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 CNR1_HUMAN Reviewed; 472 AA. AC P21554; B2R9T4; E1P512; Q13949; Q495Z0; Q4PLI4; Q4VBM6; Q5JVL5; Q5UB37; AC Q9UNN0; DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1991, sequence version 1. DT 28-JAN-2026, entry version 234. DE RecName: Full=Cannabinoid receptor 1; DE Short=CB-R; DE Short=CB1; DE AltName: Full=CANN6; GN Name=CNR1; Synonyms=CNR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain stem; RX PubMed=2263478; DOI=10.1093/nar/18.23.7142; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Nucleotide sequence of a human cannabinoid receptor cDNA."; RL Nucleic Acids Res. 18:7142-7142(1990). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RC TISSUE=Brain stem; RX PubMed=1718258; DOI=10.1042/bj2790129; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Molecular cloning of a human cannabinoid receptor which is also expressed RT in testis."; RL Biochem. J. 279:129-134(1991). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Lung; RX PubMed=7876112; DOI=10.1074/jbc.270.8.3726; RA Shire D., Carillon C., Kaghad M., Calandra B., Rinaldi-Carmona M., RA Le Fur G., Caput D., Ferrara P.; RT "An amino-terminal variant of the central cannabinoid receptor resulting RT from alternative splicing."; RL J. Biol. Chem. 270:3726-3731(1995). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION (ISOFORMS 1; 2 AND 3), AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=15620723; DOI=10.1016/j.febslet.2004.11.085; RA Ryberg E., Vu H.K., Larsson N., Groblewski T., Hjorth S., Elebring T., RA Sjoegren S., Greasley P.J.; RT "Identification and characterisation of a novel splice variant of the human RT CB1 receptor."; RL FEBS Lett. 579:259-264(2005). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; RA Kathmann M., Schlicker E.; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Bonner T.I.; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain tumor; RA Kumar S., Gupta S., Sharma G.; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kopatz S.A., Aronstam R.S., Sharma S.V.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [13] RP REVIEW ON INVOLVEMENT IN NERVOUS SYSTEM DISORDERS. RX PubMed=32549916; DOI=10.1007/s13167-020-00203-4; RA Reddy V., Grogan D., Ahluwalia M., Salles E.L., Ahluwalia P., Khodadadi H., RA Alverson K., Nguyen A., Raju S.P., Gaur P., Braun M., Vale F.L., RA Costigliola V., Dhandapani K., Baban B., Vaibhav K.; RT "Targeting the endocannabinoid system: a predictive, preventive, and RT personalized medicine-directed approach to the management of brain RT pathologies."; RL EPMA J. 11:217-250(2020). RN [14] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=8255419; DOI=10.1016/0306-4522(93)90352-g; RA Glass M., Faull R.L., Dragunow M.; RT "Loss of cannabinoid receptors in the substantia nigra in Huntington's RT disease."; RL Neuroscience 56:523-527(1993). RN [15] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=10828533; DOI=10.1016/s0306-4522(00)00008-7; RA Glass M., Dragunow M., Faull R.L.; RT "The pattern of neurodegeneration in Huntington's disease: a comparative RT study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations RT in the human basal ganglia in Huntington's disease."; RL Neuroscience 97:505-519(2000). RN [16] RP FUNCTION, AND INTERACTION WITH CNRIP1. RC TISSUE=Brain; RX PubMed=17895407; DOI=10.1124/mol.107.039263; RA Niehaus J.L., Liu Y., Wallis K.T., Egertova M., Bhartur S.G., RA Mukhopadhyay S., Shi S., He H., Selley D.E., Howlett A.C., Elphick M.R., RA Lewis D.L.; RT "CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor RT interacting protein CRIP 1a."; RL Mol. Pharmacol. 