2 and VLDL
RT   Receptor in HEK293 Cells Assessed by Time-Resolved Anisotropy and
RT   Fluorescence Lifetime Imaging Microscopy.";
RL   Front. Mol. Neurosci. 12:53-53(2019).
RN   [16]
RP   FUNCTION (MICROBIAL INFECTION), INTERACTION WITH SEMLIKI FOREST VIRUS E2-E1
RP   HETERODIMER (MICROBIAL INFECTION), AND SUBCELLULAR LOCATION.
RX   PubMed=34929721; DOI=10.1038/s41586-021-04326-0;
RA   Clark L.E., Clark S.A., Lin C., Liu J., Coscia A., Nabel K.G., Yang P.,
RA   Neel D.V., Lee H., Brusic V., Stryapunina I., Plante K.S., Ahmed A.A.,
RA   Catteruccia F., Young-Pearse T.L., Chiu I.M., Llopis P.M., Weaver S.C.,
RA   Abraham J.;
RT   "VLDLR and ApoER2 are receptors for multiple alphaviruses.";
RL   Nature 602:475-480(2022).
RN   [17]
RP   INTERACTION WITH EASTERN EQUINE ENCEPHALITIS VIRUS SPIKE GLYCOPROTEIN E2
RP   (MICROBIAL INFECTION).
RX   PubMed=39095394; DOI=10.1038/s41467-024-50887-9;
RA   Yang P., Li W., Fan X., Pan J., Mann C.J., Varnum H., Clark L.E.,
RA   Clark S.A., Coscia A., Basu H., Smith K.N., Brusic V., Abraham J.;
RT   "Structural basis for VLDLR recognition by eastern equine encephalitis
RT   virus.";
RL   Nat. Commun. 15:6548-6548(2024).
RN   [18]
RP   FUNCTION (MICROBIAL INFECTION), AND INTERACTION WITH TBEV ENVELOPE PROTEIN
RP   E (MICROBIAL INFECTION).
RX   PubMed=40993380; DOI=10.1038/s41586-025-09500-2;
RA   Mittler E., Tse A.L., Tran P.T., Florez C., Janer J., Varnaite R.,
RA   Kasikci E., Mv V.K., Loomis M., Christ W., Cazares E., Bakken R.R.,
RA   Martin C.K., Zeng X., Raymond J.L., Shahsavani M., Khanal S.,
RA   Wilkinson E.R., Oktavia R.M., Slough M.M., Haslwanter D., Han J.,
RA   Berrigan J., Rosendal E., Kielian M., Manicassamy B., Oeverby A.K.,
RA   Falk A., Barba-Spaeth G., Rey F.A., Klingstroem J., Gavathiotis E.,
RA   Herbert A.S., Chandran K., Gredmark-Russ S.;
RT   "LRP8 is a receptor for tick-borne encephalitis virus.";
RL   Nature 0:0-0(2025).
RN   [19] {ECO:0007744|PDB:3A7Q}
RP   X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 42-83 IN COMPLEX WITH REELIN/RELN
RP   AND CALCIUM, FUNCTION, AND DISULFIDE BOND.
RX   PubMed=20223215; DOI=10.1016/j.str.2010.01.010;
RA   Yasui N., Nogi T., Takagi J.;
RT   "Structural basis for specific recognition of reelin by its receptors.";
RL   Structure 18:320-331(2010).
RN   [20]
RP   VARIANTS GLU-46 AND GLN-952.
RX   PubMed=12399018; DOI=10.1016/s0304-3940(02)00942-4;
RA   Ma S.L., Ng H.K., Baum L., Pang J.C., Chiu H.F., Woo J., Tang N.L.,
RA   Lam L.C.;
RT   "Low-density lipoprotein receptor-related protein 8 (apolipoprotein E
RT   receptor 2) gene polymorphisms in Alzheimer's disease.";
RL   Neurosci. Lett. 332:216-218(2002).
RN   [21]
RP   VARIANT GLN-952, CHARACTERIZATION OF VARIANT GLN-952, AND INVOLVEMENT IN
RP   MCI1.
RX   PubMed=17847002; DOI=10.1086/521581;
RA   Shen G.-Q., Li L., Girelli D., Seidelmann S.B., Rao S., Fan C., Park J.E.,
RA   Xi Q., Li J., Hu Y., Olivieri O., Marchant K., Barnard J., Corrocher R.,
RA   Elston R., Cassano J., Henderson S., Hazen S.L., Plow E.F., Topol E.J.,
RA   Wang Q.K.;
RT   "An LRP8 variant is associated with familial and premature coronary artery
RT   disease and myocardial infarction.";
RL   Am. J. Hum. Genet. 81:780-791(2007).
CC   -!- FUNCTION: Cell surface receptor for Reelin (RELN) and apolipoprotein E
CC       (apoE)-containing ligands (PubMed:12899622, PubMed:12950167,
CC       PubMed:20223215, PubMed:30873003). LRP8 participates in transmitting
CC       the extracellular Reelin signal to intracellular signaling processes,
CC       by binding to DAB1 on its cytoplasmic tail (By similarity). Reelin acts
CC       via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine
CC       phosphorylation and microtubule function in neurons (By similarity).
CC       LRP8 has higher affinity for Reelin than VLDLR (By similarity). LRP8 is
CC       thus a key component of the Reelin pathway which governs neuronal
CC       layering of the forebrain during embryonic brain development (By
CC       similarity). Binds the endoplasmic reticulum resident receptor-
CC       associated protein (RAP) (By similarity). Binds dimers of beta 2-
CC       glycoprotein I and may be involved in the suppression of platelet
CC       aggregation in the vasculature (PubMed:12807892). Highly expressed in
CC       the initial segment of the epididymis, where it affects the functional
CC       expression of clusterin and phospholipid hydroperoxide glutathione
CC       peroxidase (PHGPx), two proteins required for sperm maturation (By
CC       similarity). May also function as an endocytic receptor (By
CC       similarity). Not required for endocytic uptake of SEPP1 in the kidney
CC       which is mediated by LRP2 (By similarity). Together with its ligand,
CC       apolipoprotein E (apoE), may indirectly play a role in the suppression
CC       of the innate immune response by controlling the survival of myeloid-
CC       derived suppressor cells (By similarity).
CC       {ECO:0000250|UniProtKB:Q924X6, ECO:0000269|PubMed:12807892,
CC       ECO:0000269|PubMed:12899622, ECO:0000269|PubMed:12950167,
CC       ECO:0000269|PubMed:20223215, ECO:0000269|PubMed:30873003}.
CC   -!- FUNCTION: (Microbial infection) Acts as a receptor for Semliki Forest
CC       virus. {ECO:0000269|PubMed:34929721}.
CC   -!- FUNCTION: (Microbial infection) Acts as a receptor for tick-borne
CC       encephalitis virus by mediating viral cell attachment and
CC       internalization. {ECO:0000269|PubMed:34929721}.
CC   -!- SUBUNIT: Homooligomer (PubMed:30873003). Interacts with VLDLR
CC       (PubMed:30873003). Reelin associates with two or more receptor
CC       molecules (PubMed:20223215). Interacts with DAB1 and JNK-interacting
CC       proteins. Interacts with SNX17 (By similarity). Interacts with PCSK9.
CC       Interacts with MDK; this interaction is calcium dependent (By
CC       similarity). Interacts with CLU (PubMed:24381170). {ECO:0000250,
CC       ECO:0000250|UniProtKB:Q924X6, ECO:0000269|PubMed:18039658,
CC       ECO:0000269|PubMed:20223215, ECO:0000269|PubMed:24381170,
CC       ECO:0000269|PubMed:30873003}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with Semliki Forest virus E2-
CC       E1 heterodimer; this interaction mediates viral entry to host cell.
CC       {ECO:0000269|PubMed:34929721}.
CC   -!- SUBUNIT: (Microbial infection) Interacts (via class A repeats) with
CC       Eastern equine encephalitis virus spike glycoprotein E2; this
CC       interaction mediates viral entry into host cell.
CC       {ECO:0000269|PubMed:39095394}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with tick-borne encephalitis
CC       virus envelope protein E; this interaction mediates viral entry to host
CC       cell. {ECO:0000269|PubMed:34929721}.
CC   -!- INTERACTION:
CC       Q14114; P25054: APC; NbExp=2; IntAct=EBI-2681187, EBI-727707;
CC       Q14114; P02649: APOE; NbExp=2; IntAct=EBI-2681187, EBI-1222467;
CC       Q14114; P30533: LRPAP1; NbExp=2; IntAct=EBI-2681187, EBI-715927;
CC       Q14114; Q60841: Reln; Xeno; NbExp=10; IntAct=EBI-2681187, EBI-9248666;
CC       Q14114-3; Q06481-5: APLP2; NbExp=3; IntAct=EBI-25832196, EBI-25646567;
CC       Q14114-3; P02649: APOE; NbExp=3; IntAct=EBI-25832196, EBI-1222467;
CC       Q14114-3; Q9UGL9: CRCT1; NbExp=3; IntAct=EBI-25832196, EBI-713677;
CC       Q14114-3; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-25832196, EBI-9087876;
CC       Q14114-3; P35222: CTNNB1; NbExp=3; IntAct=EBI-25832196, EBI-491549;
CC       Q14114-3; Q9UJY5-5: GGA1; NbExp=3; IntAct=EBI-25832196, EBI-25903400;
CC       Q14114-3; Q92993-2: KAT5; NbExp=3; IntAct=EBI-25832196, EBI-20795332;
CC       Q14114-3; Q99683: MAP3K5; NbExp=3; IntAct=EBI-25832196, EBI-476263;
CC       Q14114-3; Q96P71-2: NECAB3; NbExp=3; IntAct=EBI-25832196, EBI-15098952;
CC       Q14114-3; I6L9F6: NEFL; NbExp=3; IntAct=EBI-25832196, EBI-10178578;
CC       Q14114-3; P10599: TXN; NbExp=3; IntAct=EBI-25832196, EBI-594644;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:30873003};
CC       Single-pass type I membrane protein {ECO:0000255}. Secreted
CC       {ECO:0000250|UniProtKB:Q924X6}. Note=Isoforms that contain the exon
CC       coding for a furin-type cleavage site are proteolytically processed,
CC       leading to a secreted receptor fragment.
CC       {ECO:0000250|UniProtKB:Q924X6}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=5;
CC         Comment=Additional isoforms seem to exist. No differences were
CC         observed in the pattern splicing between control and Alzheimer
CC         brains.;
CC       Name=1; Synonyms=ApoER2 922;
CC         IsoId=Q14114-1; Sequence=Displayed;
CC       Name=2; Synonyms=ApoER2 906;
CC         IsoId=Q14114-2; Sequence=VSP_010305, VSP_010307, VSP_010308;
CC       Name=3;
CC         IsoId=Q14114-3; Sequence=VSP_010308;
CC       Name=4; Synonyms=ApoER2delta4-7;
CC         IsoId=Q14114-4; Sequence=VSP_038181, VSP_010306;
CC       Name=5;
CC         IsoId=Q14114-5; Sequence=Not described;
CC   -!- TISSUE SPECIFICITY: Expressed mainly in brain and placenta. Also
CC       expressed in platelets and megakaryocytic cells. Not expressed in the
CC       liver. {ECO:0000269|PubMed:10218790, ECO:0000269|PubMed:10508213}.
CC   -!- DOMAIN: The cytoplasmic domain is involved in the binding of DAB1 and
CC       in the recruitment of JNK-interacting proteins. Isoforms, which lack
CC       part of the cytoplasmic domain, are unable to recruit members of the
CC       family of JNK interacting proteins (JIP) to the cytoplasmic tail (By
CC       similarity). {ECO:0000250|UniProtKB:Q924X6}.
CC   -!- PTM: O-glycosylated. Some alternatively spliced isoforms lack the O-
CC       linked sugar domain (By similarity). {ECO:0000250|UniProtKB:Q924X6}.
CC   -!- PTM: Undergoes sequential, furin and gamma-secretase dependent,
CC       proteolytic processing, resulting in the extracellular release of the
CC       entire ligand-binding domain as a soluble polypeptide and in the
CC       intracellular domain (ICD) release into the cytoplasm. The gamma-
CC       secretase-dependent proteolytical processing occurs after the bulk of
CC       the extracellular domain has been shed, in a furin-dependent manner, in
CC       alternatively spliced isoforms carrying the furin cleavage site.
CC       Hypoglycosylation (mainly hypo-O-glycosylation) leads to increased
CC       extracellular cleavage, which in turn results in accelerating release
CC       of the intracellular domain (ICD) by the gamma-secretase. The resulting
CC       receptor fragment is able to inhibit Reelin signaling and in particular
CC       the Reelin-induced DAB1 phosphorylation (By similarity).
CC       {ECO:0000250|UniProtKB:Q924X6}.
CC   -!- PTM: Tyrosine phosphorylated upon apoE binding.
CC       {ECO:0000269|PubMed:12681505}.
CC   -!- PTM: Ubiquitinated by MYLIP leading to degradation.
CC       {ECO:0000269|PubMed:20427281}.
CC   -!- DISEASE: Myocardial infarction 1 (MCI1) [MIM:608446]: A condition
CC       defined by the irreversible necrosis of heart muscle secondary to
CC       prolonged ischemia. {ECO:0000269|PubMed:17847002}. Note=The disease is
CC       caused by variants affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: Natural isoforms of apoE (E2, E3, E4) have similar
CC       affinities for LRP8.
CC   -!- MISCELLANEOUS: [Isoform 5]: Contains an insert in the extracellular
CC       part which carries a furin cleavage site. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the LDLR family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAA99509.1; Type=Frameshift; Evidence={ECO:0000305};
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; D50678; BAA09328.1; -; mRNA.
DR   EMBL; D86407; BAA21824.1; -; Genomic_DNA.
DR   EMBL; D86407; BAA21825.1; -; Genomic_DNA.
DR   EMBL; Z75190; CAA99509.1; ALT_FRAME; mRNA.
DR   EMBL; AL355483; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL606760; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC006443; AAH06443.1; -; mRNA.
DR   EMBL; BC051836; AAH51836.2; -; mRNA.
DR   CCDS; CCDS30720.1; -. [Q14114-3]
DR   CCDS; CCDS578.1; -. [Q14114-1]
DR   CCDS; CCDS579.1; -. [Q14114-2]
DR   CCDS; CCDS580.1; -. [Q14114-4]
DR   RefSeq; NP_001018064.1; NM_001018054.3. [Q14114-3]
DR   RefSeq; NP_004622.2; NM_004631.5. [Q14114-1]
DR   RefSeq; NP_059992.3; NM_017522.4. [Q14114-2]
DR   RefSeq; NP_150643.2; NM_033300.4. [Q14114-4]
DR   PDB; 3A7Q; X-ray; 2.60 A; B=42-83.
DR   PDB; 5B4X; X-ray; 3.20 A; B/D=42-736.
DR   PDB; 5B4Y; X-ray; 1.90 A; B=42-124.
DR   PDB; 7UCX; X-ray; 1.72 A; B=47-65.
DR   PDBsum; 3A7Q; -.
DR   PDBsum; 5B4X; -.
DR   PDBsum; 5B4Y; -.
DR   PDBsum; 7UCX; -.
DR   AlphaFoldDB; Q14114; -.
DR   SMR; Q14114; -.
DR   BioGRID; 113579; 100.
DR   DIP; DIP-48670N; -.
DR   ELM; Q14114; -.
DR   FunCoup; Q14114; 683.
DR   IntAct; Q14114; 36.
DR   STRING; 9606.ENSP00000303634; -.
DR   GlyCosmos; Q14114; 6 sites, No reported glycans.
DR   GlyGen; Q14114; 13 sites, 5 N-linked glycans (4 sites), 2 O-linked glycans (6 sites).
DR   iPTMnet; Q14114; -.
DR   PhosphoSitePlus; Q14114; -.
DR   SwissPalm; Q14114; -.
DR   BioMuta; LRP8; -.
DR   DMDM; 259016389; -.
DR   jPOST; Q14114; -.
DR   MassIVE; Q14114; -.
DR   PaxDb; 9606-ENSP00000303634; -.
DR   PeptideAtlas; Q14114; -.
DR   ProteomicsDB; 59819; -. [Q14114-1]
DR   ProteomicsDB; 59820; -. [Q14114-2]
DR   ProteomicsDB; 59821; -. [Q14114-3]
DR   ProteomicsDB; 59822; -. [Q14114-4]
DR   Pumba; Q14114; -.
DR   Antibodypedia; 33078; 419 antibodies from 34 providers.
DR   DNASU; 7804; -.
DR   Ensembl; ENST00000306052.12; ENSP00000303634.6; ENSG00000157193.19. [Q14114-1]
DR   Ensembl; ENST00000347547.7; ENSP00000334522.2; ENSG00000157193.19. [Q14114-4]
DR   Ensembl; ENST00000354412.7; ENSP00000346391.3; ENSG00000157193.19. [Q14114-2]
DR   Ensembl; ENST00000371454.6; ENSP00000360509.2; ENSG00000157193.19. [Q14114-3]
DR   GeneID; 7804; -.
DR   KEGG; hsa:7804; -.
DR   MANE-Select; ENST00000306052.12; ENSP00000303634.6; NM_004631.5; NP_004622.2.
DR   UCSC; uc001cvi.4; human. [Q14114-1]
DR   AGR; HGNC:6700; -.
DR   ClinPGx; PA30457; -.
DR   CTD; 7804; -.
DR   DisGeNET; 7804; -.
DR   GeneCards; LRP8; -.
DR   HGNC; HGNC:6700; LRP8.
DR   HPA; ENSG00000157193; Tissue enhanced (testis, thyroid gland).
DR   MalaCards; LRP8; -.
DR   MIM; 602600; gene.
DR   MIM; 608446; phenotype.
DR   OpenTargets; ENSG00000157193; -.
DR   VEuPathDB; HostDB:ENSG00000157193; -.
DR   eggNOG; KOG1215; Eukaryota.
DR   GeneTree; ENSGT00940000154819; -.
DR   HOGENOM; CLU_008163_4_0_1; -.
DR   InParanoid; Q14114; -.
DR   OMA; CESPTKF; -.
DR   OrthoDB; 5958943at2759; -.
DR   PAN-GO; Q14114; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; Q14114; -.
DR   PathwayCommons; Q14114; -.
DR   Reactome; R-HSA-432142; Platelet sensitization by LDL.
DR   Reactome; R-HSA-975634; Retinoid metabolism and transport.
DR   SignaLink; Q14114; -.
DR   SIGNOR; Q14114; -.
DR   Agora; ENSG00000157193; -.
DR   BioGRID-ORCS; 7804; 35 hits in 1154 CRISPR screens.
DR   EvolutionaryTrace; Q14114; -.
DR   GeneWiki; Low_density_lipoprotein_receptor-related_protein_8; -.
DR   GenomeRNAi; 7804; -.
DR   Pharos; Q14114; Tbio.
DR   PRO; PR:Q14114; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; Q14114; protein.
DR   Bgee; ENSG00000157193; Expressed in ganglionic eminence and 179 other cell types or tissues.
DR   ExpressionAtlas; Q14114; baseline and differential.
DR   GO; GO:0030424; C:axon; IEA:Ensembl.
DR   GO; GO:0005901; C:caveola; IDA:BHF-UCL.
DR   GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR   GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR   GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0005875; C:microtubule associated complex; IEA:Ensembl.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProt.
DR   GO; GO:0098839; C:postsynaptic density membrane; IEA:Ensembl.
DR   GO; GO:0043235; C:receptor complex; IDA:MGI.
DR   GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl.
DR   GO; GO:0001540; F:amyloid-beta binding; IEA:Ensembl.
DR   GO; GO:0034185; F:apolipoprotein binding; IC:BHF-UCL.
DR   GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR   GO; GO:0048306; F:calcium-dependent protein binding; IEA:Ensembl.
DR   GO; GO:0038024; F:cargo receptor activity; NAS:ARUK-UCL.
DR   GO; GO:0008035; F:high-density lipoprotein particle binding; IEA:Ensembl.
DR   GO; GO:0019894; F:kinesin binding; IEA:Ensembl.
DR   GO; GO:0005041; F:low-density lipoprotein particle receptor activity; TAS:ARUK-UCL.
DR   GO; GO:0038025; F:reelin receptor activity; ISS:BHF-UCL.
DR   GO; GO:0004888; F:transmembrane signaling receptor activity; TAS:ProtInc.
DR   GO; GO:0030229; F:very-low-density lipoprotein particle receptor activity; IDA:BHF-UCL.
DR   GO; GO:0021541; P:ammon gyrus development; ISS:BHF-UCL.
DR   GO; GO:0071397; P:cellular response to cholesterol; IEA:Ensembl.
DR   GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR   GO; GO:0007268; P:chemical synaptic transmission; IEA:Ensembl.
DR   GO; GO:0019221; P:cytokine-mediated signaling pathway; NAS:UniProtKB.
DR   GO; GO:0048813; P:dendrite morphogenesis; IEA:Ensembl.
DR   GO; GO:0006897; P:endocytosis; IDA:UniProtKB.
DR   GO; GO:0021819; P:layer formation in cerebral cortex; ISS:UniProt.
DR   GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc.
DR   GO; GO:0050804; P:modulation of chemical synaptic transmission; ISS:BHF-UCL.
DR   GO; GO:1900006; P:positive regulation of dendrite development; ISS:BHF-UCL.
DR   GO; GO:0061003; P:positive regulation of dendritic spine morphogenesis; ISS:BHF-UCL.
DR   GO; GO:0006508; P:proteolysis; NAS:UniProtKB.
DR   GO; GO:0038026; P:reelin-mediated signaling pathway; ISS:BHF-UCL.
DR   GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR   GO; GO:0001523; P:retinoid metabolic process; TAS:Reactome.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   GO; GO:0021517; P:ventral spinal cord development; IBA:GO_Central.
DR   CDD; cd00054; EGF_CA; 1.
DR   CDD; cd00112; LDLa; 6.
DR   FunFam; 4.10.400.10:FF:000162; LDL receptor related protein 8; 1.
DR   FunFam; 2.10.25.10:FF:000009; Low-density lipoprotein receptor isoform 1; 1.
DR   FunFam; 2.10.25.10:FF:000052; low-density lipoprotein receptor isoform X1; 1.
DR   FunFam; 2.120.10.30:FF:000002; low-density lipoprotein receptor isoform X1; 1.
DR   FunFam; 4.10.400.10:FF:000136; low-density lipoprotein receptor isoform X5; 1.
DR   FunFam; 4.10.400.10:FF:000113; Low-density lipoprotein receptor-related protein 8; 1.
DR   FunFam; 4.10.400.10:FF:000138; Low-density lipoprotein receptor-related protein 8; 1.
DR   FunFam; 4.10.400.10:FF:000165; low-density lipoprotein receptor-related protein 8 isoform X1; 1.
DR   FunFam; 4.10.400.10:FF:000030; Sortilin related receptor 1; 1.
DR   Gene3D; 2.10.25.10; Laminin; 3.
DR   Gene3D; 4.10.400.10; Low-density Lipoprotein Receptor; 7.
DR   Gene3D; 2.120.10.30; TolB, C-terminal domain; 1.
DR   InterPro; IPR011042; 6-blade_b-propeller_TolB-like.
DR   InterPro; IPR000742; EGF.
DR   InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR   InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR   InterPro; IPR018097; EGF_Ca-bd_CS.
DR   InterPro; IPR036055; LDL_receptor-like_sf.
DR   InterPro; IPR051221; LDLR-related.
DR   InterPro; IPR023415; LDLR_class-A_CS.
DR   InterPro; IPR000033; LDLR_classB_rpt.
DR   InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR   InterPro; IPR049883; NOTCH1_EGF-like.
DR   PANTHER; PTHR22722:SF15; LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED; 1.
DR   PANTHER; PTHR22722; LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 2-RELATED; 1.
DR   Pfam; PF07645; EGF_CA; 1.
DR   Pfam; PF14670; FXa_inhibition; 1.
DR   Pfam; PF00057; Ldl_recept_a; 7.
DR   Pfam; PF00058; Ldl_recept_b; 5.
DR   PRINTS; PR00261; LDLRECEPTOR.
DR   SMART; SM00181; EGF; 4.
DR   SMART; SM00179; EGF_CA; 2.
DR   SMART; SM00192; LDLa; 7.
DR   SMART; SM00135; LY; 5.
DR   SUPFAM; SSF57196; EGF/Laminin; 3.
DR   SUPFAM; SSF57424; LDL receptor-like module; 7.
DR   SUPFAM; SSF63825; YWTD domain; 1.
DR   PROSITE; PS00010; ASX_HYDROXYL; 2.
DR   PROSITE; PS01186; EGF_2; 2.
DR   PROSITE; PS50026; EGF_3; 2.
DR   PROSITE; PS01187; EGF_CA; 1.
DR   PROSITE; PS01209; LDLRA_1; 7.
DR   PROSITE; PS50068; LDLRA_2; 7.
DR   PROSITE; PS51120; LDLRB; 5.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Calcium; Cell membrane; Disulfide bond;
KW   EGF-like domain; Endocytosis; Glycoprotein; Host-virus interaction;
KW   Membrane; Metal-binding; Phosphoprotein; Proteomics identification;
KW   Receptor; Reference proteome; Repeat; Secreted; Signal; Transmembrane;
KW   Transmembrane helix; Ubl conjugation.
FT   SIGNAL          1..32
FT                   /evidence="ECO:0000255"
FT   CHAIN           33..963
FT                   /note="Low-density lipoprotein receptor-related protein 8"
FT                   /id="PRO_0000017332"
FT   TOPO_DOM        42..826
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        827..847
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        848..963
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          46..82
FT                   /note="LDL-receptor class A 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          85..123
FT                   /note="LDL-receptor class A 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          126..164
FT                   /note="LDL-receptor class A 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          166..202
FT                   /note="LDL-receptor class A 4"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          205..246
FT                   /note="LDL-receptor class A 5"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          258..295
FT                   /note="LDL-receptor class A 6"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          298..334
FT                   /note="LDL-receptor class A 7"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DOMAIN          336..375
FT                   /note="EGF-like 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   DOMAIN          376..415
FT                   /note="EGF-like 2; calcium-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   REPEAT          462..508
FT                   /note="LDL-receptor class B 1"
FT   REPEAT          509..551
FT                   /note="LDL-receptor class B 2"
FT   REPEAT          552..595
FT                   /note="LDL-receptor class B 3"
FT   REPEAT          596..639
FT                   /note="LDL-receptor class B 4"
FT   REPEAT          640..681
FT                   /note="LDL-receptor class B 5"
FT   REGION          740..798
FT                   /note="Clustered O-linked oligosaccharides"
FT   REGION          754..815
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        765..777
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        778..799
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        800..812
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         64
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:20223215,
FT                   ECO:0007744|PDB:3A7Q"
FT   BINDING         67
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:20223215,
FT                   ECO:0007744|PDB:3A7Q"
FT   BINDING         69
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:20223215,
FT                   ECO:0007744|PDB:3A7Q"
FT   BINDING         71
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:20223215,
FT                   ECO:0007744|PDB:3A7Q"
FT   BINDING         77
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:20223215,
FT                   ECO:0007744|PDB:3A7Q"
FT   BINDING         78
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000269|PubMed:20223215,
FT                   ECO:0007744|PDB:3A7Q"
FT   CARBOHYD        176
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        441
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        518
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        538
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        772
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        807
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        47..59
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124,
FT                   ECO:0000269|PubMed:20223215, ECO:0007744|PDB:3A7Q"
FT   DISULFID        54..72
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124,
FT                   ECO:0000269|PubMed:20223215, ECO:0007744|PDB:3A7Q"
FT   DISULFID        66..81
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124,
FT                   ECO:0000269|PubMed:20223215, ECO:0007744|PDB:3A7Q"
FT   DISULFID        86..98
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        93..111
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        105..122
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        127..141
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        134..154
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        148..163
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        167..179
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        174..192
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        186..201
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        206..221
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        213..234
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        228..245
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        259..272
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        267..285
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        279..294
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        299..311
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        306..324
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        318..333
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        340..351
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        347..360
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        362..374
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        380..390
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        386..399
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   DISULFID        401..414
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT   VAR_SEQ         166..295
FT                   /note="LCAPHEFQCGNRSCLAAVFVCDGDDDCGDGSDERGCADPACGPREFRCGGDG
FT                   GGACIPERWVCDRQFDCEDRSDEAAELCGRPGPGATSAPAACATASQFACRSGECVHLG
FT                   WRCDGDRDCKDKSDEADCP -> S (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:11152697"
FT                   /id="VSP_010305"
FT   VAR_SEQ         166
FT                   /note="L -> W (in isoform 4)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_038181"
FT   VAR_SEQ         167..336
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_010306"
FT   VAR_SEQ         737..812
FT                   /note="APQSTSTTTLASTMTRTVPATTRAPGTTVHRSTYQNHSTETPSLTAAVPSSV
FT                   SVPRAPSISPSTLSPATSNHSQHY -> D (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:11152697"
FT                   /id="VSP_010307"
FT   VAR_SEQ         893..951
FT                   /note="Missing (in isoform 2 and isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:11152697,
FT                   ECO:0000303|PubMed:15489334"
FT                   /id="VSP_010308"
FT   VARIANT         25
FT                   /note="Q -> R (in dbSNP:rs4926972)"
FT                   /evidence="ECO:0000269|PubMed:11152697,
FT                   ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:8626535,
FT                   ECO:0000269|PubMed:9079678"
FT                   /id="VAR_046974"
FT   VARIANT         46
FT                   /note="D -> E (in dbSNP:rs3820198)"
FT                   /evidence="ECO:0000269|PubMed:11152697,
FT                   ECO:0000269|PubMed:12399018, ECO:0000269|PubMed:15489334,
FT                   ECO:0000269|PubMed:8626535, ECO:0000269|PubMed:9079678"
FT                   /id="VAR_018468"
FT   VARIANT         453
FT                   /note="V -> M (in dbSNP:rs5180)"
FT                   /id="VAR_037624"
FT   VARIANT         466
FT                   /note="W -> C (in dbSNP:rs5181)"
FT                   /id="VAR_037625"
FT   VARIANT         607
FT                   /note="Q -> R (in dbSNP:rs5172)"
FT                   /id="VAR_037626"
FT   VARIANT         611
FT                   /note="I -> L (in dbSNP:rs5170)"
FT                   /id="VAR_037627"
FT   VARIANT         653
FT                   /note="S -> T (in dbSNP:rs5171)"
FT                   /id="VAR_037628"
FT   VARIANT         736
FT                   /note="R -> Q (in dbSNP:rs5172)"
FT                   /id="VAR_059079"
FT   VARIANT         952
FT                   /note="R -> Q (risk factor for MCI1; increases activation
FT                   of MAPK14 by oxidized low density lipoprotein;
FT                   dbSNP:rs5174)"
FT                   /evidence="ECO:0000269|PubMed:12399018,
FT                   ECO:0000269|PubMed:17847002"
FT                   /id="VAR_018469"
FT   CONFLICT        262
FT                   /note="A -> V (in Ref. 1; BAA09328 and 2; BAA21824)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        405
FT                   /note="Y -> C (in Ref. 3; CAA99509)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        418
FT                   /note="A -> G (in Ref. 1; BAA09328 and 2; BAA21824/
FT                   BAA21825)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        430
FT                   /note="H -> Y (in Ref. 1; BAA09328, 2; BAA21824/BAA21825
FT                   and 3; CAA99509)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        488
FT                   /note="Q -> R (in Ref. 3; CAA99509)"
FT                   /evidence="ECO:0000305"
FT   HELIX           53..56
FT                   /evidence="ECO:0007829|PDB:7UCX"
FT   STRAND          59..61
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   HELIX           62..64
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   STRAND          67..69
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   STRAND          72..75
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   HELIX           76..78
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   STRAND          88..92
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   STRAND          98..100
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   HELIX           101..103
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   STRAND          106..108
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   HELIX           115..117
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            119..121
FT                   /evidence="ECO:0007829|PDB:5B4Y"
FT   TURN            339..341
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   HELIX           342..344
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          348..352
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          355..357
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          359..361
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          368..372
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   HELIX           379..381
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          385..393
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          396..400
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          405..407
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          409..412
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          414..416
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          418..420
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          423..427
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          429..439
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          442..458
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            459..462
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          463..468
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            469..472
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          473..478
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   HELIX           479..481
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   HELIX           485..487
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          489..492
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          501..505
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            506..509
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          510..515
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            516..519
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          520..525
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          530..535
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          540..548
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            549..552
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          553..558
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          560..562
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          564..569
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          576..579
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          586..592
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            593..596
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          597..602
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            603..606
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          607..612
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          619..622
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            625..627
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          629..637
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          640..645
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            646..649
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          650..655
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            656..658
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          663..666
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          675..678
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   HELIX           680..682
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   TURN            689..691
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          692..695
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   HELIX           696..699
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          701..706
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          710..714
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          716..720
FT                   /evidence="ECO:0007829|PDB:5B4X"
FT   STRAND          731..735
FT                   /evidence="ECO:0007829|PDB:5B4X"
SQ   SEQUENCE   963 AA;  105634 MW;  B10DCF72F62DE71C CRC64;
     MGLPEPGPLR LLALLLLLLL LLLLQLQHLA AAAADPLLGG QGPAKDCEKD QFQCRNERCI
     PSVWRCDEDD DCLDHSDEDD CPKKTCADSD FTCDNGHCIH ERWKCDGEEE CPDGSDESEA
     TCTKQVCPAE KLSCGPTSHK CVPASWRCDG EKDCEGGADE AGCATLCAPH EFQCGNRSCL
     AAVFVCDGDD DCGDGSDERG CADPACGPRE FRCGGDGGGA CIPERWVCDR QFDCEDRSDE
     AAELCGRPGP GATSAPAACA TASQFACRSG ECVHLGWRCD GDRDCKDKSD EADCPLGTCR
     GDEFQCGDGT CVLAIKHCNQ EQDCPDGSDE AGCLQGLNEC LHNNGGCSHI CTDLKIGFEC
     TCPAGFQLLD QKTCGDIDEC KDPDACSQIC VNYKGYFKCE CYPGYEMDLL TKNCKAAAGK
     SPSLIFTNRH EVRRIDLVKR NYSRLIPMLK NVVALDVEVA TNRIYWCDLS YRKIYSAYMD
     KASDPKEQEV LIDEQLHSPE GLAVDWVHKH IYWTDSGNKT ISVATVDGGR RRTLFSRNLS
     EPRAIAVDPL RGFMYWSDWG DQAKIEKSGL NGVDRQTLVS DNIEWPNGIT LDLLSQRLYW
     VDSKLHQLSS IDFSGGNRKT LISSTDFLSH PFGIAVFEDK VFWTDLENEA IFSANRLNGL
     EISILAENLN NPHDIVIFHE LKQPRAPDAC ELSVQPNGGC EYLCLPAPQI SSHSPKYTCA
     CPDTMWLGPD MKRCYRAPQS TSTTTLASTM TRTVPATTRA PGTTVHRSTY QNHSTETPSL
     TAAVPSSVSV PRAPSISPST LSPATSNHSQ HYANEDSKMG STVTAAVIGI IVPIVVIALL
     CMSGYLIWRN WKRKNTKSMN FDNPVYRKTT EEEDEDELHI GRTAQIGHVY PAAISSFDRP
     LWAEPCLGET REPEDPAPAL KELFVLPGEP RSQLHQLPKN PLSELPVVKS KRVALSLEDD
     GLP
//
ID   MARK1_HUMAN             Reviewed;         795 AA.
AC   Q9P0L2; D3DTB0; D3DTB1; Q2HIY1; Q5VTF9; Q5VTG0; Q96SW9; Q9P251;
DT   12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 2.
DT   28-JAN-2026, entry version 205.
DE   RecName: Full=Serine/threonine-protein kinase MARK1;
DE            EC=2.7.11.1;
DE            EC=2.7.11.26;
DE   AltName: Full=MAP/microtubule affinity-regulating kinase 1;
DE   AltName: Full=PAR1 homolog c;
DE            Short=Par-1c;
DE            Short=Par1c;
GN   Name=MARK1 {ECO:0000312|HGNC:HGNC:6896};
GN   Synonyms=KIAA1477 {ECO:0000312|EMBL:BAA96001.1},
GN   MARK {ECO:0000312|EMBL:AAF72103.1};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ACTIVITY REGULATION,
RP   PHOSPHORYLATION AT THR-215, AND MUTAGENESIS OF THR-215.
RX   PubMed=14976552; DOI=10.1038/sj.emboj.7600110;
RA   Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A., Boudeau J.,
RA   Hawley S.A., Udd L., Maekelae T.P., Hardie D.G., Alessi D.R.;
RT   "LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily,
RT   including MARK/PAR-1.";
RL   EMBO J. 23:833-843(2004).
RN   [2] {ECO:0000305, ECO:0000312|EMBL:AAF72103.1}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Zhou H.J., Huang X.W., Zhou Y., Hu S.L., Yuan J.G., Qiang B.Q.;
RT   "Cloning and isolating human MARK.";
RL   Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN   [3] {ECO:0000305, ECO:0000312|EMBL:BAA96001.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC   TISSUE=Brain {ECO:0000269|PubMed:10819331};
RX   PubMed=10819331; DOI=10.1093/dnares/7.2.143;
RA   Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. XVII. The
RT   complete sequences of 100 new cDNA clones from brain which code for large
RT   proteins in vitro.";
RL   DNA Res. 7:143-150(2000).
RN   [4] {ECO:0000305, ECO:0000312|EMBL:BAB55152.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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=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   [6] {ECO:0000305, ECO:0000312|EMBL:AAF72103.1}
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).
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] {ECO:0000305}
RP   TISSUE SPECIFICITY.
RX   PubMed=9108484; DOI=10.1016/s0092-8674(00)80208-1;
RA   Drewes G., Ebneth A., Preuss U., Mandelkow E.-M., Mandelkow E.;
RT   "MARK - a novel family of protein kinases that phosphorylate microtubule-
RT   associated proteins and trigger microtubule disruption.";
RL   Cell 89:297-308(1997).
RN   [9]
RP   NEUROFIBRILLARY TANGLES IN ALZHEIMER BRAIN.
RX   PubMed=11089574; DOI=10.1093/jnen/59.11.966;
RA   Chin J.Y., Knowles R.B., Schneider A., Drewes G., Mandelkow E.M.,
RA   Hyman B.T.;
RT   "Microtubule-affinity regulating kinase (MARK) is tightly associated with
RT   neurofibrillary tangles in Alzheimer brain: a fluorescence resonance energy
RT   transfer study.";
RL   J. Neuropathol. Exp. Neurol. 59:966-971(2000).
RN   [10]
RP   FUNCTION.
RX   PubMed=11433294; DOI=10.1038/35083016;
RA   Sun T.-Q., Lu B., Feng J.-J., Reinhard C., Jan Y.N., Fantl W.J.,
RA   Williams L.T.;
RT   "PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt
RT   signalling.";
RL   Nat. Cell Biol. 3:628-636(2001).
RN   [11]
RP   PHOSPHORYLATION AT THR-208, ACTIVITY REGULATION, AND FUNCTION.
RX   PubMed=17573348; DOI=10.1074/jbc.m700590200;
RA   Kojima Y., Miyoshi H., Clevers H.C., Oshima M., Aoki M., Taketo M.M.;
RT   "Suppression of tubulin polymerization by the LKB1-microtubule-associated
RT   protein/microtubule affinity-regulating kinase signaling.";
RL   J. Biol. Chem. 282:23532-23540(2007).
RN   [12]
RP   POSSIBLE INVOLVEMENT IN AUTISM.
RX   PubMed=18492799; DOI=10.1093/hmg/ddn154;
RA   Maussion G., Carayol J., Lepagnol-Bestel A.M., Tores F., Loe-Mie Y.,
RA   Milbreta U., Rousseau F., Fontaine K., Renaud J., Moalic J.M., Philippi A.,
RA   Chedotal A., Gorwood P., Ramoz N., Hager J., Simonneau M.;
RT   "Convergent evidence identifying MAP/microtubule affinity-regulating kinase
RT   1 (MARK1) as a susceptibility gene for autism.";
RL   Hum. Mol. Genet. 17:2541-2551(2008).
RN   [13]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18220336; DOI=10.1021/pr0705441;
RA   Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT   "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT   phosphoproteomic analysis.";
RL   J. Proteome Res. 7:1346-1351(2008).
RN   [14]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-5 AND SER-403, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [15]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-588, 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   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [17]
RP   REVIEW.
RX   PubMed=19559622; DOI=10.1016/j.tibs.2009.03.008;
RA   Matenia D., Mandelkow E.M.;
RT   "The tau of MARK: a polarized view of the cytoskeleton.";
RL   Trends Biochem. Sci. 34:332-342(2009).
RN   [18]
RP   REVIEW.
RX   PubMed=20071654; DOI=10.1096/fj.09-148064;
RA   Marx A., Nugoor C., Panneerselvam S., Mandelkow E.;
RT   "Structure and function of polarity-inducing kinase family MARK/Par-1
RT   within the branch of AMPK/Snf1-related kinases.";
RL   FASEB J. 24:1637-1648(2010).
RN   [19]
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   [20]
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   [21]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [22]
RP   FUNCTION, INTERACTION WITH MAPT, AND SUBCELLULAR LOCATION.
RX   PubMed=23666762; DOI=10.1007/s12017-013-8232-3;
RA   Gu G.J., Lund H., Wu D., Blokzijl A., Classon C., von Euler G.,
RA   Landegren U., Sunnemark D., Kamali-Moghaddam M.;
RT   "Role of individual MARK isoforms in phosphorylation of tau at Ser262 in
RT   Alzheimer's disease.";
RL   NeuroMolecular Med. 15:458-469(2013).
RN   [23]
RP   X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 45-371.
RX   PubMed=16803889; DOI=10.1074/jbc.m604865200;
RA   Marx A., Nugoor C., Muller J., Panneerselvam S., Timm T., Bilang M.,
RA   Mylonas E., Svergun D.I., Mandelkow E.M., Mandelkow E.;
RT   "Structural variations in the catalytic and ubiquitin-associated domains of
RT   microtubule-associated protein/microtubule affinity regulating kinase
RT   (MARK) 1 and MARK2.";
RL   J. Biol. Chem. 281:27586-27599(2006).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 683-795, DOMAIN KA1, SUBCELLULAR
RP   LOCATION, AND MUTAGENESIS OF ARG-698; ARG-701; 771-ARG--LYS-773 AND
RP   773-LYS-ARG-774.
RX   PubMed=21145462; DOI=10.1016/j.cell.2010.11.028;
RA   Moravcevic K., Mendrola J.M., Schmitz K.R., Wang Y.H., Slochower D.,
RA   Janmey P.A., Lemmon M.A.;
RT   "Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by
RT   binding acidic phospholipids.";
RL   Cell 143:966-977(2010).
RN   [25]
RP   VARIANTS [LARGE SCALE ANALYSIS] CYS-233; THR-355; MET-530; LEU-578 AND
RP   GLY-691.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
CC   -!- FUNCTION: Serine/threonine-protein kinase (PubMed:23666762). Involved
CC       in cell polarity and microtubule dynamics regulation. Phosphorylates
CC       DCX, MAP2 and MAP4. Phosphorylates the microtubule-associated protein
CC       MAPT/TAU (PubMed:23666762). Involved in cell polarity by
CC       phosphorylating the microtubule-associated proteins MAP2, MAP4 and
CC       MAPT/TAU at KXGS motifs, causing detachment from microtubules, and
CC       their disassembly. Involved in the regulation of neuronal migration
CC       through its dual activities in regulating cellular polarity and
CC       microtubule dynamics, possibly by phosphorylating and regulating DCX.
CC       Also acts as a positive regulator of the Wnt signaling pathway,
CC       probably by mediating phosphorylation of dishevelled proteins (DVL1,
CC       DVL2 and/or DVL3). {ECO:0000269|PubMed:11433294,
CC       ECO:0000269|PubMed:17573348, ECO:0000269|PubMed:23666762}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP +
CC         H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:14976552};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] +
CC         ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:14976552};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein]
CC         + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC         COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau
CC         protein] + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC         Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.26;
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: Inhibited by phosphorylation at Ser-219 (By
CC       similarity). Activated by phosphorylation on Thr-215. {ECO:0000250,
CC       ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:17573348}.
CC   -!- SUBUNIT: Interacts with MAPT/TAU. {ECO:0000269|PubMed:23666762}.
CC   -!- INTERACTION:
CC       Q9P0L2; P05067: APP; NbExp=3; IntAct=EBI-968587, EBI-77613;
CC       Q9P0L2; P63172: DYNLT1; NbExp=3; IntAct=EBI-968587, EBI-1176455;
CC       Q9P0L2; Q0VD86: INCA1; NbExp=3; IntAct=EBI-968587, EBI-6509505;
CC       Q9P0L2; O95988: TCL1B; NbExp=5; IntAct=EBI-968587, EBI-727338;
CC       Q9P0L2; Q8IY57-5: YAF2; NbExp=3; IntAct=EBI-968587, EBI-12111538;
CC       Q9P0L2; P61981: YWHAG; NbExp=4; IntAct=EBI-968587, EBI-359832;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21145462};
CC       Peripheral membrane protein {ECO:0000269|PubMed:21145462}. Cytoplasm,
CC       cytoskeleton {ECO:0000250}. Cytoplasm {ECO:0000269|PubMed:23666762}.
CC       Cell projection, dendrite {ECO:0000269|PubMed:23666762}. Note=Appears
CC       to localize to an intracellular network. {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q9P0L2-1; Sequence=Displayed;
CC       Name=2 {ECO:0000305};
CC         IsoId=Q9P0L2-2; Sequence=VSP_051702, VSP_051704;
CC       Name=3 {ECO:0000305};
CC         IsoId=Q9P0L2-3; Sequence=VSP_051703, VSP_051704;
CC   -!- TISSUE SPECIFICITY: Highly expressed in heart, skeletal muscle, brain,
CC       fetal brain and fetal kidney. {ECO:0000269|PubMed:9108484}.
CC   -!- DOMAIN: The UBA domain does not seem to bind ubiquitin and ubiquitin-
CC       like and might play a role in regulating the enzyme conformation and
CC       localization. Activation of the kinase activity following
CC       phosphorylation at Thr-208 is accompanied by a conformational change
CC       that alters the orientation of the UBA domain with respect to the
CC       catalytic domain (By similarity). {ECO:0000250}.
CC   -!- DOMAIN: The KA1 domain mediates binding to phospholipids and targeting
CC       to membranes. Binds phosphatidic acid (PA), phosphatidylserine (PtdSer)
CC       and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).
CC       {ECO:0000269|PubMed:21145462}.
CC   -!- PTM: Phosphorylation at Thr-613 by PRKCZ/aPKC in polarized epithelial
CC       cells inhibits the kinase activity (By similarity). Phosphorylated at
CC       Thr-215 by STK11/LKB1 in complex with STE20-related adapter-alpha
CC       (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-215 by TAOK1
CC       activates the kinase activity, leading to phosphorylation and
CC       detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-219 by
CC       GSK3-beta (GSK3B) inhibits the kinase activity. {ECO:0000250,
CC       ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:17573348}.
CC   -!- DISEASE: Note=Genetic variations in MARK1 may be associated with
CC       susceptibility to autism. MARK1 is overexpressed in the prefrontal
CC       cortex of patients with autism and causes changes in the function of
CC       cortical dendrites.
CC   -!- MISCELLANEOUS: Phosphorylation of MAPT/tau by MARK1 could play a role
CC       in early steps of Alzheimer disease. Pathological aggregation of
CC       MAPT/tau to neurofibrillary tangles, filamentous structures consisting
CC       of paired helical filaments (PHFs), is one of the hallmarks of
CC       Alzheimer disease. Hyperphosphorylation by MARK1 could be the initial
CC       step for this abnormal aggregation of tau in Alzheimer disease and
CC       animal models of tauopathy (PubMed:11089574).
CC       {ECO:0000305|PubMed:11089574}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC       protein kinase family. SNF1 subfamily. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA96001.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC       Sequence=BAB55152.1; Type=Frameshift; Evidence={ECO:0000305};
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF154845; AAF72103.1; -; mRNA.
DR   EMBL; AB040910; BAA96001.1; ALT_INIT; mRNA.
DR   EMBL; AK027493; BAB55152.1; ALT_FRAME; mRNA.
DR   EMBL; AC096640; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL592406; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471100; EAW93299.1; -; Genomic_DNA.
DR   EMBL; CH471100; EAW93300.1; -; Genomic_DNA.
DR   EMBL; CH471100; EAW93302.1; -; Genomic_DNA.
DR   EMBL; BC113869; AAI13870.1; -; mRNA.
DR   EMBL; BC114478; AAI14479.1; -; mRNA.
DR   CCDS; CCDS31029.2; -. [Q9P0L2-1]
DR   CCDS; CCDS65789.1; -. [Q9P0L2-3]
DR   RefSeq; NP_001273057.1; NM_001286128.2. [Q9P0L2-3]
DR   RefSeq; NP_061120.3; NM_018650.4. [Q9P0L2-1]
DR   PDB; 2HAK; X-ray; 2.60 A; A/B/C/D/E/F/G/H=45-371.
DR   PDB; 3OSE; X-ray; 1.70 A; A=683-795.
DR   PDB; 6C9D; X-ray; 2.50 A; A/B=45-795.
DR   PDBsum; 2HAK; -.
DR   PDBsum; 3OSE; -.
DR   PDBsum; 6C9D; -.
DR   AlphaFoldDB; Q9P0L2; -.
DR   SASBDB; Q9P0L2; -.
DR   SMR; Q9P0L2; -.
DR   BioGRID; 110309; 84.
DR   DIP; DIP-39777N; -.
DR   FunCoup; Q9P0L2; 1289.
DR   IntAct; Q9P0L2; 53.
DR   MINT; Q9P0L2; -.
DR   STRING; 9606.ENSP00000483424; -.
DR   BindingDB; Q9P0L2; -.
DR   ChEMBL; CHEMBL5940; -.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugCentral; Q9P0L2; -.
DR   GuidetoPHARMACOLOGY; 2097; -.
DR   CarbonylDB; Q9P0L2; -.
DR   iPTMnet; Q9P0L2; -.
DR   PhosphoSitePlus; Q9P0L2; -.
DR   BioMuta; MARK1; -.
DR   DMDM; 124056494; -.
DR   jPOST; Q9P0L2; -.
DR   MassIVE; Q9P0L2; -.
DR   PaxDb; 9606-ENSP00000483424; -.
DR   PeptideAtlas; Q9P0L2; -.
DR   ProteomicsDB; 83571; -. [Q9P0L2-1]
DR   ProteomicsDB; 83572; -. [Q9P0L2-2]
DR   ProteomicsDB; 83573; -. [Q9P0L2-3]
DR   Pumba; Q9P0L2; -.
DR   Antibodypedia; 2072; 432 antibodies from 33 providers.
DR   DNASU; 4139; -.
DR   Ensembl; ENST00000366917.6; ENSP00000355884.5; ENSG00000116141.18. [Q9P0L2-1]
DR   Ensembl; ENST00000366918.8; ENSP00000355885.4; ENSG00000116141.18. [Q9P0L2-3]
DR   GeneID; 4139; -.
DR   KEGG; hsa:4139; -.
DR   MANE-Select; ENST00000366917.6; ENSP00000355884.5; NM_018650.5; NP_061120.3.
DR   UCSC; uc001hmm.6; human. [Q9P0L2-1]
DR   AGR; HGNC:6896; -.
DR   ClinPGx; PA30639; -.
DR   CTD; 4139; -.
DR   DisGeNET; 4139; -.
DR   GeneCards; MARK1; -.
DR   HGNC; HGNC:6896; MARK1.
DR   HPA; ENSG00000116141; Low tissue specificity.
DR   MIM; 606511; gene.
DR   OpenTargets; ENSG00000116141; -.
DR   VEuPathDB; HostDB:ENSG00000116141; -.
DR   eggNOG; KOG0586; Eukaryota.
DR   GeneTree; ENSGT00940000157560; -.
DR   InParanoid; Q9P0L2; -.
DR   OrthoDB; 193931at2759; -.
DR   PAN-GO; Q9P0L2; 5 GO annotations based on evolutionary models.
DR   PhylomeDB; Q9P0L2; -.
DR   PathwayCommons; Q9P0L2; -.
DR   SignaLink; Q9P0L2; -.
DR   SIGNOR; Q9P0L2; -.
DR   Agora; ENSG00000116141; -.
DR   BioGRID-ORCS; 4139; 14 hits in 1190 CRISPR screens.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; MARK1; human.
DR   EvolutionaryTrace; Q9P0L2; -.
DR   GeneWiki; MARK1; -.
DR   GenomeRNAi; 4139; -.
DR   Pharos; Q9P0L2; Tchem.
DR   PRO; PR:Q9P0L2; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; Q9P0L2; protein.
DR   Bgee; ENSG00000116141; Expressed in cortical plate and 178 other cell types or tissues.
DR   ExpressionAtlas; Q9P0L2; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005856; C:cytoskeleton; ISS:UniProtKB.
DR   GO; GO:0030425; C:dendrite; IDA:UniProtKB.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0015630; C:microtubule cytoskeleton; TAS:ProtInc.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0098794; C:postsynapse; IEA:Ensembl.
DR   GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR   GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR   GO; GO:0070300; F:phosphatidic acid binding; IDA:UniProtKB.
DR   GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB.
DR   GO; GO:0001786; F:phosphatidylserine binding; IDA:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR   GO; GO:0050321; F:tau-protein kinase activity; IMP:UniProtKB.
DR   GO; GO:0007010; P:cytoskeleton organization; ISS:UniProtKB.
DR   GO; GO:0051654; P:establishment of mitochondrion localization; ISS:ARUK-UCL.
DR   GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR   GO; GO:0000226; P:microtubule cytoskeleton organization; ISS:ARUK-UCL.
DR   GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IDA:ARUK-UCL.
DR   GO; GO:0010629; P:negative regulation of gene expression; IDA:ARUK-UCL.
DR   GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; IDA:ARUK-UCL.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:0050773; P:regulation of dendrite development; ISS:ARUK-UCL.
DR   GO; GO:0010975; P:regulation of neuron projection development; ISS:ARUK-UCL.
DR   GO; GO:0150052; P:regulation of postsynapse assembly; IEA:Ensembl.
DR   GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR   CDD; cd12196; MARK1-3_C; 1.
DR   CDD; cd14072; STKc_MARK; 1.
DR   CDD; cd14405; UBA_MARK1; 1.
DR   FunFam; 1.10.510.10:FF:001032; KP78b, isoform A; 1.
DR   FunFam; 1.10.8.10:FF:000011; Non-specific serine/threonine protein kinase; 1.
DR   FunFam; 3.30.200.20:FF:000003; Non-specific serine/threonine protein kinase; 1.
DR   FunFam; 3.30.310.80:FF:000001; Non-specific serine/threonine protein kinase; 1.
DR   Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1.
DR   Gene3D; 3.30.310.80; Kinase associated domain 1, KA1; 1.
DR   Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR028375; KA1/Ssp2_C.
DR   InterPro; IPR001772; KA1_dom.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR049508; MARK1-4_cat.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR015940; UBA.
DR   PANTHER; PTHR24346; MAP/MICROTUBULE AFFINITY-REGULATING KINASE; 1.
DR   PANTHER; PTHR24346:SF21; SERINE_THREONINE-PROTEIN KINASE MARK1; 1.
DR   Pfam; PF02149; KA1; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   Pfam; PF00627; UBA; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SMART; SM00165; UBA; 1.
DR   SUPFAM; SSF103243; KA1-like; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS50032; KA1; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR   PROSITE; PS50030; UBA; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; ATP-binding; Autism;
KW   Autism spectrum disorder; Cell membrane; Cell projection; Cytoplasm;
KW   Cytoskeleton; Kinase; Lipid-binding; Magnesium; Membrane; Metal-binding;
KW   Nucleotide-binding; Phosphoprotein; Proteomics identification;
KW   Reference proteome; Serine/threonine-protein kinase; Transferase;
KW   Wnt signaling pathway.
FT   CHAIN           1..795
FT                   /note="Serine/threonine-protein kinase MARK1"
FT                   /id="PRO_0000086298"
FT   DOMAIN          60..311
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          325..370
FT                   /note="UBA"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT   DOMAIN          746..795
FT                   /note="KA1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00565"
FT   REGION          1..40
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          377..495
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          539..700
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        31..40
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        380..403
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        447..459
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        462..473
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        486..495
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        590..599
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        647..657
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        661..676
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        683..697
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        182
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:Q9H0K1,
FT                   ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT                   ProRule:PRU10027"
FT   BINDING         66..74
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:Q9H0K1,
FT                   ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         89
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:O08678,
FT                   ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         5
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:18691976"
FT   MOD_RES         208
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:17573348"
FT   MOD_RES         215
FT                   /note="Phosphothreonine; by LKB1 and TAOK1"
FT                   /evidence="ECO:0000269|PubMed:14976552"
FT   MOD_RES         219
FT                   /note="Phosphoserine; by GSK3-beta"
FT                   /evidence="ECO:0000250|UniProtKB:O08678"
FT   MOD_RES         382
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHJ5"
FT   MOD_RES         390
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHJ5"
FT   MOD_RES         393
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHJ5"
FT   MOD_RES         403
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976"
FT   MOD_RES         423
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHJ5"
FT   MOD_RES         444
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08678"
FT   MOD_RES         475
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHJ5"
FT   MOD_RES         588
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648"
FT   MOD_RES         613
FT                   /note="Phosphothreonine; by PKC/PRKCZ"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         666
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHJ5"
FT   VAR_SEQ         1..135
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_051702"
FT   VAR_SEQ         120..141
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:10819331"
FT                   /id="VSP_051703"
FT   VAR_SEQ         663..677
FT                   /note="Missing (in isoform 2 and isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:10819331,
FT                   ECO:0000303|PubMed:14702039"
FT                   /id="VSP_051704"
FT   VARIANT         233
FT                   /note="Y -> C (in a gastric adenocarcinoma sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040760"
FT   VARIANT         355
FT                   /note="N -> T (in an ovarian serous carcinoma sample;
FT                   somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040761"
FT   VARIANT         530
FT                   /note="V -> M (in dbSNP:rs56212551)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040762"
FT   VARIANT         578
FT                   /note="P -> L (in dbSNP:rs55691439)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040763"
FT   VARIANT         645
FT                   /note="R -> G (in dbSNP:rs12123778)"
FT                   /id="VAR_030018"
FT   VARIANT         691
FT                   /note="E -> G (in dbSNP:rs55688276)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040764"
FT   MUTAGEN         215
FT                   /note="T->A: Prevents phosphorylation and activation by
FT                   STK11/LKB1 complex."