72:1557-1566(2007). RN [17] RP ACTIVITY REGULATION. RX PubMed=18077343; DOI=10.1073/pnas.0706980105; RA Heimann A.S., Gomes I., Dale C.S., Pagano R.L., Gupta A., de Souza L.L., RA Luchessi A.D., Castro L.M., Giorgi R., Rioli V., Ferro E.S., Devi L.A.; RT "Hemopressin is an inverse agonist of CB1 cannabinoid receptors."; RL Proc. Natl. Acad. Sci. U.S.A. 104:20588-20593(2007). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-415, AND MUTAGENESIS RP OF CYS-415. RX PubMed=21895628; DOI=10.1111/j.1476-5381.2011.01658.x; RA Oddi S., Dainese E., Sandiford S., Fezza F., Lanuti M., Chiurchiu V., RA Totaro A., Catanzaro G., Barcaroli D., De Laurenzi V., Centonze D., RA Mukhopadhyay S., Selent J., Howlett A.C., Maccarrone M.; RT "Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid RT receptor on membrane localization and signalling."; RL Br. J. Pharmacol. 165:2635-2651(2012). RN [19] RP INVOLVEMENT IN OBESITY. RX PubMed=18177726; DOI=10.1016/j.cmet.2007.11.012; RA Addy C., Wright H., Van Laere K., Gantz I., Erondu N., Musser B.J., Lu K., RA Yuan J., Sanabria-Bohorquez S.M., Stoch A., Stevens C., Fong T.M., RA De Lepeleire I., Cilissen C., Cote J., Rosko K., Gendrano I.N. III, RA Nguyen A.M., Gumbiner B., Rothenberg P., de Hoon J., Bormans G., Depre M., RA Eng W.S., Ravussin E., Klein S., Blundell J., Herman G.A., Burns H.D., RA Hargreaves R.J., Wagner J., Gottesdiener K., Amatruda J.M., RA Heymsfield S.B.; RT "The acyclic CB1R inverse agonist taranabant mediates weight loss by RT increasing energy expenditure and decreasing caloric intake."; RL Cell Metab. 7:68-78(2008). RN [20] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=19524019; DOI=10.1016/j.neuroscience.2009.06.014; RA Dowie M.J., Bradshaw H.B., Howard M.L., Nicholson L.F., Faull R.L., RA Hannan A.J., Glass M.; RT "Altered CB1 receptor and endocannabinoid levels precede motor symptom RT onset in a transgenic mouse model of Huntington's disease."; RL Neuroscience 163:456-465(2009). RN [21] RP FUNCTION, AND INDUCTION BY ENDOCANNABINOID ANANDAMIDE. RX PubMed=23955712; DOI=10.1038/nm.3265; RA Jourdan T., Godlewski G., Cinar R., Bertola A., Szanda G., Liu J., Tam J., RA Han T., Mukhopadhyay B., Skarulis M.C., Ju C., Aouadi M., Czech M.P., RA Kunos G.; RT "Activation of the Nlrp3 inflammasome in infiltrating macrophages by RT endocannabinoids mediates beta cell loss in type 2 diabetes."; RL Nat. Med. 19:1132-1140(2013). RN [22] RP INVOLVEMENT IN ALZHEIMER DISEASE. RX PubMed=30096288; DOI=10.1016/j.bcp.2018.08.007; RA Aso E., Andres-Benito P., Ferrer I.; RT "Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer- RT like symptoms in a transgenic animal model."; RL Biochem. Pharmacol. 157:210-216(2018). RN [23] RP INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=31342135; DOI=10.1007/s00259-019-04445-x; RA Ceccarini J., Casteels C., Ahmad R., Crabbe M., Van de Vliet L., RA Vanhaute H., Vandenbulcke M., Vandenberghe W., Van Laere K.; RT "Regional changes in the type 1 cannabinoid receptor are associated with RT cognitive dysfunction in Parkinson's disease."; RL Eur. J. Nucl. Med. Mol. Imaging 46:2348-2357(2019). RN [24] RP STRUCTURE BY NMR OF 338-346, INTERACTION WITH GNAI1, AND MUTAGENESIS OF RP 341-LEU-ALA-342. RX PubMed=12237474; DOI=10.1110/ps.0218402; RA Ulfers A.L., McMurry J.L., Miller A., Wang L., Kendall D.A., Mierke D.F.; RT "Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures RT of IC3 and a mutant with altered G protein specificity."; RL Protein Sci. 11:2526-2531(2002). RN [25] {ECO:0007744|PDB:5TGZ} RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 99-306 AND 332-414, FUNCTION, AND RP TOPOLOGY. RX PubMed=27768894; DOI=10.1016/j.cell.2016.10.004; RA Hua T., Vemuri K., Pu M., Qu L., Han G.W., Wu Y., Zhao S., Shui W., Li S., RA Korde A., Laprairie R.B., Stahl E.L., Ho J.H., Zvonok N., Zhou H., RA Kufareva I., Wu B., Zhao Q., Hanson M.A., Bohn L.M., Makriyannis A., RA Stevens R.C., Liu