FT                   /evidence="ECO:0000269|PubMed:14976552"
FT   MUTAGEN         215
FT                   /note="T->E: Constitutively active."
FT                   /evidence="ECO:0000269|PubMed:14976552"
FT   MUTAGEN         698
FT                   /note="R->S: Impairs phospholipid-binding, targeting to
FT                   membrane and vesicle-binding; when associated with S-701."
FT                   /evidence="ECO:0000269|PubMed:21145462"
FT   MUTAGEN         701
FT                   /note="R->S: Impairs phospholipid-binding, targeting to
FT                   membrane and vesicle-binding; when associated with S-698."
FT                   /evidence="ECO:0000269|PubMed:21145462"
FT   MUTAGEN         771..773
FT                   /note="RFK->AFA: Impairs phospholipid-binding."
FT                   /evidence="ECO:0000269|PubMed:21145462"
FT   CONFLICT        16
FT                   /note="E -> V (in Ref. 2; AAF72103)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        20
FT                   /note="S -> T (in Ref. 2; AAF72103)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        522
FT                   /note="D -> N (in Ref. 4; BAB55152)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        544
FT                   /note="V -> A (in Ref. 4; BAB55152)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        763
FT                   /note="P -> A (in Ref. 4; BAB55152)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        794
FT                   /note="K -> M (in Ref. 3; BAA96001)"
FT                   /evidence="ECO:0000305"
FT   STRAND          55..57
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          60..68
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          70..79
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   TURN            80..82
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          85..92
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           93..95
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           98..111
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          122..127
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          129..136
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           146..151
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           156..175
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           185..187
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          188..190
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          196..198
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           201..203
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           220..222
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           225..228
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           236..252
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           262..271
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           282..291
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   TURN            296..298
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           302..305
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           309..312
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   STRAND          316..318
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           333..341
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           346..355
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           360..368
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   TURN            706..708
FT                   /evidence="ECO:0007829|PDB:6C9D"
FT   HELIX           714..727
FT                   /evidence="ECO:0007829|PDB:3OSE"
FT   STRAND          731..736
FT                   /evidence="ECO:0007829|PDB:3OSE"
FT   STRAND          739..745
FT                   /evidence="ECO:0007829|PDB:3OSE"
FT   TURN            747..750
FT                   /evidence="ECO:0007829|PDB:3OSE"
FT   STRAND          753..762
FT                   /evidence="ECO:0007829|PDB:3OSE"
FT   HELIX           763..765
FT                   /evidence="ECO:0007829|PDB:3OSE"
FT   STRAND          767..777
FT                   /evidence="ECO:0007829|PDB:3OSE"
FT   HELIX           779..792
FT                   /evidence="ECO:0007829|PDB:3OSE"
SQ   SEQUENCE   795 AA;  89003 MW;  71BF6EB76912631B CRC64;
     MSARTPLPTV NERDTENHTS VDGYTEPHIQ PTKSSSRQNI PRCRNSITSA TDEQPHIGNY
     RLQKTIGKGN FAKVKLARHV LTGREVAVKI IDKTQLNPTS LQKLFREVRI MKILNHPNIV
     KLFEVIETEK TLYLVMEYAS GGEVFDYLVA HGRMKEKEAR AKFRQIVSAV QYCHQKYIVH
     RDLKAENLLL DGDMNIKIAD FGFSNEFTVG NKLDTFCGSP PYAAPELFQG KKYDGPEVDV
     WSLGVILYTL VSGSLPFDGQ NLKELRERVL RGKYRIPFYM STDCENLLKK LLVLNPIKRG
     SLEQIMKDRW MNVGHEEEEL KPYTEPDPDF NDTKRIDIMV TMGFARDEIN DALINQKYDE
     VMATYILLGR KPPEFEGGES LSSGNLCQRS RPSSDLNNST LQSPAHLKVQ RSISANQKQR
     RFSDHAGPSI PPAVSYTKRP QANSVESEQK EEWDKDVARK LGSTTVGSKS EMTASPLVGP
     ERKKSSTIPS NNVYSGGSMA RRNTYVCERT TDRYVALQNG KDSSLTEMSV SSISSAGSSV
     ASAVPSARPR HQKSMSTSGH PIKVTLPTIK DGSEAYRPGT TQRVPAASPS AHSISTATPD
     RTRFPRGSSS RSTFHGEQLR ERRSVAYNGP PASPSHETGA FAHARRGTST GIISKITSKF
     VRRDPSEGEA SGRTDTSRST SGEPKERDKE EGKDSKPRSL RFTWSMKTTS SMDPNDMMRE
     IRKVLDANNC DYEQKERFLL FCVHGDARQD SLVQWEMEVC KLPRLSLNGV RFKRISGTSI
     AFKNIASKIA NELKL
//
ID   TAU_HUMAN               Reviewed;         758 AA.
AC   P10636; P18518; Q14799; Q15549; Q15550; Q15551; Q1RMF6; Q53YB1; Q5CZI7;
AC   Q5XWF0; Q6QT54; Q9UDJ3; Q9UMH0; Q9UQ96;
DT   01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT   31-MAY-2011, sequence version 5.
DT   28-JAN-2026, entry version 293.
DE   RecName: Full=Microtubule-associated protein tau {ECO:0000305};
DE   AltName: Full=Neurofibrillary tangle protein;
DE   AltName: Full=Paired helical filament-tau;
DE            Short=PHF-tau;
GN   Name=MAPT {ECO:0000312|HGNC:HGNC:6893}; Synonyms=MAPTL, MTBT1, TAU;
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 FETAL-TAU).
RC   TISSUE=Brain;
RX   PubMed=3131773; DOI=10.1073/pnas.85.11.4051;
RA   Goedert M., Wischik C., Crowther R., Walker J., Klug A.;
RT   "Cloning and sequencing of the cDNA encoding a core protein of the paired
RT   helical filament of Alzheimer disease: identification as the microtubule-
RT   associated protein tau.";
RL   Proc. Natl. Acad. Sci. U.S.A. 85:4051-4055(1988).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TAU-D).
RC   TISSUE=Brain;
RX   PubMed=2498079; DOI=10.1002/j.1460-2075.1989.tb03390.x;
RA   Goedert M., Spillantini M.G., Potier M.-C., Ulrich J., Crowther R.A.;
RT   "Cloning and sequencing of the cDNA encoding an isoform of microtubule-
RT   associated protein tau containing four tandem repeats: differential
RT   expression of tau protein mRNAs in human brain.";
RL   EMBO J. 8:393-399(1989).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TAU-A AND FETAL-TAU).
RC   TISSUE=Fetal brain;
RX   PubMed=2516729; DOI=10.1016/0896-6273(89)90050-0;
RA   Lee G., Neve R.L., Kosik K.S.;
RT   "The microtubule binding domain of tau protein.";
RL   Neuron 2:1615-1624(1989).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TAU-B; TAU-C; TAU-E AND TAU-F), AND
RP   ASSOCIATION WITH ALZHEIMER DISEASE.
RC   TISSUE=Brain;
RX   PubMed=2484340; DOI=10.1016/0896-6273(89)90210-9;
RA   Goedert M., Spillantini M.G., Jakes R., Rutherford D., Crowther R.A.;
RT   "Multiple isoforms of human microtubule-associated protein tau: sequences
RT   and localization in neurofibrillary tangles of Alzheimer's disease.";
RL   Neuron 3:519-526(1989).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS PNS-TAU; FETAL-TAU AND TAU-F),
RP   ALTERNATIVE SPLICING, AND VARIANT HIS-441.
RX   PubMed=1420178; DOI=10.1021/bi00158a027;
RA   Andreadis A., Brown W.M., Kosik K.S.;
RT   "Structure and novel exons of the human tau gene.";
RL   Biochemistry 31:10626-10633(1992).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TAU-E).
RA   Chun J., Kwon T., Lee E.-J., Hyun S.-H., Kang S.S.;
RT   "Cloning of tau-related genes.";
RL   Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM FETAL-TAU).
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   [8]
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   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS FETAL-TAU AND TAU-D).
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [10]
RP   PROTEIN SEQUENCE OF 2-73; 103-381; 468-497; 508-571; 577-583; 592-607;
RP   616-634; 639-657; 661-664; 671-700 AND 703-758, CLEAVAGE OF INITIATOR
RP   METHIONINE, ACETYLATION AT ALA-2, AND DEAMIDATION AT ASN-484 AND ASN-596.
RC   TISSUE=Brain;
RX   PubMed=1512244; DOI=10.1016/s0021-9258(18)41890-x;
RA   Hasegawa M., Morishima-Kawashima M., Takio K., Suzuki M., Titani K.,
RA   Ihara Y.;
RT   "Protein sequence and mass spectrometric analyses of tau in the Alzheimer's
RT   disease brain.";
RL   J. Biol. Chem. 267:17047-17054(1992).
RN   [11]
RP   PROTEIN SEQUENCE OF 25-44; 529-538; 560-571 AND 671-686, AND IDENTIFICATION
RP   BY MASS SPECTROMETRY.
RC   TISSUE=Fetal brain cortex;
RA   Lubec G., Chen W.-Q., Sun Y.;
RL   Submitted (DEC-2008) to UniProtKB.
RN   [12]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 466-740 (ISOFORMS
RP   TAU-A/TAU-B/TAU-C/FETAL-TAU).
RA   Han J., Zhang J., Dong X.-P.;
RT   "Molecular interactions of recombinant neural protein tau with recombinant
RT   and native PrP proteins in vitro.";
RL   Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   PROTEIN SEQUENCE OF 543-551; 560-574; 576-584 AND 623-634, PHOSPHORYLATION
RP   AT SER-531; THR-534; THR-548; SER-552; SER-554; SER-579; SER-713 AND
RP   SER-739, UBIQUITINATION AT LYS-571; LYS-628 AND LYS-670, AND IDENTIFICATION
RP   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   [14]
RP   PROTEIN SEQUENCE OF 577-584; 608-611; 616-628; 639-648 AND 671-686,
RP   PHOSPHORYLATION AT SER-579; SER-610; SER-622; SER-641 AND SER-673,
RP   MUTAGENESIS, AND DOMAIN.
RX   PubMed=7706316; DOI=10.1074/jbc.270.13.7679;
RA   Drewes G., Trinczek B., Illenberger S., Biernat J., Schmitt-Ulms G.,
RA   Meyer H.E., Mandelkow E.-M., Mandelkow E.;
RT   "Microtubule-associated protein/microtubule affinity-regulating kinase
RT   (p110mark). A novel protein kinase that regulates tau-microtubule
RT   interactions and dynamic instability by phosphorylation at the Alzheimer-
RT   specific site serine 262.";
RL   J. Biol. Chem. 270:7679-7688(1995).
RN   [15]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 592-622 (ISOFORMS PNS-TAU/TAU-D/TAU-E/TAU-F).
RC   TISSUE=Brain;
RX   PubMed=2495000; DOI=10.1016/0006-291x(89)92240-7;
RA   Mori H., Hamada Y., Kawaguchi M., Honda T., Kondo J., Ihara Y.;
RT   "A distinct form of tau is selectively incorporated into Alzheimer's paired
RT   helical filaments.";
RL   Biochem. Biophys. Res. Commun. 159:1221-1226(1989).
RN   [16]
RP   PROTEIN SEQUENCE OF 379-392 AND 568-581, AND PHOSPHORYLATION AT SER-713.
RX   PubMed=1899488; DOI=10.1126/science.1899488;
RA   Lee V.M., Balin B.J., Otvos L. Jr., Trojanowski J.Q.;
RT   "A68: a major subunit of paired helical filaments and derivatized forms of
RT   normal Tau.";
RL   Science 251:675-678(1991).
RN   [17]
RP   PROTEIN SEQUENCE OF 616-712.
RX   PubMed=1915258; DOI=10.1002/j.1460-2075.1991.tb07820.x;
RA   Jakes R., Novak M., Davison M., Wischik C.M.;
RT   "Identification of 3- and 4-repeat tau isoforms within the PHF in
RT   Alzheimer's disease.";
RL   EMBO J. 10:2725-2729(1991).
RN   [18]
RP   IDENTIFICATION (ISOFORM TAU-G), AND VARIANT HIS-441.
RX   PubMed=15365985; DOI=10.1002/humu.20086;
RA   Rademakers R., Cruts M., van Broeckhoven C.;
RT   "The role of tau (MAPT) in frontotemporal dementia and related
RT   tauopathies.";
RL   Hum. Mutat. 24:277-295(2004).
RN   [19]
RP   REVIEW.
RX   PubMed=1713721; DOI=10.1016/0166-2236(91)90105-4;
RA   Goedert M., Crowther R.A., Garner C.C.;
RT   "Molecular characterization of microtubule-associated proteins tau and
RT   MAP2.";
RL   Trends Neurosci. 14:193-199(1991).
RN   [20]
RP   PHOSPHORYLATION AT SER-554; SER-579; SER-602; SER-622 AND SER-669.
RX   PubMed=8999860; DOI=10.1016/s0021-9258(19)67481-8;
RA   Paudel H.K.;
RT   "The regulatory Ser262 of microtubule-associated protein tau is
RT   phosphorylated by phosphorylase kinase.";
RL   J. Biol. Chem. 272:1777-1785(1997).
RN   [21]
RP   GLYCATION AT LYS-87; LYS-383; LYS-467; LYS-480; LYS-491; LYS-542; LYS-551;
RP   LYS-576; LYS-597; LYS-598; LYS-664; LYS-670 AND LYS-686, AND LACK OF
RP   GLYCATION AT LYS-24; LYS-44; LYS-67; LYS-381; LYS-391; LYS-392; LYS-394;
RP   LYS-465; LYS-497; LYS-507; LYS-541; LYS-557; LYS-571; LYS-574; LYS-584;
RP   LYS-591; LYS-607; LYS-611; LYS-615; LYS-628; LYS-634; LYS-638; LYS-648;
RP   LYS-657; LYS-660; LYS-687; LYS-692; LYS-700; LYS-702; LYS-712 AND LYS-755.
RX   PubMed=9326300; DOI=10.1046/j.1471-4159.1997.69041709.x;
RA   Nacharaju P., Ko L., Yen S.H.;
RT   "Characterization of in vitro glycation sites of tau.";
RL   J. Neurochem. 69:1709-1719(1997).
RN   [22]
RP   PHOSPHORYLATION, AND MUTAGENESIS.
RX   PubMed=9735171; DOI=10.1006/abbi.1998.0813;
RA   Sengupta A., Kabat J., Novak M., Wu Q., Grundke-Iqbal I., Iqbal K.;
RT   "Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal
RT   inhibition of its binding to microtubules.";
RL   Arch. Biochem. Biophys. 357:299-309(1998).
RN   [23]
RP   PHOSPHORYLATION AT THR-470; SER-516; SER-519; THR-529; SER-531; SER-552;
RP   SER-579; SER-713; SER-721 AND SER-739, AND MUTAGENESIS.
RX   PubMed=9614189; DOI=10.1091/mbc.9.6.1495;
RA   Illenberger S., Zheng-Fischhofer Q., Preuss U., Stamer K., Baumann K.,
RA   Trinczek B., Biernat J., Godemann R., Mandelkow E.-M., Mandelkow E.;
RT   "The endogenous and cell cycle-dependent phosphorylation of tau protein in
RT   living cells: implications for Alzheimer's disease.";
RL   Mol. Biol. Cell 9:1495-1512(1998).
RN   [24]
RP   SUBCELLULAR LOCATION, AND PHOSPHORYLATION.
RX   PubMed=10747907; DOI=10.1074/jbc.m000389200;
RA   Maas T., Eidenmueller J., Brandt R.;
RT   "Interaction of tau with the neural membrane cortex is regulated by
RT   phosphorylation at sites that are modified in paired helical filaments.";
RL   J. Biol. Chem. 275:15733-15740(2000).
RN   [25]
RP   PHOSPHORYLATION AT SER-519; THR-522; SER-713 AND SER-721 BY CSNK1D/CK1, AND
RP   INTERACTION WITH CSNK1D.
RX   PubMed=14761950; DOI=10.1074/jbc.m314116200;
RA   Li G., Yin H., Kuret J.;
RT   "Casein kinase 1 delta phosphorylates tau and disrupts its binding to
RT   microtubules.";
RL   J. Biol. Chem. 279:15938-15945(2004).
RN   [26]
RP   PHOSPHORYLATION AT THR-548 BY GSK3B.
RX   PubMed=14690523; DOI=10.1111/j.1471-4159.2004.02155.x;
RA   Cho J.H., Johnson G.V.;
RT   "Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta
RT   (GSK3beta) plays a critical role in regulating tau's ability to bind and
RT   stabilize microtubules.";
RL   J. Neurochem. 88:349-358(2004).
RN   [27]
RP   PHOSPHORYLATION AT TYR-18 BY FYN.
RX   PubMed=14999081; DOI=10.1523/jneurosci.4162-03.2004;
RA   Lee G., Thangavel R., Sharma V.M., Litersky J.M., Bhaskar K., Fang S.M.,
RA   Do L.H., Andreadis A., Van Hoesen G., Ksiezak-Reding H.;
RT   "Phosphorylation of tau by fyn: implications for Alzheimer's disease.";
RL   J. Neurosci. 24:2304-2312(2004).
RN   [28]
RP   INTERACTION WITH SQSTM1, UBIQUITINATION, AND PROTEASOMAL DEGRADATION.
RX   PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x;
RA   Babu J.R., Geetha T., Wooten M.W.;
RT   "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal
RT   degradation.";
RL   J. Neurochem. 94:192-203(2005).
RN   [29]
RP   PHOSPHORYLATION AT THR-498; SER-516; SER-519; THR-522; THR-529; SER-531;
RP   THR-548; SER-552; SER-579; SER-713; SER-721 AND SER-726, AND
RP   DEPHOSPHORYLATION AT THR-498; SER-516; SER-519; THR-522; THR-529; SER-531;
RP   THR-548; SER-552; SER-579; SER-713; SER-721 AND SER-726 BY PPP5C.
RX   PubMed=15546861; DOI=10.1074/jbc.m410775200;
RA   Liu F., Iqbal K., Grundke-Iqbal I., Rossie S., Gong C.X.;
RT   "Dephosphorylation of tau by protein phosphatase 5: impairment in
RT   Alzheimer's disease.";
RL   J. Biol. Chem. 280:1790-1796(2005).
RN   [30]
RP   PHOSPHORYLATION AT TYR-514; SER-515; SER-516; SER-519; SER-733; SER-739 AND
RP   THR-744.
RX   PubMed=16923168; DOI=10.1111/j.1471-4159.2006.04059.x;
RA   Sato S., Cerny R.L., Buescher J.L., Ikezu T.;
RT   "Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is
RT   involved in tau phosphorylation and aggregation.";
RL   J. Neurochem. 98:1573-1584(2006).
RN   [31]
RP   PHOSPHORYLATION AT SER-214 BY SGK1, AND INTERACTION WITH SGK1.
RX   PubMed=16982696; DOI=10.1128/mcb.01017-06;
RA   Yang Y.C., Lin C.H., Lee E.H.;
RT   "Serum- and glucocorticoid-inducible kinase 1 (SGK1) increases neurite
RT   formation through microtubule depolymerization by SGK1 and by SGK1
RT   phosphorylation of tau.";
RL   Mol. Cell. Biol. 26:8357-8370(2006).
RN   [32]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=16964243; DOI=10.1038/nbt1240;
RA   Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT   "A probability-based approach for high-throughput protein phosphorylation
RT   analysis and site localization.";
RL   Nat. Biotechnol. 24:1285-1292(2006).
RN   [33]
RP   PHOSPHORYLATION BY CSNK1D/CK1.
RX   PubMed=17562708; DOI=10.1074/jbc.m703269200;
RA   Hanger D.P., Byers H.L., Wray S., Leung K.-Y., Saxton M.J., Seereeram A.,
RA   Reynolds C.H., Ward M.A., Anderton B.H.;
RT   "Novel phosphorylation sites in tau from Alzheimer brain support a role for
RT   casein kinase 1 in disease pathogenesis.";
RL   J. Biol. Chem. 282:23645-23654(2007).
RN   [34]
RP   PHOSPHORYLATION AT THR-529 BY DYRK2.
RX   PubMed=18599021; DOI=10.1016/j.bcp.2008.05.021;
RA   Yoshida K.;
RT   "Role for DYRK family kinases on regulation of apoptosis.";
RL   Biochem. Pharmacol. 76:1389-1394(2008).
RN   [35]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18220336; DOI=10.1021/pr0705441;
RA   Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT   "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT   phosphoproteomic analysis.";
RL   J. Proteome Res. 7:1346-1351(2008).
RN   [36]
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   [37]
RP   GLYCOSYLATION, PHOSPHORYLATION AT SER-516; SER-519; THR-522; THR-529;
RP   SER-531; THR-534; SER-579; SER-713; SER-721 AND SER-739, AND ASSOCIATION
RP   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   [38]
RP   INTERACTION WITH EPM2A.
RX   PubMed=19542233; DOI=10.1074/jbc.m109.009688;
RA   Puri R., Suzuki T., Yamakawa K., Ganesh S.;
RT   "Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an
RT   animal model for Lafora disease.";
RL   J. Biol. Chem. 284:22657-22663(2009).
RN   [39]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-713; SER-717; SER-721 AND
RP   SER-726, AND 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   [40]
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   [41]
RP   GLYCOSYLATION AT SER-525; SER-555 AND SER-717, PHOSPHORYLATION AT SER-519;
RP   SER-713 SER-717 AND SER-721, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=21327254; DOI=10.1039/c0mb00337a;
RA   Smet-Nocca C., Broncel M., Wieruszeski J.M., Tokarski C., Hanoulle X.,
RA   Leroy A., Landrieu I., Rolando C., Lippens G., Hackenberger C.P.;
RT   "Identification of O-GlcNAc sites within peptides of the Tau protein and
RT   their impact on phosphorylation.";
RL   Mol. Biosyst. 7:1420-1429(2011).
RN   [42]
RP   FUNCTION, AND PHOSPHORYLATION AT THR-529 AND SER-579.
RX   PubMed=21985311; DOI=10.1111/j.1471-4159.2011.07523.x;
RA   Yoshida H., Goedert M.;
RT   "Phosphorylation of microtubule-associated protein tau by AMPK-related
RT   kinases.";
RL   J. Neurochem. 120:165-176(2012).
RN   [43]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519; THR-548; SER-552;
RP   SER-713 AND SER-721, 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   [44]
RP   INTERACTION WITH MARK1; MARK2; MARK3 AND MARK4, SUBCELLULAR LOCATION, AND
RP   PHOSPHORYLATION AT SER-579.
RX   PubMed=23666762; DOI=10.1007/s12017-013-8232-3;
RA   Gu G.J., Lund H., Wu D., Blokzijl A., Classon C., von Euler G.,
RA   Landegren U., Sunnemark D., Kamali-Moghaddam M.;
RT   "Role of individual MARK isoforms in phosphorylation of tau at Ser262 in
RT   Alzheimer's disease.";
RL   NeuroMolecular Med. 15:458-469(2013).
RN   [45]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519, 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   [46]
RP   INTERACTION WITH LRRK2, AND SUBCELLULAR LOCATION.
RX   PubMed=26014385; DOI=10.1007/s12035-015-9209-z;
RA   Guerreiro P.S., Gerhardt E., Lopes da Fonseca T., Baehr M., Outeiro T.F.,
RA   Eckermann K.;
RT   "LRRK2 Promotes Tau Accumulation, Aggregation and Release.";
RL   Mol. Neurobiol. 53:3124-3135(2016).
RN   [47]
RP   INTERACTION WITH LRP1.
RX   PubMed=32296178; DOI=10.1038/s41586-020-2156-5;
RA   Rauch J.N., Luna G., Guzman E., Challis C., Sibih Y.E., Leshuk C.,
RA   Hernandez I., Wegmann S., Hyman B.T., Gradinaru V., Kampmann M.,
RA   Kosik K.S.;
RT   "LRP1 is a master regulator of tau uptake and spread.";
RL   Nature 580:381-385(2020).
RN   [48]
RP   STRUCTURE BY NMR OF 542-554 IN COMPLEX WITH PIN1.
RX   PubMed=11313338; DOI=10.1074/jbc.m010327200;
RA   Wintjens R., Wieruszeski J.-M., Drobecq H., Rousselot-Pailley P., Buee L.,
RA   Lippens G., Landrieu I.;
RT   "1H NMR study on the binding of Pin1 Trp-Trp domain with phosphothreonine
RT   peptides.";
RL   J. Biol. Chem. 276:25150-25156(2001).
RN   [49]
RP   SUBCELLULAR LOCATION.
RX   PubMed=32272059; DOI=10.1016/j.cell.2020.03.031;
RA   Zhang M., Liu L., Lin X., Wang Y., Li Y., Guo Q., Li S., Sun Y., Tao X.,
RA   Zhang D., Lv X., Zheng L., Ge L.;
RT   "A Translocation Pathway for Vesicle-Mediated Unconventional Protein
RT   Secretion.";
RL   Cell 181:637-652(2020).
RN   [50]
RP   REVIEW ON VARIANTS.
RX   PubMed=10899436; DOI=10.1016/s0925-4439(00)00037-5;
RA   Goedert M., Spillantini M.G.;
RT   "Tau mutations in frontotemporal dementia FTDP-17 and their relevance for
RT   Alzheimer's disease.";
RL   Biochim. Biophys. Acta 1502:110-121(2000).
RN   [51]
RP   VARIANT FTD1 MET-654, VARIANTS ASN-285; ALA-289; HIS-441 AND PRO-447, AND
RP   INVOLVEMENT IN FTD1.
RX   PubMed=9629852; DOI=10.1002/ana.410430617;
RA   Poorkaj P., Bird T.D., Wijsman E., Nemens E., Garruto R.M., Anderson L.,
RA   Andreadis A., Wiederholt W.C., Raskind M., Schellenberg G.D.;
RT   "Tau is a candidate gene for chromosome 17 frontotemporal dementia.";
RL   Ann. Neurol. 43:815-825(1998).
RN   [52]
RP   ERRATUM OF PUBMED:9629852.
RA   Poorkaj P., Bird T.D., Wijsman E., Nemens E., Garruto R.M., Anderson L.,
RA   Andreadis A., Wiederholt W.C., Raskind M., Schellenberg G.D.;
RL   Ann. Neurol. 44:428-428(1998).
RN   [53]
RP   VARIANT FTD1 LEU-618.
RX   PubMed=9736786; DOI=10.1093/hmg/7.11.1825;
RA   Dumanchin C., Camuzat A., Campion D., Verpillat P., Hannequin D.,
RA   Dubois B., Saugier-Veber P., Martin C., Penet C., Charbonnier F., Agid Y.,
RA   Frebourg T., Brice A.;
RT   "Segregation of a missense mutation in the microtubule-associated protein
RT   tau gene with familial frontotemporal dementia and parkinsonism.";
RL   Hum. Mol. Genet. 7:1825-1829(1998).
RN   [54]
RP   VARIANTS FTD1 VAL-589; LEU-618 AND TRP-723.
RX   PubMed=9641683; DOI=10.1038/31508;
RA   Hutton M., Lendon C.L., Rizzu P., Baker M., Froelich S., Houlden H.,
RA   Pickering-Brown S., Chakraverty S., Isaacs A., Grover A., Hackett J.,
RA   Adamson J., Lincoln S., Dickson D., Davies P., Petersen R.C., Stevens M.,
RA   de Graaff E., Wauters E., van Baren J., Hillebrand M., Joosse M.,
RA   Kwon J.M., Nowotny P., Che L.K., Norton J., Morris J.C., Reed L.A.,
RA   Trojanowski J., Basun H., Lannfelt L., Neystat M., Fahn S., Dark F.,
RA   Tannenberg T., Dodd P.R., Hayward N., Kwok J.B.J., Schofield P.R.,
RA   Andreadis A., Snowden J., Craufurd D., Neary D., Owen F., Oostra B.A.,
RA   Hardy J., Goate A., van Swieten J., Mann D., Lynch T., Heutink P.;
RT   "Association of missense and 5'-splice-site mutations in tau with the
RT   inherited dementia FTDP-17.";
RL   Nature 393:702-705(1998).
RN   [55]
RP   VARIANTS FTD1 LYS-596 AND LEU-618.
RX   PubMed=9789048; DOI=10.1073/pnas.95.22.13103;
RA   Clark L.N., Poorkaj P., Wszolek Z., Geschwind D.H., Nasreddine Z.S.,
RA   Miller B., Li D., Payami H., Awert F., Markopoulou K., Andreadis A.,
RA   D'Souza I., Lee V.M.-Y., Reed L., Trojanowski J.Q., Zhukareva V., Bird T.,
RA   Schellenberg G., Wilhelmsen K.C.;
RT   "Pathogenic implications of mutations in the tau gene in pallido-ponto-
RT   nigral degeneration and related neurodegenerative disorders linked to
RT   chromosome 17.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:13103-13107(1998).
RN   [56]
RP   VARIANT PPND LYS-596.
RX   PubMed=10412802; DOI=10.1007/s004010051052;
RA   Delisle M.-B., Murrell J.R., Richardson R., Trofatter J.A., Rascol O.,
RA   Soulages X., Mohr M., Calvas P., Ghetti B.;
RT   "A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a
RT   tauopathy with dementia and supranuclear palsy.";
RL   Acta Neuropathol. 98:62-77(1999).
RN   [57]
RP   VARIANTS FTD1 VAL-589; LYS-597 DEL; LEU-618 AND TRP-723.
RX   PubMed=9973279; DOI=10.1086/302256;
RA   Rizzu P., Van Swieten J.C., Joosse M., Hasegawa M., Stevens M., Tibben A.,
RA   Niermeijer M.F., Hillebrand M., Ravid R., Oostra B.A., Goedert M.,
RA   van Duijn C.M., Heutink P.;
RT   "High prevalence of mutations in the microtubule-associated protein tau in
RT   a population study of frontotemporal dementia in the Netherlands.";
RL   Am. J. Hum. Genet. 64:414-421(1999).
RN   [58]
RP   VARIANT FTD1 SER-618.
RX   PubMed=10553987;
RX   DOI=10.1002/1531-8249(199911)46:5<708::aid-ana5>3.0.co;2-k;
RA   Sperfeld A.D., Collatz M.B., Baier H., Palmbach M., Storch A., Schwarz J.,
RA   Tatsch K., Reske S., Joosse M., Heutink P., Ludolph A.C.;
RT   "FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures
RT   caused by a novel mutation.";
RL   Ann. Neurol. 46:708-715(1999).
RN   [59]
RP   VARIANTS FTD1 LEU-618; MET-654 AND TRP-723.
RX   PubMed=10214944; DOI=10.1016/s0014-5793(99)00294-x;
RA   Nacharaju P., Lewis J., Easson C., Yen S., Hackett J., Hutton M., Yen S.H.;
RT   "Accelerated filament formation from tau protein with specific FTDP-17
RT   missense mutations.";
RL   FEBS Lett. 447:195-199(1999).
RN   [60]
RP   VARIANT FTD1/CBD SER-618.
RX   PubMed=10374757; DOI=10.1097/00005072-199906000-00011;
RA   Bugiani O., Murrell J.R., Giaccone G., Hasegawa M., Ghigo G., Tabaton M.,
RA   Morbin M., Primavera A., Carella F., Solaro C., Grisoli M., Savoiardo M.,
RA   Spillantini M.G., Tagliavini F., Goedert M., Ghetti B.;
RT   "Frontotemporal dementia and corticobasal degeneration in a family with a
RT   P301S mutation in tau.";
RL   J. Neuropathol. Exp. Neurol. 58:667-677(1999).
RN   [61]
RP   VARIANT PIDB ARG-706.
RX   PubMed=10604746; DOI=10.1097/00005072-199912000-00002;
RA   Murrell J.R., Spillantini M.G., Zolo P., Guazzelli M., Smith M.J.,
RA   Hasegawa M., Redi F., Crowther R.A., Pietrini P., Ghetti B., Goedert M.;
RT   "Tau gene mutation G389R causes a tauopathy with abundant pick body-like
RT   inclusions and axonal deposits.";
RL   J. Neuropathol. Exp. Neurol. 58:1207-1226(1999).
RN   [62]
RP   VARIANT FTD1 LYS-596.
RX   PubMed=10489057; DOI=10.1212/wnl.53.4.864;
RA   Yasuda M., Kawamata T., Komure O., Kuno S., D'Souza I., Poorkaj P.,
RA   Kawai J., Tanimukai S., Yamamoto Y., Hasegawa H., Sasahara M., Hazama F.,
RA   Schellenberg G.D., Tanaka C.;
RT   "A mutation in the microtubule-associated protein tau in pallido-nigro-
RT   luysian degeneration.";
RL   Neurology 53:864-868(1999).
RN   [63]
RP   VARIANTS PSNP1 ASN-285 AND ALA-289.
RX   PubMed=10534245; DOI=10.1212/wnl.53.7.1421;
RA   Higgins J.J., Adler R.L., Loveless J.M.;
RT   "Mutational analysis of the tau gene in progressive supranuclear palsy.";
RL   Neurology 53:1421-1424(1999).
RN   [64]
RP   VARIANT FTD1 ASN-622.
RX   PubMed=10208578; DOI=10.1097/00001756-199902250-00010;
RA   Iijima M., Tabira T., Poorkaj P., Schellenberg G.D., Trojanowski J.Q.,
RA   Lee V.M.-Y., Schmidt M.L., Takahashi K., Nabika T., Matsumoto T.,
RA   Yamashita Y., Yoshioka S., Ishino H.;
RT   "A distinct familial presenile dementia with a novel missense mutation in
RT   the tau gene.";
RL   NeuroReport 10:497-501(1999).
RN   [65]
RP   VARIANT FTD1 VAL-659.
RX   PubMed=11117541;
RX   DOI=10.1002/1531-8249(200012)48:6<850::aid-ana5>3.3.co;2-m;
RA   Lippa C.F., Zhukareva V., Kawarai T., Uryu K., Shafiq M., Nee L.E.,
RA   Grafman J., Liang Y., St George-Hyslop P.H., Trojanowski J.Q., Lee V.M.-Y.;
RT   "Frontotemporal dementia with novel tau pathology and a Glu342Val tau
RT   mutation.";
RL   Ann. Neurol. 48:850-858(2000).
RN   [66]
RP   VARIANTS PIDB THR-574 AND ARG-706, AND CHARACTERIZATION OF VARIANTS PIDB
RP   THR-574 AND ARG-706.
RX   PubMed=11117542;
RX   DOI=10.1002/1531-8249(200012)48:6<859::aid-ana6>3.3.co;2-t;
RA   Pickering-Brown S., Baker M., Yen S.-H., Liu W.-K., Hasegawa M., Cairns N.,
RA   Lantos P.L., Rossor M., Iwatsubo T., Davies Y., Allsop D., Furlong R.,
RA   Owen F., Hardy J., Mann D., Hutton M.;
RT   "Pick's disease is associated with mutations in the tau gene.";
RL   Ann. Neurol. 48:859-867(2000).
RN   [67]
RP   VARIANT PIDB THR-574.
RX   PubMed=11089577; DOI=10.1093/jnen/59.11.990;
RA   Rizzini C., Goedert M., Hodges J.R., Smith M.J., Jakes R., Hills R.,
RA   Xuereb J.H., Crowther R.A., Spillantini M.G.;
RT   "Tau gene mutation K257T causes a tauopathy similar to Pick's disease.";
RL   J. Neuropathol. Exp. Neurol. 59:990-1001(2000).
RN   [68]
RP   VARIANT FTD1 LYS-596.
RX   PubMed=10802785; DOI=10.1212/wnl.54.9.1787;
RA   Arima K., Kowalska A., Hasegawa M., Mukoyama M., Watanabe R., Kawai M.,
RA   Takahashi K., Iwatsubo T., Tabira T., Sunohara N.;
RT   "Two brothers with frontotemporal dementia and parkinsonism with an N279K
RT   mutation of the tau gene.";
RL   Neurology 54:1787-1795(2000).
RN   [69]
RP   VARIANT FTD1 SER-618.
RX   PubMed=11071507; DOI=10.1212/wnl.55.8.1224;
RA   Yasuda M., Yokoyama K., Nakayasu T., Nishimura Y., Matsui M., Yokoyama T.,
RA   Miyoshi K., Tanaka C.;
RT   "A Japanese patient with frontotemporal dementia and parkinsonism by a tau
RT   P301S mutation.";
RL   Neurology 55:1224-1227(2000).
RN   [70]
RP   VARIANT FTD1 HIS-613.
RX   PubMed=11585254; DOI=10.1007/s004010000333;
RA   Iseki E., Matsumura T., Marui W., Hino H., Odawara T., Sugiyama N.,
RA   Suzuki K., Sawada H., Arai T., Kosaka K.;
RT   "Familial frontotemporal dementia and parkinsonism with a novel N296H
RT   mutation in exon 10 of the tau gene and a widespread tau accumulation in
RT   the glial cells.";
RL   Acta Neuropathol. 102:285-292(2001).
RN   [71]
RP   VARIANT PSNP1 ASN-613 DEL.
RX   PubMed=11220749;
RX   DOI=10.1002/1531-8249(20010201)49:2<263::aid-ana50>3.0.co;2-k;
RA   Pastor P., Pastor E., Carnero C., Vela R., Garcia T., Amer G., Tolosa E.,
RA   Oliva R.;
RT   "Familial atypical progressive supranuclear palsy associated with
RT   homozygosity for the delN296 mutation in the tau gene.";
RL   Ann. Neurol. 49:263-267(2001).
RN   [72]
RP   VARIANT PIDB ILE-686, AND CHARACTERIZATION OF VARIANT PIDB ILE-686.
RX   PubMed=11601501; DOI=10.1002/ana.1223;
RA   Neumann M., Schulz-Schaeffer W., Crowther R.A., Smith M.J.,
RA   Spillantini M.G., Goedert M., Kretzschmar H.A.;
RT   "Pick's disease associated with the novel Tau gene mutation K369I.";
RL   Ann. Neurol. 50:503-513(2001).
RN   [73]
RP   CHARACTERIZATION OF VARIANT FTD1 TRP-723.
RX   PubMed=11278002; DOI=10.1016/s0014-5793(01)02267-0;
RA   Connell J.W., Gibb G.M., Betts J.C., Blackstock W.P., Gallo J.-M.,
RA   Lovestone S., Hutton M., Anderton B.H.;
RT   "Effects of FTDP-17 mutations on the in vitro phosphorylation of tau by
RT   glycogen synthase kinase 3beta identified by mass spectrometry demonstrate
RT   certain mutations exert long-range conformational changes.";
RL   FEBS Lett. 493:40-44(2001).
RN   [74]
RP   VARIANT FTD1 LYS-596.
RX   PubMed=12473774; DOI=10.1212/01.wnl.0000038909.49164.4b;
RA   Tsuboi Y., Baker M., Hutton M.L., Uitti R.J., Rascol O., Delisle M.-B.,
RA   Soulages X., Murrell J.R., Ghetti B., Yasuda M., Komure O., Kuno S.,
RA   Arima K., Sunohara N., Kobayashi T., Mizuno Y., Wszolek Z.K.;
RT   "Clinical and genetic studies of families with the tau N279K mutation
RT   (FTDP-17).";
RL   Neurology 59:1791-1793(2002).
RN   [75]
RP   VARIANT PIDB PHE-637, AND CHARACTERIZATION OF VARIANT PIDB PHE-637.
RX   PubMed=11891833; DOI=10.1002/ana.10140;
RA   Rosso S.M., Van Herpen E., Deelen W., Kamphorst W., Severijnen L.-A.,
RA   Willemsen R., Ravid R., Niermeijer M.F., Dooijes D., Smith M.J.,
RA   Goedert M., Heutink P., Van Swieten J.C.;
RT   "A novel tau mutation, S320F, causes a tauopathy with inclusions similar to
RT   those in Pick's disease.";
RL   Ann. Neurol. 51:373-376(2002).
RN   [76]
RP   VARIANT FTD1 HIS-5, AND CHARACTERIZATION OF VARIANT FTD1 HIS-5.
RX   PubMed=11921059; DOI=10.1002/ana.10163;
RA   Hayashi S., Toyoshima Y., Hasegawa M., Umeda Y., Wakabayashi K.,
RA   Tokiguchi S., Iwatsubo T., Takahashi H.;
RT   "Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene
RT   mutation.";
RL   Ann. Neurol. 51:525-530(2002).
RN   [77]
RP   VARIANT PSNP1 LEU-5, AND CHARACTERIZATION OF VARIANT PSNP1 LEU-5.
RX   PubMed=12325083; DOI=10.1002/ana.10340;
RA   Poorkaj P., Muma N.A., Zhukareva V., Cochran E.J., Shannon K.M., Hurtig H.,
RA   Koller W.C., Bird T.D., Trojanowski J.Q., Lee V.M.-Y., Schellenberg G.D.;
RT   "An R5L tau mutation in a subject with a progressive supranuclear palsy
RT   phenotype.";
RL   Ann. Neurol. 52:511-516(2002).
RN   [78]
RP   CHARACTERIZATION OF VARIANTS FTD1 ASN-613 DEL AND HIS-613.
RX   PubMed=11906000; DOI=10.1046/j.0022-3042.2001.00729.x;
RA   Yoshida H., Crowther R.A., Goedert M.;
RT   "Functional effects of tau gene mutations deltaN296 and N296H.";
RL   J. Neurochem. 80:548-551(2002).
RN   [79]
RP   VARIANT FTD1 TRP-723.
RX   PubMed=11889249; DOI=10.1212/wnl.58.5.811;
RA   Saito Y., Geyer A., Sasaki R., Kuzuhara S., Nanba E., Miyasaka T.,
RA   Suzuki K., Murayama S.;
RT   "Early-onset, rapidly progressive familial tauopathy with R406W mutation.";
RL   Neurology 58:811-813(2002).
RN   [80]
RP   VARIANT FTD1 VAL-583, AND CHARACTERIZATION OF VARIANT FTD1 VAL-583.
RX   PubMed=12509859; DOI=10.1002/ana.10447;
RA   Kobayashi T., Ota S., Tanaka K., Ito Y., Hasegawa M., Umeda Y., Motoi Y.,
RA   Takanashi M., Yasuhara M., Anno M., Mizuno Y., Mori H.;
RT   "A novel L266V mutation of the tau gene causes frontotemporal dementia with
RT   a unique tau pathology.";
RL   Ann. Neurol. 53:133-137(2003).
RN   [81]
RP   VARIANT FATAL RESPIRATORY HYPOVENTILATION LEU-669, AND CHARACTERIZATION OF
RP   VARIANT FATAL RESPIRATORY HYPOVENTILATION LEU-669.
RX   PubMed=14595660; DOI=10.1002/ana.10747;
RA   Nicholl D.J., Greenstone M.A., Clarke C.E., Rizzu P., Crooks D., Crowe A.,
RA   Trojanowski J.Q., Lee V.M.-Y., Heutink P.;
RT   "An English kindred with a novel recessive tauopathy and respiratory
RT   failure.";
RL   Ann. Neurol. 54:682-686(2003).
RN   [82]
RP   VARIANT FTD1/ALZHEIMER DISEASE TRP-723, AND INVOLVEMENT IN ALZHEIMER
RP   DISEASE.
RX   PubMed=14517953; DOI=10.1002/humu.10269;
RA   Rademakers R., Dermaut B., Peeters K., Cruts M., Heutink P., Goate A.,
RA   Van Broeckhoven C.;
RT   "Tau (MAPT) mutation arg406trp presenting clinically with Alzheimer disease
RT   does not share a common founder in western Europe.";
RL   Hum. Mutat. 22:409-411(2003).
RN   [83]
RP   VARIANT ATYPICAL PSNP1 ASN-613 DEL.
RX   PubMed=14991829; DOI=10.1002/ana.20006;
RA   Rossi G., Gasparoli E., Pasquali C., Di Fede G., Testa D., Albanese A.,
RA   Bracco F., Tagliavini F.;
RT   "Progressive supranuclear palsy and Parkinson's disease in a family with a
RT   new mutation in the tau gene.";
RL   Ann. Neurol. 55:448-448(2004).
RN   [84]
RP   VARIANT PSNP1/ATYPICAL PSNP1 ASN-613 DEL.
RX   PubMed=14991828; DOI=10.1002/ana.20025;
RA   Oliva R., Pastor P.;
RT   "Tau gene delN296 mutation, Parkinson's disease, and atypical supranuclear
RT   palsy.";
RL   Ann. Neurol. 55:448-449(2004).
RN   [85]
RP   VARIANT FTD1 SER-618.
RX   PubMed=16240366; DOI=10.1002/ana.20668;
RA   Yasuda M., Nakamura Y., Kawamata T., Kaneyuki H., Maeda K., Komure O.;
RT   "Phenotypic heterogeneity within a new family with the MAPT P301S
RT   mutation.";
RL   Ann. Neurol. 58:920-928(2005).
RN   [86]
RP   VARIANT PSNP1 VAL-620.
RX   PubMed=16157753; DOI=10.1001/archneur.62.9.1444;
RA   Ros R., Thobois S., Streichenberger N., Kopp N., Sanchez M.P., Perez M.,
RA   Hoenicka J., Avila J., Honnorat J., de Yebenes J.G.;
RT   "A new mutation of the tau gene, G303V, in early-onset familial progressive
RT   supranuclear palsy.";
RL   Arch. Neurol. 62:1444-1450(2005).
RN   [87]
RP   VARIANT FTD1 MET-634.
RX   PubMed=15883319; DOI=10.1212/01.wnl.0000160116.65034.12;
RA   Zarranz J.J., Ferrer I., Lezcano E., Forcadas M.I., Eizaguirre B.,
RA   Atares B., Puig B., Gomez-Esteban J.C., Fernandez-Maiztegui C., Rouco I.,
RA   Perez-Concha T., Fernandez M., Rodriguez O., Rodriguez-Martinez A.B.,
RA   de Pancorbo M.M., Pastor P., Perez-Tur J.;
RT   "A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron
RT   disease.";
RL   Neurology 64:1578-1585(2005).
RN   [88]
RP   VARIANTS MET-17; ALA-30 AND ILE-617.
RX   PubMed=20020531; DOI=10.1002/humu.21152;
RA   Guerreiro R.J., Washecka N., Hardy J., Singleton A.;
RT   "A thorough assessment of benign genetic variability in GRN and MAPT.";
RL   Hum. Mutat. 31:E1126-E1140(2010).
RN   [89]
RP   VARIANT FTD1/ALZHEIMER DISEASE TRP-723.
RX   PubMed=26086902; DOI=10.1016/j.gene.2015.06.033;
RA   Behnam M., Ghorbani F., Shin J.H., Kim D.S., Jang H., Nouri N., Sedghi M.,
RA   Salehi M., Ansari B., Basiri K.;
RT   "Homozygous MAPT R406W mutation causing FTDP phenotype: A unique instance
RT   of a unique mutation.";
RL   Gene 570:150-152(2015).
RN   [90]
RP   VARIANT FTD1 ARG-590, CHARACTERIZATION OF VARIANT FTD1 ARG-590, AND
RP   FUNCTION.
RX   PubMed=32961270; DOI=10.1016/j.nbd.2020.105079;
RA   Sandberg A., Ling H., Gearing M., Dombroski B., Cantwell L., R'Bibo L.,
RA   Levey A., Schellenberg G.D., Hardy J., Wood N., Fernius J., Nystroem S.,
RA   Svensson S., Thor S., Hammarstroem P., Revesz T., Mok K.Y.;
RT   "Fibrillation and molecular characteristics are coherent with clinical and
RT   pathological features of 4-repeat tauopathy caused by MAPT variant G273R.";
RL   Neurobiol. Dis. 146:105079-105079(2020).
CC   -!- FUNCTION: Promotes microtubule assembly and stability, and might be
CC       involved in the establishment and maintenance of neuronal polarity
CC       (PubMed:21985311). The C-terminus binds axonal microtubules while the
CC       N-terminus binds neural plasma membrane components, suggesting that tau
CC       functions as a linker protein between both (PubMed:21985311,
CC       PubMed:32961270). Axonal polarity is predetermined by TAU/MAPT
CC       localization (in the neuronal cell) in the domain of the cell body
CC       defined by the centrosome. The short isoforms allow plasticity of the
CC       cytoskeleton whereas the longer isoforms may preferentially play a role
CC       in its stabilization. {ECO:0000269|PubMed:21985311,
CC       ECO:0000269|PubMed:32961270}.
CC   -!- SUBUNIT: Interacts with MARK1, MARK2, MARK3 and MARK4
CC       (PubMed:23666762). Interacts with PSMC2 through SQSTM1 (By similarity).
CC       Interacts with SQSTM1 when polyubiquitinated (PubMed:15953362).
CC       Interacts with FKBP4 (By similarity). Binds to CSNK1D
CC       (PubMed:14761950). Interacts with SGK1 (PubMed:16982696). Interacts
CC       with EPM2A; the interaction dephosphorylates MAPT at Ser-396
CC       (PubMed:19542233). Interacts with PIN1 (PubMed:11313338). Interacts
CC       with LRRK2 (PubMed:26014385). Interacts with LRP1, leading to
CC       endocytosis; this interaction is reduced in the presence of LRPAP1/RAP
CC       (PubMed:32296178). {ECO:0000250|UniProtKB:P10637,
CC       ECO:0000250|UniProtKB:P19332, ECO:0000269|PubMed:11313338,
CC       ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:15953362,
CC       ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:19542233,
CC       ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:26014385,
CC       ECO:0000269|PubMed:32296178}.
CC   -!- INTERACTION:
CC       P10636; P31749: AKT1; NbExp=2; IntAct=EBI-366182, EBI-296087;
CC       P10636; PRO_0000001987 [P02649]: APOE; NbExp=3; IntAct=EBI-366182, EBI-9209835;
CC       P10636; P05067: APP; NbExp=8; IntAct=EBI-366182, EBI-77613;
CC       P10636; PRO_0000000092 [P05067]: APP; NbExp=5; IntAct=EBI-366182, EBI-821758;
CC       P10636; Q9HC96: CAPN10; NbExp=3; IntAct=EBI-366182, EBI-3915761;
CC       P10636; Q9NR30: DDX21; NbExp=3; IntAct=EBI-366182, EBI-357942;
CC       P10636; O43583: DENR; NbExp=2; IntAct=EBI-366182, EBI-716083;
CC       P10636; Q92608-2: DOCK2; NbExp=3; IntAct=EBI-366182, EBI-25875570;
CC       P10636; P06241: FYN; NbExp=3; IntAct=EBI-366182, EBI-515315;
CC       P10636; P49841: GSK3B; NbExp=4; IntAct=EBI-366182, EBI-373586;
CC       P10636; P11142: HSPA8; NbExp=6; IntAct=EBI-366182, EBI-351896;
CC       P10636; Q8TCE9: LGALS14; NbExp=3; IntAct=EBI-366182, EBI-10274069;
CC       P10636; Q9UPY8: MAPRE3; NbExp=3; IntAct=EBI-366182, EBI-726739;
CC       P10636; P10636: MAPT; NbExp=3; IntAct=EBI-366182, EBI-366182;
CC       P10636; P04156: PRNP; NbExp=2; IntAct=EBI-366182, EBI-977302;
CC       P10636; P46779: RPL28; NbExp=4; IntAct=EBI-366182, EBI-366357;
CC       P10636; P43004: SLC1A2; NbExp=4; IntAct=EBI-366182, EBI-3440986;
CC       P10636; Q9UNE7: STUB1; NbExp=2; IntAct=EBI-366182, EBI-357085;
CC       P10636; Q9UNE7-1: STUB1; NbExp=5; IntAct=EBI-366182, EBI-15687717;
CC       P10636; O15195-2: VILL; NbExp=3; IntAct=EBI-366182, EBI-21845957;
CC       P10636; P63104: YWHAZ; NbExp=8; IntAct=EBI-366182, EBI-347088;
CC       P10636; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-366182, EBI-25850811;
CC       P10636-2; P06241: FYN; NbExp=2; IntAct=EBI-7796412, EBI-515315;
CC       P10636-2; Q5S007: LRRK2; NbExp=3; IntAct=EBI-7796412, EBI-5323863;
CC       P10636-2; P31947: SFN; NbExp=2; IntAct=EBI-7796412, EBI-476295;
CC       P10636-2; P63104: YWHAZ; NbExp=2; IntAct=EBI-7796412, EBI-347088;
CC       P10636-3; P63104: YWHAZ; NbExp=9; IntAct=EBI-7145070, EBI-347088;
CC       P10636-5; P06241: FYN; NbExp=2; IntAct=EBI-21313635, EBI-515315;
CC       P10636-6; P02649: APOE; NbExp=3; IntAct=EBI-7796455, EBI-1222467;
CC       P10636-6; Q14203-5: DCTN1; NbExp=3; IntAct=EBI-7796455, EBI-25840379;
CC       P10636-6; Q92608-2: DOCK2; NbExp=3; IntAct=EBI-7796455, EBI-25875570;
CC       P10636-6; P06241: FYN; NbExp=3; IntAct=EBI-7796455, EBI-515315;
CC       P10636-6; P11142: HSPA8; NbExp=3; IntAct=EBI-7796455, EBI-351896;
CC       P10636-6; O60260-5: PRKN; NbExp=3; IntAct=EBI-7796455, EBI-21251460;
CC       P10636-6; P37840: SNCA; NbExp=3; IntAct=EBI-7796455, EBI-985879;
CC       P10636-6; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-7796455, EBI-25850811;
CC       P10636-7; O00499-1: BIN1; NbExp=5; IntAct=EBI-6926270, EBI-6926280;
CC       P10636-8; P07355: ANXA2; NbExp=10; IntAct=EBI-366233, EBI-352622;
CC       P10636-8; P08133: ANXA6; NbExp=5; IntAct=EBI-366233, EBI-352541;
CC       P10636-8; P05067: APP; NbExp=4; IntAct=EBI-366233, EBI-77613;
CC       P10636-8; O00499-1: BIN1; NbExp=6; IntAct=EBI-366233, EBI-6926280;
CC       P10636-8; Q14203: DCTN1; NbExp=9; IntAct=EBI-366233, EBI-724352;
CC       P10636-8; P26196: DDX6; NbExp=10; IntAct=EBI-366233, EBI-351257;
CC       P10636-8; Q02790: FKBP4; NbExp=7; IntAct=EBI-366233, EBI-1047444;
CC       P10636-8; Q13451: FKBP5; NbExp=8; IntAct=EBI-366233, EBI-306914;
CC       P10636-8; P06241: FYN; NbExp=9; IntAct=EBI-366233, EBI-515315;
CC       P10636-8; P49840: GSK3A; NbExp=2; IntAct=EBI-366233, EBI-1044067;
CC       P10636-8; P49841: GSK3B; NbExp=12; IntAct=EBI-366233, EBI-373586;
CC       P10636-8; P08238: HSP90AB1; NbExp=18; IntAct=EBI-366233, EBI-352572;
CC       P10636-8; P14625: HSP90B1; NbExp=5; IntAct=EBI-366233, EBI-359129;
CC       P10636-8; Q92743: HTRA1; NbExp=9; IntAct=EBI-366233, EBI-352256;
CC       P10636-8; Q5S007: LRRK2; NbExp=9; IntAct=EBI-366233, EBI-5323863;
CC       P10636-8; P10636-8: MAPT; NbExp=6; IntAct=EBI-366233, EBI-366233;
CC       P10636-8; O43347: MSI1; NbExp=2; IntAct=EBI-366233, EBI-726515;
CC       P10636-8; Q96DH6: MSI2; NbExp=4; IntAct=EBI-366233, EBI-2462339;
CC       P10636-8; P07237: P4HB; NbExp=6; IntAct=EBI-366233, EBI-395883;
CC       P10636-8; Q12765: SCRN1; NbExp=5; IntAct=EBI-366233, EBI-2690712;
CC       P10636-8; P31947: SFN; NbExp=10; IntAct=EBI-366233, EBI-476295;
CC       P10636-8; P37840: SNCA; NbExp=12; IntAct=EBI-366233, EBI-985879;
CC       P10636-8; Q71U36: TUBA1A; NbExp=7; IntAct=EBI-366233, EBI-302552;
CC       P10636-8; P07437: TUBB; NbExp=4; IntAct=EBI-366233, EBI-350864;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10747907,
CC       ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:26014385}. Cell
CC       membrane {ECO:0000269|PubMed:10747907}; Peripheral membrane protein
CC       {ECO:0000269|PubMed:10747907}; Cytoplasmic side
CC       {ECO:0000269|PubMed:10747907}. Cytoplasm, cytoskeleton
CC       {ECO:0000269|PubMed:10747907}. Cell projection, axon
CC       {ECO:0000269|PubMed:10747907}. Cell projection, dendrite
CC       {ECO:0000269|PubMed:23666762}. Secreted {ECO:0000269|PubMed:32272059}.