Z.J.; RT "Crystal structure of the human cannabinoid receptor CB1."; RL Cell 167:750-762(2016). RN [26] {ECO:0007744|PDB:5U09} RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 90-301 AND 334-421 IN COMPLEX RP WITH INVERSE AGONIST TARANABANT, MUTAGENESIS OF THR-210, TOPOLOGY, AND RP FUNCTION. RX PubMed=27851727; DOI=10.1038/nature20613; RA Shao Z., Yin J., Chapman K., Grzemska M., Clark L., Wang J., RA Rosenbaum D.M.; RT "High-resolution crystal structure of the human CB1 cannabinoid receptor."; RL Nature 540:602-606(2016). RN [27] {ECO:0007744|PDB:7FEE, ECO:0007744|PDB:7WV9} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 74-305 AND 333-414, INTERACTION RP WITH GNAI2, FUNCTION, AND MUTAGENESIS OF PHE-155. RX PubMed=35637350; DOI=10.1038/s41589-022-01038-y; RA Yang X., Wang X., Xu Z., Wu C., Zhou Y., Wang Y., Lin G., Li K., Wu M., RA Xia A., Liu J., Cheng L., Zou J., Yan W., Shao Z., Yang S.; RT "Molecular mechanism of allosteric modulation for the cannabinoid receptor RT CB1."; RL Nat. Chem. Biol. 18:831-840(2022). CC -!- FUNCTION: G-protein coupled receptor for endogenous cannabinoids CC (eCBs), including N-arachidonoylethanolamide (also called anandamide or CC AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, CC such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, CC PubMed:27768894, PubMed:27851727, PubMed:35637350). Mediates many CC cannabinoid-induced effects, acting, among others, on food intake, CC memory loss, gastrointestinal motility, catalepsy, ambulatory activity, CC anxiety, chronic pain. Signaling typically involves reduction in cyclic CC AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the CC hypothalamus, may have a dual effect on mitochondrial respiration CC depending upon the agonist dose and possibly upon the cell type. CC Increases respiration at low doses, while decreases respiration at high CC doses. At high doses, CNR1 signal transduction involves G-protein CC alpha-i protein activation and subsequent inhibition of mitochondrial CC soluble adenylate cyclase, decrease in cyclic AMP concentration, CC inhibition of protein kinase A (PKA)-dependent phosphorylation of CC specific subunits of the mitochondrial electron transport system, CC including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive CC oxygen species (ROS) formation and mediates cannabinoid-induced CC increase in SREBF1 and FASN gene expression. In response to CC cannabinoids, drives the release of orexigenic beta-endorphin, but not CC that of melanocyte-stimulating hormone alpha/alpha-MSH, from CC hypothalamic POMC neurons, hence promoting food intake. In the CC hippocampus, regulates cellular respiration and energy production in CC response to cannabinoids. Involved in cannabinoid-dependent CC depolarization-induced suppression of inhibition (DSI), a process in CC which depolarization of CA1 postsynaptic pyramidal neurons mobilizes CC eCBs, which retrogradely activate presynaptic CB1 receptors, CC transiently decreasing GABAergic inhibitory neurotransmission. Also CC reduces excitatory synaptic transmission (By similarity). In superior CC cervical ganglions and cerebral vascular smooth muscle cells, inhibits CC voltage-gated Ca(2+) channels in a constitutive, as well as agonist- CC dependent manner (PubMed:17895407). In cerebral vascular smooth muscle CC cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels CC leads to vasodilation and decreased vascular tone (By similarity). CC Induces leptin production in adipocytes and reduces LRP2-mediated CC leptin clearance in the kidney, hence participating in hyperleptinemia. CC In adipose tissue, CNR1 signaling leads to increased expression of CC SREBF1, ACACA and FASN genes (By similarity). In the liver, activation CC by endocannabinoids leads to increased de novo