CC       Note=Mostly found in the axons of neurons, in the cytosol and in
CC       association with plasma membrane components (PubMed:10747907). Can be
CC       secreted; the secretion is dependent on protein unfolding and
CC       facilitated by the cargo receptor TMED10; it results in protein
CC       translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-
CC       Golgi intermediate compartment) followed by vesicle entry and secretion
CC       (PubMed:32272059). {ECO:0000269|PubMed:10747907,
CC       ECO:0000269|PubMed:32272059}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=9;
CC         Comment=Additional isoforms seem to exist. Isoforms differ from each
CC         other by the presence or absence of up to 5 of the 15 exons. One of
CC         these optional exons contains the additional tau/MAP repeat.;
CC       Name=PNS-tau;
CC         IsoId=P10636-1; Sequence=Displayed;
CC       Name=Fetal-tau; Synonyms=0N3R {ECO:0000303|PubMed:9789048};
CC         IsoId=P10636-2; Sequence=VSP_003176, VSP_003177, VSP_003179,
CC                                  VSP_003180, VSP_003181;
CC       Name=Tau-A;
CC         IsoId=P10636-3; Sequence=VSP_003175, VSP_003176, VSP_003177,
CC                                  VSP_003178, VSP_003179, VSP_003180,
CC                                  VSP_003181;
CC       Name=Tau-B; Synonyms=1N3R {ECO:0000303|PubMed:9789048};
CC         IsoId=P10636-4; Sequence=VSP_003177, VSP_003179, VSP_003180,
CC                                  VSP_003181;
CC       Name=Tau-C; Synonyms=Tau-3, 2N3R {ECO:0000303|PubMed:9789048};
CC         IsoId=P10636-5; Sequence=VSP_003179, VSP_003180, VSP_003181;
CC       Name=Tau-D; Synonyms=0N4R {ECO:0000303|PubMed:9789048};
CC         IsoId=P10636-6; Sequence=VSP_003176, VSP_003177, VSP_003179,
CC                                  VSP_003180;
CC       Name=Tau-E; Synonyms=1N4R {ECO:0000303|PubMed:9789048};
CC         IsoId=P10636-7; Sequence=VSP_003177, VSP_003179, VSP_003180;
CC       Name=Tau-F; Synonyms=Tau-4, 2N4R {ECO:0000303|PubMed:9789048};
CC         IsoId=P10636-8; Sequence=VSP_003179, VSP_003180;
CC       Name=Tau-G;
CC         IsoId=P10636-9; Sequence=VSP_026780;
CC   -!- TISSUE SPECIFICITY: Expressed in neurons. Isoform PNS-tau is expressed
CC       in the peripheral nervous system while the others are expressed in the
CC       central nervous system.
CC   -!- DEVELOPMENTAL STAGE: Four-repeat (type II) TAU/MAPT is expressed in an
CC       adult-specific manner and is not found in fetal brain, whereas three-
CC       repeat (type I) TAU/MAPT is found in both adult and fetal brain.
CC   -!- DOMAIN: The tau/MAP repeat binds to tubulin. Type I isoforms contain 3
CC       repeats while type II isoforms contain 4 repeats.
CC   -!- PTM: Phosphorylation at serine and threonine residues in S-P or T-P
CC       motifs by proline-directed protein kinases (PDPK1, CDK1, CDK5, GSK3,
CC       MAPK) (only 2-3 sites per protein in interphase, seven-fold increase in
CC       mitosis, and in the form associated with paired helical filaments (PHF-
CC       tau)), and at serine residues in K-X-G-S motifs by MAP/microtubule
CC       affinity-regulating kinase (MARK1, MARK2, MARK3 or MARK4), causing
CC       detachment from microtubules, and their disassembly (PubMed:23666762,
CC       PubMed:7706316). Phosphorylation decreases with age. Phosphorylation
CC       within tau/MAP's repeat domain or in flanking regions seems to reduce
CC       tau/MAP's interaction with, respectively, microtubules or plasma
CC       membrane components (PubMed:7706316). Phosphorylation on Ser-610, Ser-
CC       622, Ser-641 and Ser-673 in several isoforms during mitosis.
CC       Phosphorylation at Ser-548 by GSK3B reduces ability to bind and
CC       stabilize microtubules. Phosphorylation at Ser-579 by BRSK1 and BRSK2
CC       in neurons affects ability to bind microtubules and plays a role in
CC       neuron polarization. Phosphorylated at Ser-554, Ser-579, Ser-602, Ser-
CC       606 and Ser-669 by PHK. Phosphorylation at Ser-214 by SGK1 mediates
CC       microtubule depolymerization and neurite formation in hippocampal
CC       neurons. There is a reciprocal down-regulation of phosphorylation and
CC       O-GlcNAcylation. Phosphorylation on Ser-717 completely abolishes the O-
CC       GlcNAcylation on this site, while phosphorylation on Ser-713 and Ser-
CC       721 reduces glycosylation by a factor of 2 and 4 respectively.
CC       Phosphorylation on Ser-721 is reduced by about 41.5% by GlcNAcylation
CC       on Ser-717. Dephosphorylated at several serine and threonine residues
CC       by the serine/threonine phosphatase PPP5C.
CC       {ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:14761950,
CC       ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603,
CC       ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:19451179,
CC       ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:21985311,
CC       ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:7706316,
CC       ECO:0000269|PubMed:8999860, ECO:0000269|PubMed:9614189}.
CC   -!- PTM: Polyubiquitinated. Requires functional TRAF6 and may provoke
CC       SQSTM1-dependent degradation by the proteasome (By similarity). PHF-tau
CC       can be modified by three different forms of polyubiquitination. 'Lys-
CC       48'-linked polyubiquitination is the major form, 'Lys-6'-linked and
CC       'Lys-11'-linked polyubiquitination also occur. {ECO:0000250,
CC       ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16443603}.
CC   -!- PTM: O-glycosylated. O-GlcNAcylation content is around 8.2%. There is
CC       reciprocal down-regulation of phosphorylation and O-GlcNAcylation.
CC       Phosphorylation on Ser-717 completely abolishes the O-GlcNAcylation on
CC       this site, while phosphorylation on Ser-713 and Ser-721 reduces O-
CC       GlcNAcylation by a factor of 2 and 4 respectively. O-GlcNAcylation on
CC       Ser-717 decreases the phosphorylation on Ser-721 by about 41.5%.
CC       {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:15546861,
CC       ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179,
CC       ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189}.
CC   -!- PTM: Glycation of PHF-tau, but not normal brain TAU/MAPT. Glycation is
CC       a non-enzymatic post-translational modification that involves a
CC       covalent linkage between a sugar and an amino group of a protein
CC       molecule forming ketoamine. Subsequent oxidation, fragmentation and/or
CC       cross-linking of ketoamine leads to the production of advanced
CC       glycation endproducts (AGES). Glycation may play a role in stabilizing
CC       PHF aggregation leading to tangle formation in AD.
CC   -!- DISEASE: Note=In Alzheimer disease, the neuronal cytoskeleton in the
CC       brain is progressively disrupted and replaced by tangles of paired
CC       helical filaments (PHF) and straight filaments, mainly composed of
CC       hyperphosphorylated forms of TAU (PHF-TAU or AD P-TAU). O-GlcNAcylation
CC       is greatly reduced in Alzheimer disease brain cerebral cortex leading
CC       to an increase in TAU/MAPT phosphorylations.
CC       {ECO:0000269|PubMed:14517953, ECO:0000269|PubMed:26086902}.
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:10208578, ECO:0000269|PubMed:10214944,
CC       ECO:0000269|PubMed:10374757, ECO:0000269|PubMed:10489057,
CC       ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:10802785,
CC       ECO:0000269|PubMed:11071507, ECO:0000269|PubMed:11117541,
CC       ECO:0000269|PubMed:11278002, ECO:0000269|PubMed:11585254,
CC       ECO:0000269|PubMed:11889249, ECO:0000269|PubMed:11906000,
CC       ECO:0000269|PubMed:11921059, ECO:0000269|PubMed:12473774,
CC       ECO:0000269|PubMed:12509859, ECO:0000269|PubMed:14517953,
CC       ECO:0000269|PubMed:15883319, ECO:0000269|PubMed:16240366,
CC       ECO:0000269|PubMed:26086902, ECO:0000269|PubMed:32961270,
CC       ECO:0000269|PubMed:9629852, ECO:0000269|PubMed:9641683,
CC       ECO:0000269|PubMed:9736786, ECO:0000269|PubMed:9789048,
CC       ECO:0000269|PubMed:9973279}. 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:10604746,
CC       ECO:0000269|PubMed:11089577, ECO:0000269|PubMed:11117542,
CC       ECO:0000269|PubMed:11601501, ECO:0000269|PubMed:11891833}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Note=Defects in MAPT are a cause of corticobasal degeneration
CC       (CBD). It is marked by extrapyramidal signs and apraxia and can be
CC       associated with memory loss. Neuropathologic features may overlap
CC       Alzheimer disease, progressive supranuclear palsy, and Parkinson
CC       disease.
CC   -!- DISEASE: Progressive supranuclear palsy 1 (PSNP1) [MIM:601104]:
CC       Characterized by akinetic-rigid syndrome, supranuclear gaze palsy,
CC       pyramidal tract dysfunction, pseudobulbar signs and cognitive
CC       capacities deterioration. Neurofibrillary tangles and gliosis but no
CC       amyloid plaques are found in diseased brains. Most cases appear to be
CC       sporadic, with a significant association with a common haplotype
CC       including the MAPT gene and the flanking regions. Familial cases show
CC       an autosomal dominant pattern of transmission with incomplete
CC       penetrance; genetic analysis of a few cases showed the occurrence of
CC       tau mutations, including a deletion of Asn-613.
CC       {ECO:0000269|PubMed:10534245, ECO:0000269|PubMed:11220749,
CC       ECO:0000269|PubMed:12325083, ECO:0000269|PubMed:14991828,
CC       ECO:0000269|PubMed:14991829, ECO:0000269|PubMed:16157753}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Parkinson-dementia syndrome (PARDE) [MIM:260540]: A syndrome
CC       characterized by parkinsonism, tremor, rigidity, dementia,
CC       ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration
CC       occurs in the hippocampus, basal ganglia and brainstem nuclei. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- WEB RESOURCE: Name=Alzforum; Note=MAPT mutations;
CC       URL="https://www.alzforum.org/mutations/mapt";
CC   -!- WEB RESOURCE: Name=Protein Spotlight; Note=Vita minima - Issue 68 of
CC       March 2006;
CC       URL="https://www.proteinspotlight.org/back_issues/068";
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Tau protein entry;
CC       URL="https://en.wikipedia.org/wiki/Tau_protein";
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; J03778; AAA60615.1; -; mRNA.
DR   EMBL; X14474; CAA32636.1; -; mRNA.
DR   EMBL; AF047863; AAC04277.1; -; Genomic_DNA.
DR   EMBL; AF027491; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF047856; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF047857; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF027492; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF047858; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF027493; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF047859; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF047860; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF047862; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF027494; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF027495; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF027496; AAC04277.1; JOINED; Genomic_DNA.
DR   EMBL; AF027491; AAC04278.1; -; Genomic_DNA.
DR   EMBL; AF027492; AAC04278.1; JOINED; Genomic_DNA.
DR   EMBL; AF027493; AAC04278.1; JOINED; Genomic_DNA.
DR   EMBL; AF047860; AAC04278.1; JOINED; Genomic_DNA.
DR   EMBL; AF047862; AAC04278.1; JOINED; Genomic_DNA.
DR   EMBL; AF027495; AAC04278.1; JOINED; Genomic_DNA.
DR   EMBL; AF027496; AAC04278.1; JOINED; Genomic_DNA.
DR   EMBL; AF047863; AAC04278.1; JOINED; Genomic_DNA.
DR   EMBL; AF027491; AAC04279.1; -; Genomic_DNA.
DR   EMBL; AF047856; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF047857; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF027492; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF027493; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF047860; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF047862; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF027494; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF027495; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF027496; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF047863; AAC04279.1; JOINED; Genomic_DNA.
DR   EMBL; AF047861; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AY730549; AAU45390.1; -; mRNA.
DR   EMBL; BT006772; AAP35418.1; -; mRNA.
DR   EMBL; AC004139; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC010792; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC217771; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC217779; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC000558; AAH00558.1; -; mRNA.
DR   EMBL; BC098281; AAH98281.1; -; mRNA.
DR   EMBL; BC099721; AAH99721.1; -; mRNA.
DR   EMBL; BC101936; AAI01937.1; -; mRNA.
DR   EMBL; BC114504; AAI14505.1; -; mRNA.
DR   EMBL; BC114948; AAI14949.1; -; mRNA.
DR   EMBL; AY526356; AAS17881.1; -; mRNA.
DR   EMBL; M25298; AAA57264.1; -; mRNA.
DR   EMBL; BN000503; CAG26750.1; -; mRNA.
DR   CCDS; CCDS11499.1; -. [P10636-8]
DR   CCDS; CCDS11500.1; -. [P10636-6]
DR   CCDS; CCDS11501.1; -. [P10636-1]
DR   CCDS; CCDS11502.1; -. [P10636-2]
DR   CCDS; CCDS45715.1; -. [P10636-9]
DR   CCDS; CCDS45716.1; -. [P10636-7]
DR   CCDS; CCDS56033.1; -. [P10636-5]
DR   CCDS; CCDS92347.1; -. [P10636-4]
DR   PIR; I52232; I52232.
DR   PIR; JS0370; QRHUT1.
DR   PIR; PN0001; QRHUT2.
DR   PIR; S26663; S26663.
DR   RefSeq; NP_001116538.2; NM_001123066.4. [P10636-9]
DR   RefSeq; NP_001116539.1; NM_001123067.4. [P10636-7]
DR   RefSeq; NP_001190180.1; NM_001203251.2. [P10636-4]
DR   RefSeq; NP_001190181.1; NM_001203252.2. [P10636-5]
DR   RefSeq; NP_001364197.1; NM_001377268.1. [P10636-2]
DR   RefSeq; NP_005901.2; NM_005910.5. [P10636-8]
DR   RefSeq; NP_058518.1; NM_016834.5. [P10636-6]
DR   RefSeq; NP_058519.3; NM_016835.5. [P10636-1]
DR   RefSeq; NP_058525.1; NM_016841.5. [P10636-2]
DR   PDB; 1I8H; NMR; -; A=542-554.
DR   PDB; 2MZ7; NMR; -; A=584-629.
DR   PDB; 2ON9; X-ray; 1.51 A; A/B=623-628.
DR   PDB; 3OVL; X-ray; 1.81 A; A=623-628.
DR   PDB; 4E0M; X-ray; 1.75 A; A/B/C/D=622-634.
DR   PDB; 4E0N; X-ray; 1.65 A; A/B/C/D=622-634.
DR   PDB; 4E0O; X-ray; 1.82 A; A/B/C/D=622-634.
DR   PDB; 4FL5; X-ray; 1.90 A; P/Q=527-536.
DR   PDB; 4GLR; X-ray; 1.90 A; A/B=541-557.
DR   PDB; 4NP8; X-ray; 1.51 A; A=623-628.
DR   PDB; 4TQE; X-ray; 1.60 A; A=532-547.
DR   PDB; 4Y32; X-ray; 1.70 A; C/D=528-534.
DR   PDB; 4Y5I; X-ray; 1.40 A; F/G=528-534.
DR   PDB; 5DMG; X-ray; 2.50 A; P/X/Z=733-747.
DR   PDB; 5E2V; X-ray; 1.64 A; P=511-528.
DR   PDB; 5E2W; X-ray; 1.50 A; P=511-528.
DR   PDB; 5HF3; X-ray; 1.80 A; B=528-534.
DR   PDB; 5K7N; EM; 1.10 A; Z=623-628.
DR   PDB; 5MO3; X-ray; 1.69 A; A=615-628.
DR   PDB; 5MP1; X-ray; 3.10 A; A/B/E/I=615-628.
DR   PDB; 5MP3; X-ray; 2.75 A; C/D=609-638.
DR   PDB; 5MP5; X-ray; 2.31 A; I/J/K=615-628.
DR   PDB; 5N5A; NMR; -; A=571-607.
DR   PDB; 5N5B; NMR; -; A=609-636.
DR   PDB; 5NVB; NMR; -; A=571-585.
DR   PDB; 5O3L; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=623-695.
DR   PDB; 5O3O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=623-695.
DR   PDB; 5O3T; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=623-695.
DR   PDB; 5V5B; EM; 1.50 A; A=591-600.
DR   PDB; 5V5C; EM; 1.25 A; A=592-597.
DR   PDB; 5ZIA; X-ray; 2.60 A; C/F/J/N/Q/R=552-560.
DR   PDB; 5ZV3; X-ray; 2.09 A; A=52-71.
DR   PDB; 6BB4; X-ray; 2.10 A; P/Q/R=703-725.
DR   PDB; 6CVJ; EM; 3.20 A; D=514-717.
DR   PDB; 6CVN; EM; 3.90 A; D=514-717.
DR   PDB; 6DC8; X-ray; 1.80 A; P=696-725.
DR   PDB; 6DC9; X-ray; 3.00 A; P/Q=696-725.
DR   PDB; 6DCA; X-ray; 2.60 A; P/Q/R/S=696-725.
DR   PDB; 6FBW; X-ray; 1.45 A; B/D=528-533.
DR   PDB; 6FI5; X-ray; 1.70 A; B=529-533.
DR   PDB; 6GK7; X-ray; 2.95 A; A=625-635.
DR   PDB; 6GK8; X-ray; 2.85 A; I=52-71.
DR   PDB; 6GX5; EM; 3.20 A; A/B/C=602-695.
DR   PDB; 6H06; X-ray; 2.63 A; G/I/J/K=721-746.
DR   PDB; 6HRE; EM; 3.20 A; A/B/C/D/E/F=1-758.
DR   PDB; 6HRF; EM; 3.30 A; A/B/C/D/E/F=1-758.
DR   PDB; 6LRA; X-ray; 1.90 A; C=592-597.
DR   PDB; 6N4P; X-ray; 1.85 A; A/C=5-10.
DR   PDB; 6NK4; EM; 1.99 A; A=591-599.
DR   PDB; 6NWP; EM; 2.30 A; A/B/C/D/E/F=1-758.
DR   PDB; 6NWQ; EM; 3.40 A; A/B/C/D/E/F=1-758.
DR   PDB; 6ODG; X-ray; 1.00 A; A/B=622-627.
DR   PDB; 6PXR; X-ray; 1.56 A; A=15-22.
DR   PDB; 6QJH; EM; 3.30 A; A/B/C=589-647.
DR   PDB; 6QJM; EM; 3.30 A; A/B/C=591-638.
DR   PDB; 6QJP; EM; 3.50 A; A/B/C=591-638.
DR   PDB; 6QJQ; EM; 3.70 A; A/B/C/D/E/F=620-647.
DR   PDB; 6TJO; EM; 3.20 A; A/B/C=1-758.
DR   PDB; 6TJX; EM; 3.00 A; A/B/C/D/E/F=1-758.
DR   PDB; 6VH7; EM; 3.80 A; A/B/C/E/F/G=591-697.
DR   PDB; 6VHA; EM; 4.30 A; E/F/G=591-697.
DR   PDB; 6VHL; EM; 3.30 A; E/F=621-697.
DR   PDB; 6VI3; EM; 3.30 A; E/F=621-697.
DR   PDB; 6XLI; X-ray; 2.00 A; E/F/P=527-539.
DR   PDB; 7EYC; X-ray; 2.49 A; P/Q=594-601.
DR   PDB; 7KQK; X-ray; 2.60 A; C/P=541-550.
DR   PDB; 7MKF; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7MKG; EM; 3.07 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7MKH; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7NRQ; EM; 2.76 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7NRS; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7NRT; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7NRV; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7NRX; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7P65; EM; 2.70 A; A/B/C/D/E=1-758.
DR   PDB; 7P66; EM; 3.00 A; A/B/C/D/E=1-758.
DR   PDB; 7P67; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7P68; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7P6A; EM; 1.90 A; A/B/C/D/E=1-758.
DR   PDB; 7P6B; EM; 2.20 A; A/B/C/D/E=1-758.
DR   PDB; 7P6C; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7P6D; EM; 3.30 A; A/B/C/D/E=1-758.
DR   PDB; 7P6E; EM; 3.40 A; A/B/C/D/E/F/I/J/Q/R=1-758.
DR   PDB; 7PQC; EM; 4.10 A; O=519-712.
DR   PDB; 7PQP; EM; 4.10 A; O=519-712.
DR   PDB; 7QJV; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758.
DR   PDB; 7QJW; EM; 2.81 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QJX; EM; 2.99 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758.
DR   PDB; 7QJY; EM; 3.14 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QJZ; EM; 3.40 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QK1; EM; 3.03 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QK2; EM; 2.61 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QK3; EM; 2.44 A; A/B/C=1-758.
DR   PDB; 7QK5; EM; 1.92 A; A/B/C/D/E/F/G/H/K=1-758.
DR   PDB; 7QK6; EM; 2.27 A; A/B/C=1-758.
DR   PDB; 7QKF; EM; 2.83 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QKG; EM; 3.36 A; A/B/C=1-758.
DR   PDB; 7QKH; EM; 3.17 A; A/B/C/D/E/G=1-758.
DR   PDB; 7QKI; EM; 3.13 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QKJ; EM; 3.26 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758.
DR   PDB; 7QKK; EM; 2.80 A; A/B/C=1-758.
DR   PDB; 7QKL; EM; 2.07 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QKM; EM; 2.66 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QKU; EM; 2.57 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QKV; EM; 3.23 A; A/B/C/D/E/F/G/H/I=1-758.
DR   PDB; 7QKW; EM; 2.32 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QKX; EM; 3.16 A; A/B/C/D/E/G=1-758.
DR   PDB; 7QKY; EM; 1.86 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QKZ; EM; 2.65 A; A/B/C/D/E/F/G/H/I=1-758.
DR   PDB; 7QL0; EM; 3.13 A; A/B/C/D/E/c=1-758.
DR   PDB; 7QL1; EM; 3.34 A; A/C/D=1-758.
DR   PDB; 7QL2; EM; 2.95 A; A/B/C=1-758.
DR   PDB; 7QL3; EM; 3.32 A; A/B/C/D/E/F=1-758.
DR   PDB; 7QL4; EM; 3.20 A; A/B/C/D/E/F=1-758.
DR   PDB; 7R4T; EM; 2.75 A; A/B/C/D/E/F=1-758.
DR   PDB; 7R5H; EM; 2.59 A; A/B/C/D/E/F=1-758.
DR   PDB; 7SP1; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=1-758.
DR   PDB; 7U0Z; EM; 4.20 A; A/B/C=589-698.
DR   PDB; 7UPE; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7UPF; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7UPG; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 7YMN; EM; 3.46 A; A/B/C/D/E/F=614-708.
DR   PDB; 7YPG; EM; 2.50 A; A/B/C/D/E/F=614-708.
DR   PDB; 8AZU; EM; 3.10 A; C=1-758.
DR   PDB; 8BGS; EM; 3.16 A; A/B/C/D/E/F/r=1-758.
DR   PDB; 8BGV; EM; 3.27 A; A/B/C/D/E/F/n=1-758.
DR   PDB; 8BYN; EM; 2.60 A; A/B/C/D/E/F=1-758.
DR   PDB; 8CAQ; EM; 2.30 A; A/B/C/D/E=1-758.
DR   PDB; 8CAX; EM; 3.70 A; A/B/C/D/E/F=1-758.
DR   PDB; 8FNZ; EM; 3.88 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/a/b/c/d/e/f=580-597.
DR   PDB; 8FUG; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W=623-695.
DR   PDB; 8FYU; X-ray; 1.85 A; C/E=729-738.
DR   PDB; 8G54; NMR; -; A/B/C/D/E=515-716.
DR   PDB; 8G55; NMR; -; A/B/C/D/E/F/G/H/I/J=515-716.
DR   PDB; 8G58; NMR; -; A/B/C/D/E/F/G/H/I/J=614-708.
DR   PDB; 8GCK; X-ray; 1.37 A; C/E=733-738.
DR   PDB; 8KDX; X-ray; 1.01 A; B=524-538.
DR   PDB; 8OH2; EM; 2.60 A; 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/b/c/d=666-680.
DR   PDB; 8OHI; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=667-679.
DR   PDB; 8OHP; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X=667-679.
DR   PDB; 8OI0; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X=667-679.
DR   PDB; 8OP0; X-ray; 1.54 A; B=618-629.
DR   PDB; 8OPI; X-ray; 1.83 A; B=618-629.
DR   PDB; 8ORE; EM; 2.50 A; A/B/C=404-758.
DR   PDB; 8ORF; EM; 2.50 A; A/B/C=404-758.
DR   PDB; 8ORG; EM; 2.30 A; A/B/C=404-758.
DR   PDB; 8OT6; EM; 2.00 A; A/B/C/D/E=1-758.
DR   PDB; 8OT9; EM; 3.40 A; A/B/C/D/E/F=1-758.
DR   PDB; 8OTC; EM; 3.20 A; A/B/C/D/E/F=1-758.
DR   PDB; 8OTG; EM; 2.10 A; A/B/C/D/E=1-758.
DR   PDB; 8OTH; EM; 3.40 A; A/B/C/D/E=1-758.
DR   PDB; 8OTI; EM; 2.70 A; A/B/C/D/E/F=1-758.
DR   PDB; 8OTJ; EM; 3.30 A; A/B/C/D/E/F/G=1-758.
DR   PDB; 8P34; EM; 2.61 A; A=602-695.
DR   PDB; 8PII; X-ray; 2.35 A; B=618-631.
DR   PDB; 8PPO; EM; 2.00 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=1-758.
DR   PDB; 8Q27; EM; 2.02 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q2J; EM; 2.23 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q2K; EM; 2.88 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q2L; EM; 2.20 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q7F; EM; 3.72 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q7L; EM; 2.82 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q7M; EM; 3.26 A; A/B/C/D/E/F/G/H/I=427-758.
DR   PDB; 8Q7P; EM; 3.28 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q7T; EM; 3.00 A; A/B/C/D/E/F/G/H/I=427-758.
DR   PDB; 8Q88; EM; 2.95 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8C; EM; 1.92 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8D; EM; 3.04 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8E; EM; 3.81 A; A/B/C/D/E/F/G/H/I/J/K/L=427-758.
DR   PDB; 8Q8F; EM; 2.93 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8L; EM; 3.04 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8M; EM; 2.95 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8R; EM; 2.10 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8S; EM; 2.68 A; A/B/C/D/E/F/G/H/I=427-758.
DR   PDB; 8Q8U; EM; 3.30 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8V; EM; 3.80 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8W; EM; 2.85 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8X; EM; 2.54 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8Y; EM; 2.88 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q8Z; EM; 3.16 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q92; EM; 3.05 A; A/B/C=588-681.
DR   PDB; 8Q97; EM; 2.99 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q98; EM; 1.75 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q99; EM; 2.70 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9A; EM; 3.04 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9B; EM; 3.10 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9C; EM; 3.40 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9D; EM; 3.16 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9E; EM; 2.97 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9F; EM; 1.91 A; A/B/C/D/E/c=427-758.
DR   PDB; 8Q9G; EM; 2.65 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9H; EM; 2.18 A; A/B/C/D/E/G=427-758.
DR   PDB; 8Q9I; EM; 2.56 A; A/C/E=427-758.
DR   PDB; 8Q9J; EM; 2.96 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9K; EM; 3.20 A; A/B/C/D/E/F=427-758.
DR   PDB; 8Q9L; EM; 2.76 A; A/B/C/D/E/F/G/H/I=427-758.
DR   PDB; 8Q9M; EM; 2.65 A; A/B/C/D/E/G=427-758.
DR   PDB; 8Q9O; EM; 3.10 A; A/B/C/D/E/G=427-758.
DR   PDB; 8QCP; EM; 3.21 A; A/B/C/D/E/F=427-758.
DR   PDB; 8QCR; EM; 2.75 A; A/C/E=427-758.
DR   PDB; 8QDV; X-ray; 2.50 A; C/F=527-539, C/F=635-648.
DR   PDB; 8QJJ; EM; 3.35 A; A/B/C/D/E/F=427-758.
DR   PDB; 8R3T; EM; 3.10 A; A/B/C/D/E/F=1-758.
DR   PDB; 8SEH; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=623-695.
DR   PDB; 8SEI; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=623-695.
DR   PDB; 8TTL; EM; 2.60 A; A/B/C/D/E/F=427-758.
DR   PDB; 8TTN; EM; 2.40 A; A/B/C/D/E=427-758.
DR   PDB; 8UQ7; EM; 2.31 A; A/B/C/D/E/F=622-696.
DR   PDB; 8V1N; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J/K/L=612-630.
DR   PDB; 8WCP; EM; 3.28 A; A/B/C=427-758.
DR   PDB; 8ZWL; EM; 3.40 A; A/B/C/D/E/F=1-758.
DR   PDB; 8ZWM; EM; 3.20 A; A/B/C/D/E/F=1-758.
DR   PDB; 8ZX6; EM; 3.50 A; A/B/C/D/E/F=1-758.
DR   PDB; 9B3A; EM; 3.20 A; A/C/E/G/I/K/M/O/Q/S/U/W/Y/a/c=612-630.
DR   PDB; 9B3C; EM; 2.95 A; A/C/E/G/I/K/M/O/Q/S/U/W/Y/a/c=612-630.
DR   PDB; 9B4L; EM; 3.10 A; 0/1/A/B/C/D/M/N/O/P/Y/Z=1-758.
DR   PDB; 9B4M; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 9B4N; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 9B4O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 9BBL; EM; 2.50 A; A/B/C/D/E/F/G/H/I=1-758.
DR   PDB; 9BBM; EM; 3.20 A; A/B/C/D/E/F=1-758.
DR   PDB; 9BXI; EM; 2.70 A; A/B/C/D/E/F=621-697.
DR   PDB; 9BXO; EM; 3.00 A; A/B/C/D/E/F=621-697.
DR   PDB; 9BXQ; EM; 3.10 A; C/D/E/F/G/H=621-697.
DR   PDB; 9BXR; EM; 3.20 A; C/D/E/F/G/H=621-697.
DR   PDB; 9CGX; EM; 2.97 A; A/B/C/D/E/F=427-758.
DR   PDB; 9CGZ; EM; 2.69 A; A/B/C/D/E/F=427-758.
DR   PDB; 9CZI; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=623-695.
DR   PDB; 9CZL; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=622-695.
DR   PDB; 9DME; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=612-630.
DR   PDB; 9EO7; EM; 2.80 A; A=1-758.
DR   PDB; 9EO9; EM; 3.30 A; A/B=1-758.
DR   PDB; 9EOE; EM; 2.30 A; A=1-758.
DR   PDB; 9EOG; EM; 3.00 A; A/B/C/D/E/F=1-758.
DR   PDB; 9EOH; EM; 2.80 A; A/B/C/D/E/F=1-758.
DR   PDB; 9ERM; EM; 2.30 A; A/B/C/D/E=1-758.
DR   PDB; 9ERN; EM; 2.50 A; A/B/C/D/E/F=1-758.
DR   PDB; 9ERO; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=1-758.
DR   PDB; 9G13; X-ray; 1.80 A; B/D/F/H=686-698.
DR   PDB; 9GG0; EM; 2.81 A; A/B/C=588-694.
DR   PDB; 9GG1; EM; 2.26 A; A/B/C/D=590-696.
DR   PDB; 9GG6; EM; 3.36 A; A/B/C=586-681.
DR   PDB; 9H5G; EM; 2.48 A; A/B/C/D/E/F=427-758.
DR   PDB; 9H5J; EM; 2.72 A; A/B/C/D/E/F=427-758.
DR   PDB; 9HBB; EM; 3.00 A; A/B/C/D/E/F=608-708.
DR   PDB; 9MR8; EM; 2.90 A; C=590-679.
DR   PDBsum; 1I8H; -.
DR   PDBsum; 2MZ7; -.
DR   PDBsum; 2ON9; -.
DR   PDBsum; 3OVL; -.
DR   PDBsum; 4E0M; -.
DR   PDBsum; 4E0N; -.
DR   PDBsum; 4E0O; -.
DR   PDBsum; 4FL5; -.
DR   PDBsum; 4GLR; -.
DR   PDBsum; 4NP8; -.
DR   PDBsum; 4TQE; -.
DR   PDBsum; 4Y32; -.
DR   PDBsum; 4Y5I; -.
DR   PDBsum; 5DMG; -.
DR   PDBsum; 5E2V; -.
DR   PDBsum; 5E2W; -.
DR   PDBsum; 5HF3; -.
DR   PDBsum; 5K7N; -.
DR   PDBsum; 5MO3; -.
DR   PDBsum; 5MP1; -.
DR   PDBsum; 5MP3; -.
DR   PDBsum; 5MP5; -.
DR   PDBsum; 5N5A; -.
DR   PDBsum; 5N5B; -.
DR   PDBsum; 5NVB; -.
DR   PDBsum; 5O3L; -.
DR   PDBsum; 5O3O; -.
DR   PDBsum; 5O3T; -.
DR   PDBsum; 5V5B; -.
DR   PDBsum; 5V5C; -.
DR   PDBsum; 5ZIA; -.
DR   PDBsum; 5ZV3; -.
DR   PDBsum; 6BB4; -.
DR   PDBsum; 6CVJ; -.
DR   PDBsum; 6CVN; -.
DR   PDBsum; 6DC8; -.
DR   PDBsum; 6DC9; -.
DR   PDBsum; 6DCA; -.
DR   PDBsum; 6FBW; -.
DR   PDBsum; 6FI5; -.
DR   PDBsum; 6GK7; -.
DR   PDBsum; 6GK8; -.
DR   PDBsum; 6GX5; -.
DR   PDBsum; 6H06; -.
DR   PDBsum; 6HRE; -.
DR   PDBsum; 6HRF; -.
DR   PDBsum; 6LRA; -.
DR   PDBsum; 6N4P; -.
DR   PDBsum; 6NK4; -.
DR   PDBsum; 6NWP; -.
DR   PDBsum; 6NWQ; -.
DR   PDBsum; 6ODG; -.
DR   PDBsum; 6PXR; -.
DR   PDBsum; 6QJH; -.
DR   PDBsum; 6QJM; -.
DR   PDBsum; 6QJP; -.
DR   PDBsum; 6QJQ; -.
DR   PDBsum; 6TJO; -.
DR   PDBsum; 6TJX; -.
DR   PDBsum; 6VH7; -.
DR   PDBsum; 6VHA; -.
DR   PDBsum; 6VHL; -.
DR   PDBsum; 6VI3; -.
DR   PDBsum; 6XLI; -.
DR   PDBsum; 7EYC; -.
DR   PDBsum; 7KQK; -.
DR   PDBsum; 7MKF; -.
DR   PDBsum; 7MKG; -.
DR   PDBsum; 7MKH; -.
DR   PDBsum; 7NRQ; -.
DR   PDBsum; 7NRS; -.
DR   PDBsum; 7NRT; -.
DR   PDBsum; 7NRV; -.
DR   PDBsum; 7NRX; -.
DR   PDBsum; 7P65; -.
DR   PDBsum; 7P66; -.
DR   PDBsum; 7P67; -.
DR   PDBsum; 7P68; -.
DR   PDBsum; 7P6A; -.
DR   PDBsum; 7P6B; -.
DR   PDBsum; 7P6C; -.
DR   PDBsum; 7P6D; -.
DR   PDBsum; 7P6E; -.
DR   PDBsum; 7PQC; -.
DR   PDBsum; 7PQP; -.
DR   PDBsum; 7QJV; -.
DR   PDBsum; 7QJW; -.
DR   PDBsum; 7QJX; -.
DR   PDBsum; 7QJY; -.
DR   PDBsum; 7QJZ; -.
DR   PDBsum; 7QK1; -.
DR   PDBsum; 7QK2; -.
DR   PDBsum; 7QK3; -.
DR   PDBsum; 7QK5; -.
DR   PDBsum; 7QK6; -.
DR   PDBsum; 7QKF; -.
DR   PDBsum; 7QKG; -.
DR   PDBsum; 7QKH; -.
DR   PDBsum; 7QKI; -.
DR   PDBsum; 7QKJ; -.
DR   PDBsum; 7QKK; -.
DR   PDBsum; 7QKL; -.
DR   PDBsum; 7QKM; -.
DR   PDBsum; 7QKU; -.
DR   PDBsum; 7QKV; -.
DR   PDBsum; 7QKW; -.
DR   PDBsum; 7QKX; -.
DR   PDBsum; 7QKY; -.
DR   PDBsum; 7QKZ; -.
DR   PDBsum; 7QL0; -.
DR   PDBsum; 7QL1; -.
DR   PDBsum; 7QL2; -.
DR   PDBsum; 7QL3; -.
DR   PDBsum; 7QL4; -.
DR   PDBsum; 7R4T; -.
DR   PDBsum; 7R5H; -.
DR   PDBsum; 7SP1; -.
DR   PDBsum; 7U0Z; -.
DR   PDBsum; 7UPE; -.
DR   PDBsum; 7UPF; -.
DR   PDBsum; 7UPG; -.
DR   PDBsum; 7YMN; -.
DR   PDBsum; 7YPG; -.
DR   PDBsum; 8AZU; -.
DR   PDBsum; 8BGS; -.
DR   PDBsum; 8BGV; -.
DR   PDBsum; 8BYN; -.
DR   PDBsum; 8CAQ; -.
DR   PDBsum; 8CAX; -.
DR   PDBsum; 8FNZ; -.
DR   PDBsum; 8FUG; -.
DR   PDBsum; 8FYU; -.
DR   PDBsum; 8G54; -.
DR   PDBsum; 8G55; -.
DR   PDBsum; 8G58; -.
DR   PDBsum; 8GCK; -.
DR   PDBsum; 8KDX; -.
DR   PDBsum; 8OH2; -.
DR   PDBsum; 8OHI; -.
DR   PDBsum; 8OHP; -.
DR   PDBsum; 8OI0; -.
DR   PDBsum; 8OP0; -.
DR   PDBsum; 8OPI; -.
DR   PDBsum; 8ORE; -.
DR   PDBsum; 8ORF; -.
DR   PDBsum; 8ORG; -.
DR   PDBsum; 8OT6; -.
DR   PDBsum; 8OT9; -.
DR   PDBsum; 8OTC; -.
DR   PDBsum; 8OTG; -.
DR   PDBsum; 8OTH; -.
DR   PDBsum; 8OTI; -.
DR   PDBsum; 8OTJ; -.
DR   PDBsum; 8P34; -.
DR   PDBsum; 8PII; -.
DR   PDBsum; 8PPO; -.
DR   PDBsum; 8Q27; -.
DR   PDBsum; 8Q2J; -.
DR   PDBsum; 8Q2K; -.
DR   PDBsum; 8Q2L; -.
DR   PDBsum; 8Q7F; -.
DR   PDBsum; 8Q7L; -.
DR   PDBsum; 8Q7M; -.
DR   PDBsum; 8Q7P; -.
DR   PDBsum; 8Q7T; -.
DR   PDBsum; 8Q88; -.
DR   PDBsum; 8Q8C; -.
DR   PDBsum; 8Q8D; -.
DR   PDBsum; 8Q8E; -.
DR   PDBsum; 8Q8F; -.
DR   PDBsum; 8Q8L; -.
DR   PDBsum; 8Q8M; -.
DR   PDBsum; 8Q8R; -.
DR   PDBsum; 8Q8S; -.
DR   PDBsum; 8Q8U; -.
DR   PDBsum; 8Q8V; -.
DR   PDBsum; 8Q8W; -.
DR   PDBsum; 8Q8X; -.
DR   PDBsum; 8Q8Y; -.
DR   PDBsum; 8Q8Z; -.
DR   PDBsum; 8Q92; -.
DR   PDBsum; 8Q97; -.
DR   PDBsum; 8Q98; -.
DR   PDBsum; 8Q99; -.
DR   PDBsum; 8Q9A; -.
DR   PDBsum; 8Q9B; -.
DR   PDBsum; 8Q9C; -.
DR   PDBsum; 8Q9D; -.
DR   PDBsum; 8Q9E; -.
DR   PDBsum; 8Q9F; -.
DR   PDBsum; 8Q9G; -.
DR   PDBsum; 8Q9H; -.
DR   PDBsum; 8Q9I; -.
DR   PDBsum; 8Q9J; -.
DR   PDBsum; 8Q9K; -.
DR   PDBsum; 8Q9L; -.
DR   PDBsum; 8Q9M; -.
DR   PDBsum; 8Q9O; -.
DR   PDBsum; 8QCP; -.
DR   PDBsum; 8QCR; -.
DR   PDBsum; 8QDV; -.
DR   PDBsum; 8QJJ; -.
DR   PDBsum; 8R3T; -.
DR   PDBsum; 8SEH; -.
DR   PDBsum; 8SEI; -.
DR   PDBsum; 8TTL; -.
DR   PDBsum; 8TTN; -.
DR   PDBsum; 8UQ7; -.
DR   PDBsum; 8V1N; -.
DR   PDBsum; 8WCP; -.
DR   PDBsum; 8ZWL; -.
DR   PDBsum; 8ZWM; -.
DR   PDBsum; 8ZX6; -.
DR   PDBsum; 9B3A; -.
DR   PDBsum; 9B3C; -.
DR   PDBsum; 9B4L; -.
DR   PDBsum; 9B4M; -.
DR   PDBsum; 9B4N; -.
DR   PDBsum; 9B4O; -.
DR   PDBsum; 9BBL; -.
DR   PDBsum; 9BBM; -.
DR   PDBsum; 9BXI; -.
DR   PDBsum; 9BXO; -.
DR   PDBsum; 9BXQ; -.
DR   PDBsum; 9BXR; -.
DR   PDBsum; 9CGX; -.
DR   PDBsum; 9CGZ; -.
DR   PDBsum; 9CZI; -.
DR   PDBsum; 9CZL; -.
DR   PDBsum; 9DME; -.
DR   PDBsum; 9EO7; -.
DR   PDBsum; 9EO9; -.
DR   PDBsum; 9EOE; -.
DR   PDBsum; 9EOG; -.
DR   PDBsum; 9EOH; -.
DR   PDBsum; 9ERM; -.
DR   PDBsum; 9ERN; -.
DR   PDBsum; 9ERO; -.
DR   PDBsum; 9G13; -.
DR   PDBsum; 9GG0; -.
DR   PDBsum; 9GG1; -.
DR   PDBsum; 9GG6; -.
DR   PDBsum; 9H5G; -.
DR   PDBsum; 9H5J; -.
DR   PDBsum; 9HBB; -.
DR   PDBsum; 9MR8; -.
DR   AlphaFoldDB; P10636; -.
DR   BMRB; P10636; -.
DR   EMDB; EMD-0077; -.
DR   EMDB; EMD-0259; -.
DR   EMDB; EMD-0260; -.
DR   EMDB; EMD-0527; -.
DR   EMDB; EMD-0528; -.
DR   EMDB; EMD-10512; -.
DR   EMDB; EMD-10514; -.
DR   EMDB; EMD-12549; -.
DR   EMDB; EMD-12550; -.
DR   EMDB; EMD-12551; -.
DR   EMDB; EMD-12552; -.
DR   EMDB; EMD-12553; -.
DR   EMDB; EMD-13218; -.
DR   EMDB; EMD-13219; -.
DR   EMDB; EMD-13220; -.
DR   EMDB; EMD-13221; -.
DR   EMDB; EMD-13223; -.
DR   EMDB; EMD-13224; -.
DR   EMDB; EMD-13225; -.
DR   EMDB; EMD-13226; -.
DR   EMDB; EMD-13227; -.
DR   EMDB; EMD-14023; -.
DR   EMDB; EMD-14024; -.
DR   EMDB; EMD-14025; -.
DR   EMDB; EMD-14026; -.
DR   EMDB; EMD-14027; -.
DR   EMDB; EMD-14028; -.
DR   EMDB; EMD-14029; -.
DR   EMDB; EMD-14030; -.
DR   EMDB; EMD-14038; -.
DR   EMDB; EMD-14039; -.
DR   EMDB; EMD-14040; -.
DR   EMDB; EMD-14041; -.
DR   EMDB; EMD-14042; -.
DR   EMDB; EMD-14043; -.
DR   EMDB; EMD-14044; -.
DR   EMDB; EMD-14045; -.
DR   EMDB; EMD-14046; -.
DR   EMDB; EMD-14047; -.
DR   EMDB; EMD-14053; -.
DR   EMDB; EMD-14054; -.
DR   EMDB; EMD-14055; -.
DR   EMDB; EMD-14056; -.
DR   EMDB; EMD-14057; -.
DR   EMDB; EMD-14058; -.
DR   EMDB; EMD-14059; -.
DR   EMDB; EMD-14060; -.
DR   EMDB; EMD-14061; -.
DR   EMDB; EMD-14062; -.
DR   EMDB; EMD-14063; -.
DR   EMDB; EMD-14316; -.
DR   EMDB; EMD-14320; -.
DR   EMDB; EMD-15772; -.
DR   EMDB; EMD-16035; -.
DR   EMDB; EMD-16039; -.
DR   EMDB; EMD-16329; -.
DR   EMDB; EMD-16532; -.
DR   EMDB; EMD-16535; -.
DR   EMDB; EMD-16876; -.
DR   EMDB; EMD-16881; -.
DR   EMDB; EMD-16883; -.
DR   EMDB; EMD-16886; -.
DR   EMDB; EMD-17121; -.
DR   EMDB; EMD-17122; -.
DR   EMDB; EMD-17123; -.
DR   EMDB; EMD-17171; -.
DR   EMDB; EMD-17173; -.
DR   EMDB; EMD-17174; -.
DR   EMDB; EMD-17178; -.
DR   EMDB; EMD-17179; -.
DR   EMDB; EMD-17180; -.
DR   EMDB; EMD-17181; -.
DR   EMDB; EMD-17383; -.
DR   EMDB; EMD-17806; -.
DR   EMDB; EMD-18070; -.
DR   EMDB; EMD-18109; -.
DR   EMDB; EMD-18111; -.
DR   EMDB; EMD-18112; -.
DR   EMDB; EMD-18215; -.
DR   EMDB; EMD-18219; -.
DR   EMDB; EMD-18224; -.
DR   EMDB; EMD-18228; -.
DR   EMDB; EMD-18233; -.
DR   EMDB; EMD-18249; -.
DR   EMDB; EMD-18250; -.
DR   EMDB; EMD-18251; -.
DR   EMDB; EMD-18252; -.
DR   EMDB; EMD-18253; -.
DR   EMDB; EMD-18254; -.
DR   EMDB; EMD-18255; -.
DR   EMDB; EMD-18258; -.
DR   EMDB; EMD-18259; -.
DR   EMDB; EMD-18261; -.
DR   EMDB; EMD-18262; -.
DR   EMDB; EMD-18263; -.
DR   EMDB; EMD-18264; -.
DR   EMDB; EMD-18265; -.
DR   EMDB; EMD-18266; -.
DR   EMDB; EMD-18268; -.
DR   EMDB; EMD-18270; -.
DR   EMDB; EMD-18271; -.
DR   EMDB; EMD-18272; -.
DR   EMDB; EMD-18273; -.
DR   EMDB; EMD-18275; -.
DR   EMDB; EMD-18276; -.
DR   EMDB; EMD-18277; -.
DR   EMDB; EMD-18278; -.
DR   EMDB; EMD-18279; -.
DR   EMDB; EMD-18280; -.
DR   EMDB; EMD-18281; -.
DR   EMDB; EMD-18282; -.
DR   EMDB; EMD-18283; -.
DR   EMDB; EMD-18284; -.
DR   EMDB; EMD-18285; -.
DR   EMDB; EMD-18286; -.
DR   EMDB; EMD-18287; -.
DR   EMDB; EMD-18331; -.
DR   EMDB; EMD-18333; -.
DR   EMDB; EMD-18448; -.
DR   EMDB; EMD-18874; -.
DR   EMDB; EMD-18990; -.
DR   EMDB; EMD-19846; -.
DR   EMDB; EMD-19849; -.
DR   EMDB; EMD-19852; -.
DR   EMDB; EMD-19854; -.
DR   EMDB; EMD-19855; -.
DR   EMDB; EMD-19926; -.
DR   EMDB; EMD-19927; -.
DR   EMDB; EMD-19928; -.
DR   EMDB; EMD-21200; -.
DR   EMDB; EMD-21201; -.
DR   EMDB; EMD-21207; -.
DR   EMDB; EMD-26268; -.
DR   EMDB; EMD-29458; -.
DR   EMDB; EMD-33934; -.
DR   EMDB; EMD-33999; -.
DR   EMDB; EMD-35403; -.
DR   EMDB; EMD-35404; -.
DR   EMDB; EMD-35405; -.
DR   EMDB; EMD-35406; -.
DR   EMDB; EMD-35407; -.
DR   EMDB; EMD-35408; -.
DR   EMDB; EMD-35409; -.
DR   EMDB; EMD-3741; -.
DR   EMDB; EMD-3742; -.
DR   EMDB; EMD-3743; -.
DR   EMDB; EMD-3744; -.
DR   EMDB; EMD-40411; -.
DR   EMDB; EMD-40413; -.
DR   EMDB; EMD-41610; -.
DR   EMDB; EMD-41611; -.
DR   EMDB; EMD-42463; -.
DR   EMDB; EMD-42886; -.
DR   EMDB; EMD-44133; -.
DR   EMDB; EMD-44134; -.
DR   EMDB; EMD-44184; -.
DR   EMDB; EMD-44185; -.
DR   EMDB; EMD-44186; -.
DR   EMDB; EMD-44187; -.
DR   EMDB; EMD-44421; -.
DR   EMDB; EMD-44422; -.
DR   EMDB; EMD-45005; -.
DR   EMDB; EMD-45007; -.
DR   EMDB; EMD-45008; -.
DR   EMDB; EMD-45009; -.
DR   EMDB; EMD-45588; -.
DR   EMDB; EMD-45589; -.
DR   EMDB; EMD-4563; -.
DR   EMDB; EMD-4565; -.
DR   EMDB; EMD-4566; -.
DR   EMDB; EMD-46417; -.
DR   EMDB; EMD-46420; -.
DR   EMDB; EMD-46689; -.
DR   EMDB; EMD-47002; -.
DR   EMDB; EMD-48555; -.
DR   EMDB; EMD-50148; -.
DR   EMDB; EMD-50152; -.
DR   EMDB; EMD-50153; -.
DR   EMDB; EMD-50155; -.
DR   EMDB; EMD-50156; -.
DR   EMDB; EMD-50157; -.
DR   EMDB; EMD-50159; -.
DR   EMDB; EMD-50160; -.
DR   EMDB; EMD-50161; -.
DR   EMDB; EMD-50162; -.
DR   EMDB; EMD-50441; -.
DR   EMDB; EMD-51319; -.
DR   EMDB; EMD-51320; -.
DR   EMDB; EMD-51325; -.
DR   EMDB; EMD-51884; -.
DR   EMDB; EMD-51886; -.
DR   EMDB; EMD-52014; -.
DR   EMDB; EMD-53527; -.
DR   EMDB; EMD-53530; -.
DR   EMDB; EMD-54485; -.
DR   EMDB; EMD-60531; -.
DR   EMDB; EMD-60532; -.
DR   EMDB; EMD-60533; -.
DR   EMDB; EMD-60539; -.
DR   EMDB; EMD-71636; -.
DR   EMDB; EMD-7520; -.
DR   EMDB; EMD-7522; -.
DR   EMDB; EMD-7523; -.
DR   EMDB; EMD-7769; -.
DR   EMDB; EMD-7771; -.
DR   EMDB; EMD-8634; -.
DR   EMDB; EMD-8635; -.
DR   SASBDB; P10636; -.
DR   SMR; P10636; -.
DR   BioGRID; 110308; 1104.
DR   CORUM; P10636; -.
DR   DIP; DIP-29753N; -.
DR   ELM; P10636; -.
DR   FunCoup; P10636; 523.
DR   IntAct; P10636; 2082.
DR   MINT; P10636; -.
DR   STRING; 9606.ENSP00000340820; -.
DR   BindingDB; P10636; -.
DR   ChEMBL; CHEMBL1293224; -.
DR   DrugBank; DB00637; Astemizole.
DR   DrugBank; DB15033; Flortaucipir.
DR   DrugBank; DB14914; Flortaucipir F-18.
DR   DrugBank; DB00448; Lansoprazole.
DR   DrugBank; DB05565; PBT-1033.
DR   DrugCentral; P10636; -.
DR   GlyConnect; 2885; 1 O-GlcNAc glycan (6 sites).
DR   GlyCosmos; P10636; 34 sites, 1 glycan.
DR   GlyGen; P10636; 12 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (6 sites).
DR   iPTMnet; P10636; -.
DR   MetOSite; P10636; -.
DR   PhosphoSitePlus; P10636; -.
DR   SwissPalm; P10636; -.
DR   BioMuta; MAPT; -.
DR   DMDM; 334302961; -.
DR   jPOST; P10636; -.
DR   MassIVE; P10636; -.
DR   PaxDb; 9606-ENSP00000340820; -.
DR   PeptideAtlas; P10636; -.
DR   ProteomicsDB; 52624; -. [P10636-1]
DR   ProteomicsDB; 52625; -. [P10636-2]
DR   ProteomicsDB; 52626; -. [P10636-3]
DR   ProteomicsDB; 52627; -. [P10636-4]
DR   ProteomicsDB; 52628; -. [P10636-5]
DR   ProteomicsDB; 52629; -. [P10636-6]
DR   ProteomicsDB; 52630; -. [P10636-7]
DR   ProteomicsDB; 52631; -. [P10636-8]
DR   ProteomicsDB; 52632; -. [P10636-9]
DR   Pumba; P10636; -.
DR   TopDownProteomics; P10636-3; -. [P10636-3]
DR   ABCD; P10636; 86 sequenced antibodies.
DR   Antibodypedia; 3124; 5679 antibodies from 54 providers.
DR   DNASU; 4137; -.
DR   Ensembl; ENST00000334239.12; ENSP00000334886.8; ENSG00000186868.19. [P10636-2]
DR   Ensembl; ENST00000351559.10; ENSP00000303214.7; ENSG00000186868.19. [P10636-8]
DR   Ensembl; ENST00000415613.6; ENSP00000410838.2; ENSG00000186868.19. [P10636-9]
DR   Ensembl; ENST00000420682.7; ENSP00000413056.2; ENSG00000186868.19. [P10636-7]
DR   Ensembl; ENST00000431008.7; ENSP00000389250.3; ENSG00000186868.19. [P10636-5]
DR   Ensembl; ENST00000446361.7; ENSP00000408975.3; ENSG00000186868.19. [P10636-6]
DR   Ensembl; ENST00000535772.6; ENSP00000443028.2; ENSG00000186868.19. [P10636-4]
DR   Ensembl; ENST00000571987.5; ENSP00000458742.1; ENSG00000186868.19. [P10636-1]
DR   Ensembl; ENST00000574436.5; ENSP00000460965.1; ENSG00000186868.19. [P10636-8]
DR   Ensembl; ENST00000612872.4; ENSP00000478602.1; ENSG00000277956.4. [P10636-7]
DR   Ensembl; ENST00000613360.4; ENSP00000483784.1; ENSG00000276155.4. [P10636-7]
DR   Ensembl; ENST00000620070.4; ENSP00000484491.1; ENSG00000277956.4. [P10636-8]
DR   Ensembl; ENST00000620818.4; ENSP00000484321.1; ENSG00000277956.4. [P10636-5]
DR   Ensembl; ENST00000620981.4; ENSP00000481769.1; ENSG00000276155.4. [P10636-5]
DR   Ensembl; ENST00000621329.4; ENSP00000477703.1; ENSG00000276155.4. [P10636-8]
DR   Ensembl; ENST00000622106.2; ENSP00000482244.1; ENSG00000277956.4. [P10636-6]
DR   Ensembl; ENST00000622728.1; ENSP00000479142.1; ENSG00000276155.4. [P10636-6]
DR   Ensembl; ENST00000626571.2; ENSP00000486039.1; ENSG00000276155.4. [P10636-6]
DR   Ensembl; ENST00000628393.2; ENSP00000487570.1; ENSG00000276155.4. [P10636-2]
DR   Ensembl; ENST00000631447.1; ENSP00000488373.1; ENSG00000277956.4. [P10636-5]
DR   Ensembl; ENST00000632500.1; ENSP00000487837.1; ENSG00000277956.4. [P10636-7]
DR   Ensembl; ENST00000633047.1; ENSP00000488245.1; ENSG00000277956.4. [P10636-2]
DR   Ensembl; ENST00000634049.1; ENSP00000487819.1; ENSG00000277956.4. [P10636-8]
DR   Ensembl; ENST00000680542.1; ENSP00000505258.1; ENSG00000186868.19. [P10636-7]
DR   Ensembl; ENST00000703922.1; ENSP00000515557.1; ENSG00000186868.19. [P10636-7]
DR   Ensembl; ENST00000703923.1; ENSP00000515558.1; ENSG00000186868.19. [P10636-6]
DR   Ensembl; ENST00000703924.1; ENSP00000515559.1; ENSG00000186868.19. [P10636-7]
DR   Ensembl; ENST00000703978.1; ENSP00000515600.1; ENSG00000186868.19. [P10636-8]
DR   GeneID; 4137; -.
DR   KEGG; hsa:4137; -.
DR   UCSC; uc002ijr.5; human. [P10636-1]
DR   AGR; HGNC:6893; -.
DR   ClinPGx; PA238; -.
DR   CTD; 4137; -.
DR   DisGeNET; 4137; -.
DR   GeneCards; MAPT; -.
DR   GeneReviews; MAPT; -.
DR   HGNC; HGNC:6893; MAPT.
DR   HPA; ENSG00000186868; Tissue enhanced (brain, skeletal muscle).
DR   MalaCards; MAPT; -.
DR   MIM; 157140; gene+phenotype.
DR   MIM; 172700; phenotype.
DR   MIM; 260540; phenotype.
DR   MIM; 600274; phenotype.
DR   MIM; 601104; phenotype.
DR   OpenTargets; ENSG00000186868; -.
DR   Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR   Orphanet; 240071; Classic progressive supranuclear palsy syndrome.
DR   Orphanet; 100070; Progressive non-fluent aphasia.
DR   Orphanet; 240103; Progressive supranuclear palsy-corticobasal syndrome.
DR   Orphanet; 240085; Progressive supranuclear palsy-predominant parkinsonism syndrome.
DR   Orphanet; 240112; Progressive supranuclear palsy-progressive non-fluent aphasia syndrome.
DR   Orphanet; 240094; Progressive supranuclear palsy-pure akinesia with gait freezing syndrome.