lipogenesis and reduced CC fatty acid catabolism, associated with increased expression of CC SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de CC novo cholesterol synthesis and HDL-cholesteryl ether uptake. CC Peripherally modulates energy metabolism (By similarity). In high CC carbohydrate diet-induced obesity, may decrease the expression of CC mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as CC well as that of selected glucose/ pyruvate metabolic enzymes, hence CC affecting energy expenditure through mitochondrial metabolism (By CC similarity). In response to cannabinoid anandamide, elicits a pro- CC inflammatory response in macrophages, which involves NLRP3 inflammasome CC activation and IL1B and IL18 secretion (By similarity). In macrophages CC infiltrating pancreatic islets, this process may participate in the CC progression of type-2 diabetes and associated loss of pancreatic beta- CC cells (PubMed:23955712). {ECO:0000250|UniProtKB:O02777, CC ECO:0000250|UniProtKB:P47746, ECO:0000269|PubMed:15620723, CC ECO:0000269|PubMed:1718258, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:21895628, ECO:0000269|PubMed:23955712, CC ECO:0000269|PubMed:27768894, ECO:0000269|PubMed:27851727, CC ECO:0000269|PubMed:35637350}. CC -!- FUNCTION: [Isoform 1]: Binds both 2-arachidonoylglycerol (2-AG) and CC anandamide. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 2]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 2 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 3]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 3 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- ACTIVITY REGULATION: Hemopressin, a peptide derived from hemoglobin CC subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide: CC hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and CC subsequent signaling. {ECO:0000269|PubMed:18077343}. CC -!- SUBUNIT: Interacts (via C-terminus) with CNRIP1; this interaction CC attenuates constitutive, but not agonist-dependent, inhibition of CC voltage-gated Ca(2+) channels in neurons (PubMed:17895407). Associates CC with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) CC alpha-2/GNAI2, G(i) alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation CC is important for interaction with GNAI3 and GNAO1 (PubMed:12237474). CC {ECO:0000269|PubMed:12237474, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:35637350}. CC -!- INTERACTION: CC P21554; P29274: ADORA2A; NbExp=8; IntAct=EBI-2909859, EBI-2902702; CC P21554; P21554: CNR1; NbExp=8; IntAct=EBI-2909859, EBI-2909859; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21895628}; CC Multi-pass membrane protein {ECO:0000269|PubMed:27768894, CC ECO:0000269|PubMed:27851727}. Membrane raft CC {ECO:0000269|PubMed:21895628}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:P47746}. Cell projection, axon CC {ECO:0000250|UniProtKB:P20272}. Presynapse CC {ECO:0000250|UniProtKB:P20272}. Note=Unexpectedly, in the mitochondria, CC the C-terminus is located in the mitochondrial intermembrane space, a CC compartment topologically considered as extracellular. In canonical CC seven-transmembrane G-protein coupled receptors, the C-terminus is CC cytosolic (By similarity). Found on presynaptic axon terminals in some CC GABAergic neurons in the somatosensory cortex (By similarity). CC {ECO:0000250|UniProtKB:P20272, ECO:0000250|UniProtKB:P47746}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Long; CC IsoId=P21554-1; Sequence=Displayed; CC Name=2; Synonyms=CB1a {ECO:0000303|PubMed:15620723}, Short; CC IsoId=P21554-2; Sequence=VSP_001868; CC Name=3; Synonyms=CB1b {ECO:0000303|PubMed:15620723}; CC IsoId=P21554-3; Sequence=VSP_016529; CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in fetal and CC adult brain. Expression levels of isoform 2 and isoform 3 are much CC lower than those of isoform 1. {ECO:0000269|PubMed:15620723}. CC -!