DR   Orphanet; 100069; Semantic dementia.
DR   VEuPathDB; HostDB:ENSG00000186868; -.
DR   eggNOG; KOG2418; Eukaryota.
DR   GeneTree; ENSGT00940000155494; -.
DR   HOGENOM; CLU_021741_2_0_1; -.
DR   InParanoid; P10636; -.
DR   OrthoDB; 9378527at2759; -.
DR   PAN-GO; P10636; 4 GO annotations based on evolutionary models.
DR   PathwayCommons; P10636; -.
DR   Reactome; R-HSA-264870; Caspase-mediated cleavage of cytoskeletal proteins.
DR   Reactome; R-HSA-9619483; Activation of AMPK downstream of NMDARs. [P10636-8]
DR   Reactome; R-HSA-9833482; PKR-mediated signaling. [P10636-8]
DR   SABIO-RK; P10636; -.
DR   SignaLink; P10636; -.
DR   SIGNOR; P10636; -.
DR   Agora; ENSG00000186868; -.
DR   BioGRID-ORCS; 4137; 23 hits in 1151 CRISPR screens.
DR   CD-CODE; 03D56D03; Tau inclusion.
DR   CD-CODE; 24B12ACB; Synthetic Condensate 000346.
DR   CD-CODE; 804901D1; Nuclear speckle.
DR   CD-CODE; 8188F968; Tau-Prion Multiphasic condensate.
DR   CD-CODE; 8C2F96ED; Centrosome.
DR   CD-CODE; DEE660B4; Stress granule.
DR   CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities.
DR   ChiTaRS; MAPT; human.
DR   EvolutionaryTrace; P10636; -.
DR   GeneWiki; Tau_protein; -.
DR   GenomeRNAi; 4137; -.
DR   Pharos; P10636; Tclin.
DR   PRO; PR:P10636; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; P10636; protein.
DR   Bgee; ENSG00000186868; Expressed in cortical plate and 104 other cell types or tissues.
DR   ExpressionAtlas; P10636; baseline and differential.
DR   GO; GO:0030673; C:axolemma; IDA:CAFA.
DR   GO; GO:0030424; C:axon; IDA:UniProtKB.
DR   GO; GO:1904115; C:axon cytoplasm; IEA:GOC.
DR   GO; GO:0044297; C:cell body; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005829; C:cytosol; IDA:CAFA.
DR   GO; GO:0030425; C:dendrite; IDA:UniProtKB.
DR   GO; GO:0043197; C:dendritic spine; TAS:ARUK-UCL.
DR   GO; GO:0005576; C:extracellular region; NAS:ARUK-UCL.
DR   GO; GO:0097386; C:glial cell projection; ISS:ARUK-UCL.
DR   GO; GO:0030426; C:growth cone; IDA:UniProtKB.
DR   GO; GO:0044304; C:main axon; ISS:ARUK-UCL.
DR   GO; GO:0045121; C:membrane raft; ISS:ARUK-UCL.
DR   GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
DR   GO; GO:0015630; C:microtubule cytoskeleton; IDA:CAFA.
DR   GO; GO:0005739; C:mitochondrion; TAS:ARUK-UCL.
DR   GO; GO:0097418; C:neurofibrillary tangle; IDA:CAFA.
DR   GO; GO:0043005; C:neuron projection; IBA:GO_Central.
DR   GO; GO:0043025; C:neuronal cell body; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0034399; C:nuclear periphery; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; ISS:ParkinsonsUK-UCL.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0036477; C:somatodendritic compartment; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0045298; C:tubulin complex; IDA:UniProtKB.
DR   GO; GO:0003779; F:actin binding; TAS:ARUK-UCL.
DR   GO; GO:0034185; F:apolipoprotein binding; IPI:BHF-UCL.
DR   GO; GO:0003677; F:DNA binding; ISS:ParkinsonsUK-UCL.
DR   GO; GO:0003690; F:double-stranded DNA binding; TAS:ARUK-UCL.
DR   GO; GO:0034452; F:dynactin binding; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR   GO; GO:0004857; F:enzyme inhibitor activity; IDA:ARUK-UCL.
DR   GO; GO:0099077; F:histone-dependent DNA binding; TAS:ARUK-UCL.
DR   GO; GO:0051879; F:Hsp90 protein binding; IPI:ARUK-UCL.
DR   GO; GO:0042802; F:identical protein binding; IDA:CAFA.
DR   GO; GO:0071813; F:lipoprotein particle binding; IPI:UniProtKB.
DR   GO; GO:0008017; F:microtubule binding; IDA:UniProtKB.
DR   GO; GO:0099609; F:microtubule lateral binding; IMP:CAFA.
DR   GO; GO:0003680; F:minor groove of adenine-thymine-rich DNA binding; TAS:ARUK-UCL.
DR   GO; GO:0035091; F:phosphatidylinositol binding; TAS:ARUK-UCL.
DR   GO; GO:1902936; F:phosphatidylinositol bisphosphate binding; TAS:ARUK-UCL.
DR   GO; GO:0019901; F:protein kinase binding; IPI:ARUK-UCL.
DR   GO; GO:0051721; F:protein phosphatase 2A binding; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0051087; F:protein-folding chaperone binding; IPI:ARUK-UCL.
DR   GO; GO:0030674; F:protein-macromolecule adaptor activity; TAS:ARUK-UCL.
DR   GO; GO:0003723; F:RNA binding; TAS:ARUK-UCL.
DR   GO; GO:0043565; F:sequence-specific DNA binding; TAS:ARUK-UCL.
DR   GO; GO:0017124; F:SH3 domain binding; IPI:UniProtKB.
DR   GO; GO:0003697; F:single-stranded DNA binding; TAS:ARUK-UCL.
DR   GO; GO:1990000; P:amyloid fibril formation; IDA:DisProt.
DR   GO; GO:0048143; P:astrocyte activation; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0061564; P:axon development; TAS:ARUK-UCL.
DR   GO; GO:0098930; P:axonal transport; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0019896; P:axonal transport of mitochondrion; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0007267; P:cell-cell signaling; NAS:ARUK-UCL.
DR   GO; GO:1990416; P:cellular response to brain-derived neurotrophic factor stimulus; TAS:ARUK-UCL.
DR   GO; GO:0034605; P:cellular response to heat; TAS:ParkinsonsUK-UCL.
DR   GO; GO:1990090; P:cellular response to nerve growth factor stimulus; TAS:ARUK-UCL.
DR   GO; GO:0034614; P:cellular response to reactive oxygen species; TAS:ARUK-UCL.
DR   GO; GO:0021954; P:central nervous system neuron development; TAS:ARUK-UCL.
DR   GO; GO:0031122; P:cytoplasmic microtubule organization; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0006974; P:DNA damage response; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0048699; P:generation of neurons; NAS:UniProtKB.
DR   GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0007611; P:learning or memory; IMP:ARUK-UCL.
DR   GO; GO:0007613; P:memory; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0001774; P:microglial cell activation; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0000226; P:microtubule cytoskeleton organization; IDA:UniProtKB.
DR   GO; GO:0046785; P:microtubule polymerization; IDA:ARUK-UCL.
DR   GO; GO:1903748; P:negative regulation of establishment of protein localization to mitochondrion; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0010629; P:negative regulation of gene expression; IMP:ARUK-UCL.
DR   GO; GO:0090258; P:negative regulation of mitochondrial fission; IMP:ARUK-UCL.
DR   GO; GO:0010917; P:negative regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL.
DR   GO; GO:1902988; P:neurofibrillary tangle assembly; NAS:ParkinsonsUK-UCL.
DR   GO; GO:0031175; P:neuron projection development; IBA:GO_Central.
DR   GO; GO:0072386; P:plus-end-directed organelle transport along microtubule; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0045773; P:positive regulation of axon extension; IDA:UniProtKB.
DR   GO; GO:0031116; P:positive regulation of microtubule polymerization; IDA:UniProtKB.
DR   GO; GO:1903829; P:positive regulation of protein localization; IMP:CAFA.
DR   GO; GO:1902474; P:positive regulation of protein localization to synapse; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0032930; P:positive regulation of superoxide anion generation; IMP:ARUK-UCL.
DR   GO; GO:0051260; P:protein homooligomerization; IPI:ARUK-UCL.
DR   GO; GO:0051258; P:protein polymerization; IMP:UniProtKB.
DR   GO; GO:0010506; P:regulation of autophagy; IGI:MGI.
DR   GO; GO:0050848; P:regulation of calcium-mediated signaling; IDA:ARUK-UCL.
DR   GO; GO:1900034; P:regulation of cellular response to heat; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0033044; P:regulation of chromosome organization; TAS:ARUK-UCL.
DR   GO; GO:1900452; P:regulation of long-term synaptic depression; TAS:ARUK-UCL.
DR   GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IMP:CAFA.
DR   GO; GO:0031113; P:regulation of microtubule polymerization; TAS:ARUK-UCL.
DR   GO; GO:0031110; P:regulation of microtubule polymerization or depolymerization; IMP:CAFA.
DR   GO; GO:0060632; P:regulation of microtubule-based movement; IGI:ARUK-UCL.
DR   GO; GO:0090140; P:regulation of mitochondrial fission; IC:ParkinsonsUK-UCL.
DR   GO; GO:0048167; P:regulation of synaptic plasticity; TAS:ARUK-UCL.
DR   GO; GO:0010288; P:response to lead ion; ISS:ARUK-UCL.
DR   GO; GO:0016072; P:rRNA metabolic process; TAS:ARUK-UCL.
DR   GO; GO:0034063; P:stress granule assembly; TAS:ARUK-UCL.
DR   GO; GO:0097435; P:supramolecular fiber organization; IDA:CAFA.
DR   GO; GO:0007416; P:synapse assembly; IMP:ARUK-UCL.
DR   GO; GO:0050808; P:synapse organization; IMP:ParkinsonsUK-UCL.
DR   DisProt; DP01100; -. [P10636-8]
DR   DisProt; DP03552; -. [P10636-2]
DR   InterPro; IPR027324; MAP2/MAP4/Tau.
DR   InterPro; IPR001084; MAP_tubulin-bd_rpt.
DR   InterPro; IPR002955; Tau.
DR   PANTHER; PTHR11501; MICROTUBULE-ASSOCIATED PROTEIN; 1.
DR   PANTHER; PTHR11501:SF14; MICROTUBULE-ASSOCIATED PROTEIN TAU; 1.
DR   Pfam; PF00418; Tubulin-binding; 4.
DR   PRINTS; PR01261; TAUPROTEIN.
DR   PROSITE; PS00229; TAU_MAP_1; 4.
DR   PROSITE; PS51491; TAU_MAP_2; 4.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Alzheimer disease;
KW   Cell membrane; Cell projection; Cytoplasm; Cytoskeleton;
KW   Direct protein sequencing; Disease variant; Disulfide bond; Glycation;
KW   Glycoprotein; Isopeptide bond; Membrane; Methylation; Microtubule;
KW   Neurodegeneration; Parkinsonism; Phosphoprotein; Proteomics identification;
KW   Reference proteome; Repeat; Secreted; Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:1512244"
FT   CHAIN           2..758
FT                   /note="Microtubule-associated protein tau"
FT                   /id="PRO_0000072739"
FT   REPEAT          561..591
FT                   /note="Tau/MAP 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00824,
FT                   ECO:0000305|PubMed:7706316"
FT   REPEAT          592..622
FT                   /note="Tau/MAP 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00824,
FT                   ECO:0000305|PubMed:7706316"
FT   REPEAT          623..653
FT                   /note="Tau/MAP 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00824,
FT                   ECO:0000305|PubMed:7706316"
FT   REPEAT          654..685
FT                   /note="Tau/MAP 4"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00824,
FT                   ECO:0000305|PubMed:7706316"
FT   REGION          1..573
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          561..685
FT                   /note="Microtubule-binding domain"
FT                   /evidence="ECO:0000269|PubMed:7706316"
FT   REGION          715..734
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..26
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        61..71
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        179..189
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        207..216
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        217..228
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        314..323
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        324..340
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        344..356
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        381..393
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        442..453
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        455..466
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        491..503
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        504..531
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        718..733
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            24
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            44
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            67
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            381
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            391
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            392
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            394
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            465
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            497
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            507
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            541
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            557
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            571
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            574
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            584
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            591
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            607
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            611
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            615
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            628
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            634
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            638
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            648
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            657
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            660
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            687
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            692
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            700
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            702
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            712
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   SITE            755
FT                   /note="Not glycated"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0000269|PubMed:1512244"
FT   MOD_RES         18
FT                   /note="Phosphotyrosine; by FYN"
FT                   /evidence="ECO:0000269|PubMed:14999081"
FT   MOD_RES         29
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         46
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P19332"
FT   MOD_RES         61
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P19332"
FT   MOD_RES         69
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         71
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P19332"
FT   MOD_RES         111
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         214
FT                   /note="Phosphoserine; by SGK1"
FT                   /evidence="ECO:0000269|PubMed:16982696"
FT   MOD_RES         470
FT                   /note="Phosphothreonine; by PDPK1"
FT                   /evidence="ECO:0000269|PubMed:9614189"
FT   MOD_RES         472
FT                   /note="Omega-N-methylarginine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         480
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         480
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         484
FT                   /note="Deamidated asparagine; in tau and PHF-tau; partial"
FT                   /evidence="ECO:0000269|PubMed:1512244"
FT   MOD_RES         486
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         492
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         498
FT                   /note="Phosphothreonine; by PDPK1"
FT                   /evidence="ECO:0000269|PubMed:15546861"
FT   MOD_RES         502
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         508
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         512
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         514
FT                   /note="Phosphotyrosine; by TTBK1"
FT                   /evidence="ECO:0000269|PubMed:16923168"
FT   MOD_RES         515
FT                   /note="Phosphoserine; by PDPK1 and TTBK1"
FT                   /evidence="ECO:0000269|PubMed:16923168"
FT   MOD_RES         516
FT                   /note="Phosphoserine; by PDPK1 and TTBK1"
FT                   /evidence="ECO:0000269|PubMed:15546861,
FT                   ECO:0000269|PubMed:16923168, ECO:0000269|PubMed:19451179,
FT                   ECO:0000269|PubMed:9614189"
FT   MOD_RES         519
FT                   /note="Phosphoserine; by CK1, PDPK1 and TTBK1"
FT                   /evidence="ECO:0000269|PubMed:14761950,
FT                   ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16923168,
FT                   ECO:0000269|PubMed:19451179, ECO:0000269|PubMed:21327254,
FT                   ECO:0000269|PubMed:9614189, ECO:0007744|PubMed:18220336,
FT                   ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT   MOD_RES         522
FT                   /note="Phosphothreonine; by CK1 and PDPK1"
FT                   /evidence="ECO:0000269|PubMed:14761950,
FT                   ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:19451179"
FT   MOD_RES         529
FT                   /note="Phosphothreonine; by BRSK1, BRSK2, DYRK2 and PDPK1"
FT                   /evidence="ECO:0000269|PubMed:15546861,
FT                   ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19451179,
FT                   ECO:0000269|PubMed:21985311, ECO:0000269|PubMed:9614189"
FT   MOD_RES         531
FT                   /note="Phosphoserine; by PKA"
FT                   /evidence="ECO:0000269|PubMed:15546861,
FT                   ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179,
FT                   ECO:0000269|PubMed:9614189"
FT   MOD_RES         534
FT                   /note="Phosphothreonine; by PDPK1"
FT                   /evidence="ECO:0000269|PubMed:16443603,
FT                   ECO:0000269|PubMed:19451179"
FT   MOD_RES         542
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         548
FT                   /note="Phosphothreonine; by GSK3-beta and PDPK1"
FT                   /evidence="ECO:0000269|PubMed:14690523,
FT                   ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         552
FT                   /note="Phosphoserine; by PDPK1"
FT                   /evidence="ECO:0000269|PubMed:15546861,
FT                   ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:9614189,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         554
FT                   /note="Phosphoserine; by PHK"
FT                   /evidence="ECO:0000269|PubMed:16443603,
FT                   ECO:0000269|PubMed:8999860"
FT   MOD_RES         576
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         576
FT                   /note="N6-methyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         579
FT                   /note="Phosphoserine; by MARK1, MARK2, MARK3, MARK4, BRSK1,
FT                   BRSK2 and PHK"
FT                   /evidence="ECO:0000269|PubMed:15546861,
FT                   ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179,
FT                   ECO:0000269|PubMed:21985311, ECO:0000269|PubMed:23666762,
FT                   ECO:0000269|PubMed:7706316, ECO:0000269|PubMed:8999860,
FT                   ECO:0000269|PubMed:9614189"
FT   MOD_RES         596
FT                   /note="Deamidated asparagine; in tau and PHF-tau; partial"
FT                   /evidence="ECO:0000269|PubMed:1512244"
FT   MOD_RES         598
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         602
FT                   /note="Phosphoserine; by PHK"
FT                   /evidence="ECO:0000269|PubMed:8999860"
FT   MOD_RES         607
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         610
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:7706316"
FT   MOD_RES         615
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         622
FT                   /note="Phosphoserine; by PHK"
FT                   /evidence="ECO:0000269|PubMed:7706316,
FT                   ECO:0000269|PubMed:8999860"
FT   MOD_RES         628
FT                   /note="N6,N6-dimethyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         628
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         634
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         638
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         641
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:7706316"
FT   MOD_RES         648
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         660
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         664
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         666
FT                   /note="Omega-N-methylarginine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         669
FT                   /note="Phosphoserine; by PHK"
FT                   /evidence="ECO:0000269|PubMed:8999860"
FT   MOD_RES         673
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:7706316"
FT   MOD_RES         686
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         702
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         711
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         713
FT                   /note="Phosphoserine; by CK1 and PDPK1"
FT                   /evidence="ECO:0000269|PubMed:14761950,
FT                   ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603,
FT                   ECO:0000269|PubMed:1899488, ECO:0000269|PubMed:19451179,
FT                   ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189,
FT                   ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT   MOD_RES         717
FT                   /note="Phosphoserine; alternate"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         720
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   MOD_RES         721
FT                   /note="Phosphoserine; by CK1 and PDPK1"
FT                   /evidence="ECO:0000269|PubMed:14761950,
FT                   ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:19451179,
FT                   ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189,
FT                   ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT   MOD_RES         726
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:15546861,
FT                   ECO:0007744|PubMed:19690332"
FT   MOD_RES         733
FT                   /note="Phosphoserine; by CaMK2 and TTBK1"
FT                   /evidence="ECO:0000269|PubMed:16923168"
FT   MOD_RES         739
FT                   /note="Phosphoserine; by PDPK1 and TTBK1"
FT                   /evidence="ECO:0000269|PubMed:16443603,
FT                   ECO:0000269|PubMed:16923168, ECO:0000269|PubMed:19451179,
FT                   ECO:0000269|PubMed:9614189"
FT   MOD_RES         744
FT                   /note="Phosphothreonine; by TTBK1"
FT                   /evidence="ECO:0000269|PubMed:16923168"
FT   CARBOHYD        87
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        383
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        467
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        480
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        491
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        525
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:21327254"
FT   CARBOHYD        542
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        551
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        555
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:21327254"
FT   CARBOHYD        576
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        597
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        598
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        664
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        670
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        686
FT                   /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in
FT                   vitro"
FT                   /evidence="ECO:0000269|PubMed:9326300"
FT   CARBOHYD        717
FT                   /note="O-linked (GlcNAc) serine; alternate"
FT                   /evidence="ECO:0000269|PubMed:21327254"
FT   DISULFID        608..639
FT                   /evidence="ECO:0000250"
FT   CROSSLNK        44
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        571
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); in PHF-tau"
FT                   /evidence="ECO:0000269|PubMed:16443603"
FT   CROSSLNK        576
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        584
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        598
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        615
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        628
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); in PHF-tau"
FT                   /evidence="ECO:0000269|PubMed:16443603"
FT   CROSSLNK        634
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        638
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        648
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        660
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        664
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        670
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); in PHF-tau"
FT                   /evidence="ECO:0000269|PubMed:16443603"
FT   CROSSLNK        686
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        692
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   CROSSLNK        702
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P10637"
FT   VAR_SEQ         1..44
FT                   /note="MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLK -> MLRA
FT                   LQQRKR (in isoform Tau-A)"
FT                   /evidence="ECO:0000303|PubMed:2516729"
FT                   /id="VSP_003175"
FT   VAR_SEQ         45..73
FT                   /note="Missing (in isoform Tau-A, isoform Tau-D and isoform
FT                   Fetal-tau)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:2498079, ECO:0000303|PubMed:2516729,
FT                   ECO:0000303|PubMed:3131773, ECO:0000303|Ref.7"
FT                   /id="VSP_003176"
FT   VAR_SEQ         74..102
FT                   /note="Missing (in isoform Tau-A, isoform Tau-B, isoform
FT                   Tau-D, isoform Tau-E and isoform Fetal-tau)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079,
FT                   ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773,
FT                   ECO:0000303|Ref.6, ECO:0000303|Ref.7"
FT                   /id="VSP_003177"
FT   VAR_SEQ         103..104
FT                   /note="Missing (in isoform Tau-A)"
FT                   /evidence="ECO:0000303|PubMed:2516729"
FT                   /id="VSP_003178"
FT   VAR_SEQ         125..375
FT                   /note="Missing (in isoform Tau-A, isoform Tau-B, isoform
FT                   Tau-C, isoform Tau-D, isoform Tau-E, isoform Tau-F and
FT                   isoform Fetal-tau)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079,
FT                   ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773,
FT                   ECO:0000303|Ref.6, ECO:0000303|Ref.7"
FT                   /id="VSP_003179"
FT   VAR_SEQ         395..460
FT                   /note="Missing (in isoform Tau-A, isoform Tau-B, isoform
FT                   Tau-C, isoform Tau-D, isoform Tau-E, isoform Tau-F and
FT                   isoform Fetal-tau)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079,
FT                   ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773,
FT                   ECO:0000303|Ref.6, ECO:0000303|Ref.7"
FT                   /id="VSP_003180"
FT   VAR_SEQ         502
FT                   /note="S -> SATKQVQRRPPPAGPRSER (in isoform Tau-G)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_026780"
FT   VAR_SEQ         592..622
FT                   /note="Missing (in isoform Tau-A, isoform Tau-B, isoform
FT                   Tau-C and isoform Fetal-tau)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2516729,
FT                   ECO:0000303|PubMed:3131773, ECO:0000303|Ref.7"
FT                   /id="VSP_003181"
FT   VARIANT         5
FT                   /note="R -> H (in FTD1; reduces the ability of tau to
FT                   promote microtubule assembly and promotes fibril formation
FT                   in vitro; dbSNP:rs63750959)"
FT                   /evidence="ECO:0000269|PubMed:11921059"
FT                   /id="VAR_019660"
FT   VARIANT         5
FT                   /note="R -> L (in PSNP1; delays assembly initiation and
FT                   lowers the mass of microtubules formed; but the assembly
FT                   rate is increased compared to normal tau;
FT                   dbSNP:rs63750959)"
FT                   /evidence="ECO:0000269|PubMed:12325083"
FT                   /id="VAR_019661"
FT   VARIANT         17
FT                   /note="T -> M (in dbSNP:rs144611688)"
FT                   /evidence="ECO:0000269|PubMed:20020531"
FT                   /id="VAR_064622"
FT   VARIANT         30
FT                   /note="T -> A (in dbSNP:rs748728879)"
FT                   /evidence="ECO:0000269|PubMed:20020531"
FT                   /id="VAR_064623"
FT   VARIANT         285
FT                   /note="D -> N (risk factor for PSNP1; dbSNP:rs62063786)"
FT                   /evidence="ECO:0000269|PubMed:10534245,
FT                   ECO:0000269|PubMed:9629852"
FT                   /id="VAR_010340"
FT   VARIANT         289
FT                   /note="V -> A (risk factor for PSNP1; dbSNP:rs62063787)"
FT                   /evidence="ECO:0000269|PubMed:10534245,
FT                   ECO:0000269|PubMed:9629852"
FT                   /id="VAR_010341"
FT   VARIANT         370
FT                   /note="R -> W (in dbSNP:rs17651549)"
FT                   /id="VAR_056121"
FT   VARIANT         441
FT                   /note="Y -> H (in dbSNP:rs2258689)"
FT                   /evidence="ECO:0000269|PubMed:1420178,
FT                   ECO:0000269|PubMed:15365985, ECO:0000269|PubMed:9629852"
FT                   /id="VAR_010342"
FT   VARIANT         447
FT                   /note="S -> P (in dbSNP:rs10445337)"
FT                   /evidence="ECO:0000269|PubMed:9629852"
FT                   /id="VAR_010343"
FT   VARIANT         574
FT                   /note="K -> T (in PIDB; reduces the ability to promote
FT                   microtubule assembly by 70%; dbSNP:rs63750129)"
FT                   /evidence="ECO:0000269|PubMed:11089577,
FT                   ECO:0000269|PubMed:11117542"
FT                   /id="VAR_010344"
FT   VARIANT         583
FT                   /note="L -> V (in FTD1; less able to promote microtubule
FT                   assembly than wild-type tau; dbSNP:rs63750349)"
FT                   /evidence="ECO:0000269|PubMed:12509859"
FT                   /id="VAR_019662"
FT   VARIANT         589
FT                   /note="G -> V (in FTD1; dbSNP:rs63750376)"
FT                   /evidence="ECO:0000269|PubMed:9641683,
FT                   ECO:0000269|PubMed:9973279"
FT                   /id="VAR_010345"
FT   VARIANT         590
FT                   /note="G -> R (in FTD1; increased aggregation propensity
FT                   and altered binding affinity towards microtubules and F-
FT                   actin; dbSNP:rs1247408229)"
FT                   /evidence="ECO:0000269|PubMed:32961270"
FT                   /id="VAR_084361"
FT   VARIANT         596
FT                   /note="N -> K (in FTD1; with parkinsonism;
FT                   dbSNP:rs63750756)"
FT                   /evidence="ECO:0000269|PubMed:10412802,
FT                   ECO:0000269|PubMed:10489057, ECO:0000269|PubMed:10802785,
FT                   ECO:0000269|PubMed:12473774, ECO:0000269|PubMed:9789048"
FT                   /id="VAR_010346"
FT   VARIANT         597
FT                   /note="Missing (in FTD1; dbSNP:rs63750688)"
FT                   /evidence="ECO:0000269|PubMed:9973279"
FT                   /id="VAR_010347"
FT   VARIANT         613
FT                   /note="N -> H (in FTD1; reduced the ability of tau to
FT                   promote microtubule assembly without having a significant
FT                   effect on tau filament formation; effects at both the RNA
FT                   and the protein level; dbSNP:rs63750416)"
FT                   /evidence="ECO:0000269|PubMed:11585254,
FT                   ECO:0000269|PubMed:11906000"
FT                   /id="VAR_019663"
FT   VARIANT         613
FT                   /note="Missing (in PSNP1/atypical PSNP1; heterozygosity may
FT                   be a risk factor for both a PSNP1-like syndrome and
FT                   Parkinson disease; reduced the ability of tau to promote
FT                   microtubule assembly without having a significant effect on
FT                   tau filament formation; effects at both the RNA and the
FT                   protein level)"
FT                   /evidence="ECO:0000269|PubMed:11220749,
FT                   ECO:0000269|PubMed:11906000, ECO:0000269|PubMed:14991828,
FT                   ECO:0000269|PubMed:14991829"
FT                   /id="VAR_019664"
FT   VARIANT         617
FT                   /note="V -> I (in dbSNP:rs116733906)"
FT                   /evidence="ECO:0000269|PubMed:20020531"
FT                   /id="VAR_064624"
FT   VARIANT         618
FT                   /note="P -> L (in FTD1; most common mutation; reduction in
FT                   the ability to promote microtubule assembly; accelerates
FT                   aggregation of tau into filaments; dbSNP:rs63751273)"
FT                   /evidence="ECO:0000269|PubMed:10214944,
FT                   ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9736786,
FT                   ECO:0000269|PubMed:9789048, ECO:0000269|PubMed:9973279"
FT                   /id="VAR_010348"
FT   VARIANT         618
FT                   /note="P -> S (in FTD1 and CBD; reduction in the ability to
FT                   promote microtubule assembly; dbSNP:rs63751438)"
FT                   /evidence="ECO:0000269|PubMed:10374757,
FT                   ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:11071507,
FT                   ECO:0000269|PubMed:16240366"
FT                   /id="VAR_010349"
FT   VARIANT         620
FT                   /note="G -> V (in PSNP1; dbSNP:rs63751391)"
FT                   /evidence="ECO:0000269|PubMed:16157753"
FT                   /id="VAR_037439"
FT   VARIANT         622
FT                   /note="S -> N (in FTD1; minimal parkinsonism; very early
FT                   age of onset; dbSNP:rs63751165)"
FT                   /evidence="ECO:0000269|PubMed:10208578"
FT                   /id="VAR_010350"
FT   VARIANT         634
FT                   /note="K -> M (in FTD1; dbSNP:rs63750092)"
FT                   /evidence="ECO:0000269|PubMed:15883319"
FT                   /id="VAR_037440"
FT   VARIANT         637
FT                   /note="S -> F (in PIDB; markedly reduced ability of tau to
FT                   promote microtubule assembly; dbSNP:rs63750635)"
FT                   /evidence="ECO:0000269|PubMed:11891833"
FT                   /id="VAR_019665"
FT   VARIANT         654
FT                   /note="V -> M (in FTD1; ultrastructural and biochemical
FT                   characteristics indistinguishable from Alzheimer disease;
FT                   accelerates aggregation of tau into filaments;
FT                   dbSNP:rs63750570)"
FT                   /evidence="ECO:0000269|PubMed:10214944,
FT                   ECO:0000269|PubMed:9629852"
FT                   /id="VAR_010351"
FT   VARIANT         659
FT                   /note="E -> V (in FTD1; dbSNP:rs63750711)"
FT                   /evidence="ECO:0000269|PubMed:11117541"
FT                   /id="VAR_019666"
FT   VARIANT         669
FT                   /note="S -> L (in fatal respiratory hypoventilation;
FT                   unusual apparent autosomal recessive inheritance; reduced
FT                   binding to microtubules as well as increased fibrillization
FT                   and aggregation; dbSNP:rs63750425)"
FT                   /evidence="ECO:0000269|PubMed:14595660"
FT                   /id="VAR_019667"
FT   VARIANT         686
FT                   /note="K -> I (in PIDB; 90% reduction in the rate of
FT                   microtubule assembly; dbSNP:rs63751264)"
FT                   /evidence="ECO:0000269|PubMed:11601501"
FT                   /id="VAR_019668"
FT   VARIANT         706
FT                   /note="G -> R (in PIDB; in vitro the mutation reduces the
FT                   ability of tau to promote microtubule assembly by 25 to
FT                   30%; dbSNP:rs63750512)"
FT                   /evidence="ECO:0000269|PubMed:10604746,
FT                   ECO:0000269|PubMed:11117542"
FT                   /id="VAR_010352"
FT   VARIANT         723
FT                   /note="R -> W (in FTD1/Alzheimer disease; accelerates
FT                   aggregation of tau into filaments; reduces tau
FT                   phosphorylation in cells compared to both the wild-type and
FT                   other mutant forms; dbSNP:rs63750424)"
FT                   /evidence="ECO:0000269|PubMed:10214944,
FT                   ECO:0000269|PubMed:11278002, ECO:0000269|PubMed:11889249,
FT                   ECO:0000269|PubMed:14517953, ECO:0000269|PubMed:26086902,
FT                   ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9973279"
FT                   /id="VAR_010353"
FT   MUTAGEN         515
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         516
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         519
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         531
FT                   /note="S->A: No decrease in microtubule-binding and
FT                   nucleation activity after in vitro phosphorylation of
FT                   mutant protein."
FT   MUTAGEN         548
FT                   /note="T->A: 50% Decrease in microtubule-binding after in
FT                   vitro phosphorylation of mutant protein."
FT   MUTAGEN         548
FT                   /note="T->E: No association with plasma membrane."
FT   MUTAGEN         552
FT                   /note="S->A: 70% decrease in microtubule-binding after in
FT                   vitro phosphorylation of mutant protein."
FT   MUTAGEN         552
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         579
FT                   /note="S->A: 8% decrease in microtubule-binding after in
FT                   vitro phosphorylation of mutant protein."
FT   MUTAGEN         713
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         721
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         726
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         730
FT                   /note="S->E: No association with plasma membrane."
FT   MUTAGEN         739
FT                   /note="S->E: No association with plasma membrane."
FT   CONFLICT        48
FT                   /note="L -> P (in Ref. 6; AAU45390)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        414
FT                   /note="H -> L (in Ref. 5; AAC04277)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        557
FT                   /note="K -> M (in Ref. 12; AAS17881)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        591
FT                   /note="K -> S (in Ref. 12; AAS17881)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        617
FT                   /note="V -> Q (in Ref. 17; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        622
FT                   /note="S -> K (in Ref. 17; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   STRAND          7..9
FT                   /evidence="ECO:0007829|PDB:6N4P"
FT   HELIX           60..62
FT                   /evidence="ECO:0007829|PDB:5ZV3"
FT   TURN            63..65
FT                   /evidence="ECO:0007829|PDB:5ZV3"
FT   TURN            579..582
FT                   /evidence="ECO:0007829|PDB:6CVJ"
FT   STRAND          587..590
FT                   /evidence="ECO:0007829|PDB:5N5A"
FT   STRAND          592..610
FT                   /evidence="ECO:0007829|PDB:7P6A"
FT   STRAND          613..615
FT                   /evidence="ECO:0007829|PDB:7QK6"
FT   STRAND          618..620
FT                   /evidence="ECO:0007829|PDB:5MP5"
FT   STRAND          624..626
FT                   /evidence="ECO:0007829|PDB:8OP0"
FT   STRAND          629..631
FT                   /evidence="ECO:0007829|PDB:7QKZ"
FT   STRAND          634..643
FT                   /evidence="ECO:0007829|PDB:8Q98"
FT   STRAND          645..648
FT                   /evidence="ECO:0007829|PDB:8Q98"
FT   STRAND          654..660
FT                   /evidence="ECO:0007829|PDB:8Q98"
FT   STRAND          662..665
FT                   /evidence="ECO:0007829|PDB:8Q98"
FT   STRAND          667..671
FT                   /evidence="ECO:0007829|PDB:8Q98"
FT   STRAND          673..679
FT                   /evidence="ECO:0007829|PDB:8Q98"
FT   STRAND          682..684
FT                   /evidence="ECO:0007829|PDB:7P6A"
FT   STRAND          685..695
FT                   /evidence="ECO:0007829|PDB:8Q98"
FT   STRAND          698..703
FT                   /evidence="ECO:0007829|PDB:7R5H"
FT   STRAND          709..712
FT                   /evidence="ECO:0007829|PDB:7QKY"
FT   STRAND          716..720
FT                   /evidence="ECO:0007829|PDB:7SP1"
FT   STRAND          723..732
FT                   /evidence="ECO:0007829|PDB:7QKY"
FT   STRAND          734..736
FT                   /evidence="ECO:0007829|PDB:8FYU"
FT   STRAND          741..751
FT                   /evidence="ECO:0007829|PDB:7QKY"
FT   STRAND          753..755
FT                   /evidence="ECO:0007829|PDB:7QKY"
SQ   SEQUENCE   758 AA;  78928 MW;  D46C66CDBCD196E8 CRC64;
     MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG
     SETSDAKSTP TAEDVTAPLV DEGAPGKQAA AQPHTEIPEG TTAEEAGIGD TPSLEDEAAG
     HVTQEPESGK VVQEGFLREP GPPGLSHQLM SGMPGAPLLP EGPREATRQP SGTGPEDTEG
     GRHAPELLKH QLLGDLHQEG PPLKGAGGKE RPGSKEEVDE DRDVDESSPQ DSPPSKASPA
     QDGRPPQTAA REATSIPGFP AEGAIPLPVD FLSKVSTEIP ASEPDGPSVG RAKGQDAPLE
     FTFHVEITPN VQKEQAHSEE HLGRAAFPGA PGEGPEARGP SLGEDTKEAD LPEPSEKQPA
     AAPRGKPVSR VPQLKARMVS KSKDGTGSDD KKAKTSTRSS AKTLKNRPCL SPKHPTPGSS
     DPLIQPSSPA VCPEPPSSPK YVSSVTSRTG SSGAKEMKLK GADGKTKIAT PRGAAPPGQK
     GQANATRIPA KTPPAPKTPP SSGEPPKSGD RSGYSSPGSP GTPGSRSRTP SLPTPPTREP
     KKVAVVRTPP KSPSSAKSRL QTAPVPMPDL KNVKSKIGST ENLKHQPGGG KVQIINKKLD
     LSNVQSKCGS KDNIKHVPGG GSVQIVYKPV DLSKVTSKCG SLGNIHHKPG GGQVEVKSEK
     LDFKDRVQSK IGSLDNITHV PGGGNKKIET HKLTFRENAK AKTDHGAEIV YKSPVVSGDT
     SPRHLSNVSS TGSIDMVDSP QLATLADEVS ASLAKQGL
//
ID   UNC5C_HUMAN             Reviewed;         931 AA.
AC   O95185; Q8IUT0;
DT   11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT   05-MAY-2009, sequence version 2.
DT   28-JAN-2026, entry version 191.
DE   RecName: Full=Netrin receptor UNC5C;
DE   AltName: Full=Protein unc-5 homolog 3;
DE   AltName: Full=Protein unc-5 homolog C;
DE   Flags: Precursor;
GN   Name=UNC5C; Synonyms=UNC5H3;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP   THR-721.
RC   TISSUE=Brain;
RX   PubMed=9782087; DOI=10.1006/geno.1998.5425;
RA   Ackerman S.L., Knowles B.B.;
RT   "Cloning and mapping of the UNC5C gene to human chromosome 4q21-q23.";
RL   Genomics 52:205-208(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   DOWN-REGULATION IN CANCER.
RX   PubMed=12655055; DOI=10.1073/pnas.0738063100;
RA   Thiebault K., Mazelin L., Pays L., Llambi F., Joly M.-O., Scoazec J.-Y.,
RA   Saurin J.-C., Romeo G., Mehlen P.;
RT   "The netrin-1 receptors UNC5H are putative tumor suppressors controlling
RT   cell death commitment.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:4173-4178(2003).
RN   [5]
RP   INTERACTION WITH DSCAM.
RX   PubMed=22685302; DOI=10.1074/jbc.m112.340174;
RA   Purohit A.A., Li W., Qu C., Dwyer T., Shao Q., Guan K.L., Liu G.;
RT   "Down syndrome cell adhesion molecule (DSCAM) associates with
RT   uncoordinated-5C (UNC5C) in netrin-1-mediated growth cone collapse.";
RL   J. Biol. Chem. 287:27126-27138(2012).
RN   [6]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INVOLVEMENT IN AD, VARIANT AD
RP   MET-835, AND CHARACTERIZATION OF VARIANT AD MET-835.
RX   PubMed=25419706; DOI=10.1038/nm.3736;
RG   Alzheimer's Disease Genetics Consortium;
RA   Wetzel-Smith M.K., Hunkapiller J., Bhangale T.R., Srinivasan K.,
RA   Maloney J.A., Atwal J.K., Sa S.M., Yaylaoglu M.B., Foreman O., Ortmann W.,
RA   Rathore N., Hansen D.V., Tessier-Lavigne M., Mayeux R., Pericak-Vance M.,
RA   Haines J., Farrer L.A., Schellenberg G.D., Goate A., Behrens T.W.,
RA   Cruchaga C., Watts R.J., Graham R.R.;
RT   "A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and
RT   increases neuronal cell death.";
RL   Nat. Med. 20:1452-1457(2014).
RN   [7]
RP   INTERACTION WITH DAPK1, AND CHARACTERIZATION OF VARIANT AD MET-835.
RX   PubMed=27068745; DOI=10.1074/jbc.m115.698092;
RA   Hashimoto Y., Toyama Y., Kusakari S., Nawa M., Matsuoka M.;
RT   "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor
RT   Uncoordinated-5C-induced Signaling That Merges with Amyloid beta Precursor
RT   Protein Signaling.";
RL   J. Biol. Chem. 291:12282-12293(2016).
RN   [8]
RP   FUNCTION, AND INTERACTION WITH TUBB3.
RX   PubMed=28483977; DOI=10.1523/jneurosci.2617-16.2017;
RA   Shao Q., Yang T., Huang H., Alarmanazi F., Liu G.;
RT   "Uncoupling of UNC5C with Polymerized TUBB3 in Microtubules Mediates
RT   Netrin-1 Repulsion.";
RL   J. Neurosci. 37:5620-5633(2017).
CC   -!- FUNCTION: Receptor for netrin required for axon guidance (By
CC       similarity). Mediates axon repulsion of neuronal growth cones in the
CC       developing nervous system upon ligand binding (By similarity).
CC       NTN1/Netrin-1 binding might cause dissociation of UNC5C from
CC       polymerized TUBB3 in microtubules and thereby lead to increased
CC       microtubule dynamics and axon repulsion (PubMed:28483977). Axon
CC       repulsion in growth cones may also be caused by its association with
CC       DCC that may trigger signaling for repulsion (By similarity). Might
CC       also collaborate with DSCAM in NTN1-mediated axon repulsion
CC       independently of DCC (By similarity). Also involved in corticospinal
CC       tract axon guidance independently of DCC (By similarity). Involved in
CC       dorsal root ganglion axon projection towards the spinal cord
CC       (PubMed:28483977). It also acts as a dependence receptor required for
CC       apoptosis induction when not associated with netrin ligand (By
CC       similarity). {ECO:0000250|UniProtKB:O08747,
CC       ECO:0000250|UniProtKB:Q761X5, ECO:0000269|PubMed:28483977}.
CC   -!- SUBUNIT: Interacts with DCC (via cytoplasmic domain) (By similarity).
CC       Interacts (tyrosine phosphorylated form) with PTPN11 (By similarity).
CC       Interacts (via extracellular domain) with FLRT3 (via extracellular
CC       domain) (By similarity). Interacts (via Ig-like C2-type domain) with
CC       DSCAM (via extracellular domain) (PubMed:22685302). Interacts (via
CC       death domain) with DAPK1 (PubMed:27068745). Interacts (via cytoplasmic
CC       domain) with TUBB3; this interaction is decreased by NTN1/Netrin-1
CC       (PubMed:28483977). {ECO:0000250|UniProtKB:O08747,
CC       ECO:0000269|PubMed:22685302, ECO:0000269|PubMed:27068745,
CC       ECO:0000269|PubMed:28483977}.
CC   -!- INTERACTION:
CC       O95185; Q13509: TUBB3; NbExp=2; IntAct=EBI-11343380, EBI-350989;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:25419706};
CC       Single-pass type I membrane protein {ECO:0000255}. Cell surface
CC       {ECO:0000269|PubMed:25419706}. Synapse, synaptosome
CC       {ECO:0000250|UniProtKB:Q761X5}. Cell projection, axon
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, dendrite
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, growth cone
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, lamellipodium
CC       {ECO:0000250|UniProtKB:O08747}. Cell projection, filopodium
CC       {ECO:0000250|UniProtKB:O08747}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=O95185-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O95185-2; Sequence=VSP_011700, VSP_011701;
CC   -!- TISSUE SPECIFICITY: Mainly expressed in brain (PubMed:9782087).
CC       Expressed in temporal lobe cortical neurons and in neurons of the
CC       hippocampal pyramidal layer (PubMed:25419706). Also expressed in kidney
CC       (PubMed:9782087). Not expressed in developing or adult lung
CC       (PubMed:9782087). {ECO:0000269|PubMed:25419706,
CC       ECO:0000269|PubMed:9782087}.
CC   -!- PTM: Proteolytically cleaved by caspases during apoptosis. The cleavage
CC       does not take place when the receptor is associated with netrin ligand.
CC       Its cleavage by caspases is required to induce apoptosis.
CC       {ECO:0000250|UniProtKB:Q761X5}.
CC   -!- PTM: Phosphorylated on different cytoplasmic tyrosine residues.
CC       Phosphorylation of Tyr-568 leads to an interaction with PTPN11
CC       phosphatase, suggesting that its activity is regulated by
CC       phosphorylation/dephosphorylation. Tyrosine phosphorylation is netrin-
CC       dependent. {ECO:0000250|UniProtKB:O08747}.
CC   -!- DISEASE: Alzheimer disease (AD) [MIM:104300]: Alzheimer disease is a
CC       neurodegenerative disorder characterized by progressive dementia, loss
CC       of cognitive abilities, and deposition of fibrillar amyloid proteins as
CC       intraneuronal neurofibrillary tangles, extracellular amyloid plaques
CC       and vascular amyloid deposits. The major constituents of these plaques
CC       are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42,
CC       that are produced by the proteolysis of the transmembrane APP protein.
CC       The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved
CC       products, such as C31, are also implicated in neuronal death.
CC       {ECO:0000269|PubMed:25419706, ECO:0000269|PubMed:27068745}.
CC       Note=Disease susceptibility may be associated with variants affecting
CC       the gene represented in this entry.
CC   -!- MISCELLANEOUS: Down-regulated in multiple cancers including colorectal,
CC       breast, ovary, uterus, stomach, lung, or kidney cancers.
CC       {ECO:0000269|PubMed:12655055}.
CC   -!- SIMILARITY: Belongs to the unc-5 family. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF055634; AAC67491.1; -; mRNA.
DR   EMBL; AC098584; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC105395; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC106881; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC041156; AAH41156.1; -; mRNA.
DR   CCDS; CCDS3643.1; -. [O95185-1]
DR   RefSeq; NP_003719.3; NM_003728.3. [O95185-1]
DR   AlphaFoldDB; O95185; -.
DR   SMR; O95185; -.
DR   BioGRID; 114186; 38.
DR   DIP; DIP-46276N; -.
DR   FunCoup; O95185; 326.
DR   IntAct; O95185; 9.
DR   MINT; O95185; -.
DR   STRING; 9606.ENSP00000406022; -.
DR   GlyCosmos; O95185; 2 sites, No reported glycans.
DR   GlyGen; O95185; 3 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; O95185; -.
DR   PhosphoSitePlus; O95185; -.
DR   BioMuta; UNC5C; -.
DR   jPOST; O95185; -.
DR   MassIVE; O95185; -.
DR   PaxDb; 9606-ENSP00000406022; -.
DR   PeptideAtlas; O95185; -.
DR   ProteomicsDB; 50694; -. [O95185-1]
DR   ProteomicsDB; 50695; -. [O95185-2]
DR   Pumba; O95185; -.
DR   Antibodypedia; 2665; 258 antibodies from 33 providers.
DR   DNASU; 8633; -.
DR   Ensembl; ENST00000453304.6; ENSP00000406022.1; ENSG00000182168.16. [O95185-1]
DR   Ensembl; ENST00000506749.5; ENSP00000426153.1; ENSG00000182168.16. [O95185-2]
DR   GeneID; 8633; -.
DR   KEGG; hsa:8633; -.
DR   MANE-Select; ENST00000453304.6; ENSP00000406022.1; NM_003728.4; NP_003719.3.
DR   UCSC; uc003hto.4; human. [O95185-1]
DR   AGR; HGNC:12569; -.
DR   ClinPGx; PA37206; -.
DR   CTD; 8633; -.
DR   DisGeNET; 8633; -.
DR   GeneCards; UNC5C; -.
DR   HGNC; HGNC:12569; UNC5C.
DR   HPA; ENSG00000182168; Tissue enhanced (thyroid).
DR   MalaCards; UNC5C; -.
DR   MIM; 104300; phenotype.
DR   MIM; 603610; gene.
DR   OpenTargets; ENSG00000182168; -.
DR   VEuPathDB; HostDB:ENSG00000182168; -.
DR   eggNOG; KOG1480; Eukaryota.
DR   GeneTree; ENSGT00950000182815; -.
DR   HOGENOM; CLU_014383_2_1_1; -.
DR   InParanoid; O95185; -.
DR   OMA; CECQAWS; -.
DR   OrthoDB; 5973910at2759; -.
DR   PAN-GO; O95185; 2 GO annotations based on evolutionary models.
DR   PhylomeDB; O95185; -.
DR   PathwayCommons; O95185; -.
DR   Reactome; R-HSA-418886; Netrin mediated repulsion signals.
DR   SignaLink; O95185; -.
DR   SIGNOR; O95185; -.
DR   Agora; ENSG00000182168; Agora Nominated Target for Alzheimer's Disease.
DR   BioGRID-ORCS; 8633; 6 hits in 1142 CRISPR screens.
DR   ChiTaRS; UNC5C; human.
DR   GeneWiki; UNC5C; -.
DR   GenomeRNAi; 8633; -.
DR   Pharos; O95185; Tbio.
DR   PRO; PR:O95185; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; O95185; protein.
DR   Bgee; ENSG00000182168; Expressed in corpus callosum and 134 other cell types or tissues.
DR   ExpressionAtlas; O95185; baseline and differential.
DR   GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR   GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR   GO; GO:0030175; C:filopodium; ISS:UniProtKB.
DR   GO; GO:0030426; C:growth cone; ISS:UniProtKB.
DR   GO; GO:0030027; C:lamellipodium; ISS:UniProtKB.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR   GO; GO:0005042; F:netrin receptor activity; IBA:GO_Central.
DR   GO; GO:0005043; F:netrin receptor activity involved in chemorepulsion; ISS:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0015631; F:tubulin binding; IPI:UniProtKB.
DR   GO; GO:0033564; P:anterior/posterior axon guidance; IEA:Ensembl.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0007411; P:axon guidance; IBA:GO_Central.
DR   GO; GO:0007420; P:brain development; TAS:ProtInc.
DR   GO; GO:0061643; P:chemorepulsion of axon; ISS:UniProtKB.
DR   GO; GO:1990791; P:dorsal root ganglion development; IDA:UniProtKB.
DR   GO; GO:0035234; P:ectopic germ cell programmed cell death; IEA:Ensembl.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0051094; P:positive regulation of developmental process; IEA:Ensembl.
DR   GO; GO:2000243; P:positive regulation of reproductive process; IEA:Ensembl.
DR   GO; GO:2001222; P:regulation of neuron migration; IEA:Ensembl.
DR   CDD; cd08799; Death_UNC5C; 1.
DR   FunFam; 1.10.533.10:FF:000001; Unc-5 netrin receptor B; 1.
DR   FunFam; 2.20.100.10:FF:000002; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.20.100.10:FF:000008; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.60.220.30:FF:000003; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.60.40.10:FF:000037; Unc-5 netrin receptor C; 1.
DR   FunFam; 2.60.40.10:FF:000039; Unc-5 netrin receptor C; 1.
DR   Gene3D; 2.60.220.30; -; 1.
DR   Gene3D; 1.10.533.10; Death Domain, Fas; 1.
DR   Gene3D; 2.60.40.10; Immunoglobulins; 2.
DR   Gene3D; 2.20.100.10; Thrombospondin type-1 (TSP1) repeat; 2.
DR   InterPro; IPR011029; DEATH-like_dom_sf.
DR   InterPro; IPR000488; Death_dom.
DR   InterPro; IPR042154; Death_UNC5C.
DR   InterPro; IPR007110; Ig-like_dom.
DR   InterPro; IPR036179; Ig-like_dom_sf.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR013098; Ig_I-set.
DR   InterPro; IPR003599; Ig_sub.
DR   InterPro; IPR003598; Ig_sub2.
DR   InterPro; IPR000884; TSP1_rpt.
DR   InterPro; IPR036383; TSP1_rpt_sf.
DR   InterPro; IPR037936; UNC5A-D.
DR   InterPro; IPR057755; UNC5A-D-like_N.
DR   InterPro; IPR033772; UPA.
DR   InterPro; IPR000906; ZU5_dom.
DR   PANTHER; PTHR12582; NETRIN RECEPTOR UNC5; 1.
DR   PANTHER; PTHR12582:SF7; NETRIN RECEPTOR UNC5C; 1.
DR   Pfam; PF00531; Death; 1.
DR   Pfam; PF07679; I-set; 1.
DR   Pfam; PF00090; TSP_1; 2.
DR   Pfam; PF25609; Unc5_NetrinR_N; 1.
DR   Pfam; PF17217; UPA; 1.
DR   Pfam; PF00791; ZU5; 1.
DR   PRINTS; PR01705; TSP1REPEAT.
DR   SMART; SM00005; DEATH; 1.
DR   SMART; SM00409; IG; 1.
DR   SMART; SM00408; IGc2; 1.
DR   SMART; SM00209; TSP1; 2.
DR   SMART; SM00218; ZU5; 1.
DR   SUPFAM; SSF47986; DEATH domain; 1.
DR   SUPFAM; SSF48726; Immunoglobulin; 2.
DR   SUPFAM; SSF82895; TSP-1 type 1 repeat; 2.
DR   PROSITE; PS50835; IG_LIKE; 1.
DR   PROSITE; PS50092; TSP1; 2.
DR   PROSITE; PS51145; ZU5; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Alzheimer disease; Amyloidosis; Apoptosis;
KW   Cell membrane; Cell projection; Developmental protein; Disulfide bond;
KW   Glycoprotein; Immunoglobulin domain; Membrane; Neurodegeneration;
KW   Phosphoprotein; Proteomics identification; Receptor; Reference proteome;
KW   Repeat; Signal; Synapse; Synaptosome; Transmembrane; Transmembrane helix.
FT   SIGNAL          1..40
FT                   /evidence="ECO:0000255"
FT   CHAIN           41..931
FT                   /note="Netrin receptor UNC5C"
FT                   /id="PRO_0000036075"
FT   TOPO_DOM        41..380
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        381..401
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        402..931
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          62..159
FT                   /note="Ig-like"
FT   DOMAIN          161..256
FT                   /note="Ig-like C2-type"
FT   DOMAIN          260..314
FT                   /note="TSP type-1 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DOMAIN          316..368
FT                   /note="TSP type-1 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DOMAIN          530..673
FT                   /note="ZU5"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00485"
FT   DOMAIN          850..929
FT                   /note="Death"
FT   REGION          402..931
FT                   /note="Required for netrin-mediated axon repulsion of
FT                   neuronal growth cones"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   REGION          694..712
FT                   /note="Interaction with DCC"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   SITE            415..416
FT                   /note="Cleavage; by caspase-3"
FT                   /evidence="ECO:0000250|UniProtKB:Q761X5"
FT   MOD_RES         502
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   MOD_RES         568
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:O08747"
FT   CARBOHYD        236
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        361
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        83..144
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        95..142
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        188..239
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        272..309
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DISULFID        276..313
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DISULFID        287..299
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT   DISULFID        328..362
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        332..367
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   DISULFID        340..352
FT                   /evidence="ECO:0000250|UniProtKB:Q6ZN44"
FT   VAR_SEQ         370
FT                   /note="T -> SFIYPISTEQRTQNEYGFSS (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_011700"
FT   VAR_SEQ         579..931
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_011701"
FT   VARIANT         37
FT                   /note="G -> V (in dbSNP:rs2306715)"
FT                   /id="VAR_019731"
FT   VARIANT         721
FT                   /note="M -> T (in dbSNP:rs2289043)"
FT                   /evidence="ECO:0000269|PubMed:9782087"
FT                   /id="VAR_019732"
FT   VARIANT         835
FT                   /note="T -> M (in AD; increased susceptibility to neuronal
FT                   cell death; dbSNP:rs137875858)"
FT                   /evidence="ECO:0000269|PubMed:25419706,
FT                   ECO:0000269|PubMed:27068745"
FT                   /id="VAR_081368"
FT   VARIANT         841
FT                   /note="A -> T (in dbSNP:rs34585936)"
FT                   /id="VAR_055327"
FT   CONFLICT        219
FT                   /note="T -> I (in Ref. 3; AAH41156)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        489
FT                   /note="T -> S (in Ref. 1; AAC67491)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        651
FT                   /note="Q -> K (in Ref. 1; AAC67491)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   931 AA;  103146 MW;  98A95995129532A7 CRC64;
     MRKGLRATAA RCGLGLGYLL QMLVLPALAL LSASGTGSAA QDDDFFHELP ETFPSDPPEP
     LPHFLIEPEE AYIVKNKPVN LYCKASPATQ IYFKCNSEWV HQKDHIVDER VDETSGLIVR
     EVSIEISRQQ VEELFGPEDY WCQCVAWSSA GTTKSRKAYV RIAYLRKTFE QEPLGKEVSL
     EQEVLLQCRP PEGIPVAEVE WLKNEDIIDP VEDRNFYITI DHNLIIKQAR LSDTANYTCV
     AKNIVAKRKS TTATVIVYVN GGWSTWTEWS VCNSRCGRGY QKRTRTCTNP APLNGGAFCE
     GQSVQKIACT TLCPVDGRWT PWSKWSTCGT ECTHWRRREC TAPAPKNGGK DCDGLVLQSK
     NCTDGLCMQT APDSDDVALY VGIVIAVIVC LAISVVVALF VYRKNHRDFE SDIIDSSALN
     GGFQPVNIKA ARQDLLAVPP DLTSAAAMYR GPVYALHDVS DKIPMTNSPI LDPLPNLKIK
     VYNTSGAVTP QDDLSEFTSK LSPQMTQSLL ENEALSLKNQ SLARQTDPSC TAFGSFNSLG
     GHLIVPNSGV SLLIPAGAIP QGRVYEMYVT VHRKETMRPP MDDSQTLLTP VVSCGPPGAL
     LTRPVVLTMH HCADPNTEDW KILLKNQAAQ GQWEDVVVVG EENFTTPCYI QLDAEACHIL
     TENLSTYALV GHSTTKAAAK RLKLAIFGPL CCSSLEYSIR VYCLDDTQDA LKEILHLERQ
     MGGQLLEEPK ALHFKGSTHN LRLSIHDIAH SLWKSKLLAK YQEIPFYHVW SGSQRNLHCT
     FTLERFSLNT VELVCKLCVR QVEGEGQIFQ LNCTVSEEPT GIDLPLLDPA NTITTVTGPS
     AFSIPLPIRQ KLCSSLDAPQ TRGHDWRMLA HKLNLDRYLN YFATKSSPTG VILDLWEAQN
     FPDGNLSMLA AVLEEMGRHE TVVSLAAEGQ Y
//