- INDUCTION: Up-regulated by endocannabinoid anandamide. CC {ECO:0000269|PubMed:23955712}. CC -!- PTM: Palmitoylation at Cys-415 is important for recruitment at plasma CC membrane and lipid rafts and association with G protein alpha subunits. CC {ECO:0000269|PubMed:21895628}. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by CC an increase of body weight beyond the limitation of skeletal and CC physical requirements, as the result of excessive accumulation of body CC fat. {ECO:0000269|PubMed:18177726}. Note=The protein represented in CC this entry may be involved in disease pathogenesis. May contribute to CC the development of diet-induced obesity and several obesity-associated CC features, such as dyslipidemia and liver steatosis, regulating CC peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 CC inverse agonists have been shown to reduce body weight and improve CC metabolic abnormalities in obese subjects, although adverse CC neuropsychiatric effects, including anxiety, irritability, and CC depressed mood, halted their therapeutic development (PubMed:18177726). CC In obese mice, peripherally restricted CNR1 inverse agonists have been CC shown to normalize metabolic abnormalities, including insulin CC resistance and fatty liver, and to reverse leptin resistance. CC {ECO:0000269|PubMed:18177726}. CC -!- DISEASE: Note=Dysfunction of the endogenous cannabinoid system CC including CNR1 has been implicated in the pathogenesis of a number of CC central nervous system disorders, including Huntington disease, CC Parkinson disease, and Alzheimer disease (PubMed:32549916). In post- CC mortem brains from Huntington disease patients, a progressive CNR1 loss CC has been observed in the caudate nucleus, putamen, and substantia nigra CC pars reticulata, and altered expression and abnormal endocannabinoid CC levels precede motor symptoms in a disease mouse model CC (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson CC disease, low CNR1 expression in mid-superior frontal gyrus and mid- CC cingulate cortex has been associated with poor mind, poor executive CC functioning and poor episode memory, while patients with more severe CC visuospatial dysfunction showed decreased receptor availability in the CC precuneus, mid-cingulate, supplementary motor cortex, inferior CC orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model CC for Alzheimer disease, CNR1 heterozygous deletion has been associated CC with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) CC and accelerated memory impairment, suggesting synaptic dysfunction and CC a crucial role for CNR1 in the progression of disease symptoms CC (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135, CC PubMed:8255419). {ECO:0000269|PubMed:10828533, CC ECO:0000269|PubMed:19524019, ECO:0000269|PubMed:30096288, CC ECO:0000269|PubMed:31342135, ECO:0000269|PubMed:32549916, CC ECO:0000269|PubMed:8255419}. CC -!- MISCELLANEOUS: High-fat diet also increases the hepatic levels of CNR1 CC ligand anandamide, but not that of 2-arachidonoylglycerol. CC {ECO:0000250|UniProtKB:P47746}. CC -!- MISCELLANEOUS: [Isoform 2]: Dubious isoform. A putative downstream CC initiation AUG is used to produce isoform 2 (PubMed:1718258). The use CC of the first AUG (same as isoform 1) gives a truncated protein of 36 CC AA. {ECO:0000305|PubMed:1718258}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. 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; X54937; CAA38699.1; -; mRNA. DR EMBL; X81120; CAA57018.1; -; mRNA. DR EMBL; X81121; CAA57019.1; -; mRNA. DR EMBL; AY766182; AAV35030.1; -; mRNA. DR EMBL; AF107262; AAD34320.1; -; mRNA. DR EMBL; U73304; AAB18200.1; -; Genomic_DNA. DR EMBL; DQ067455; AAY68486.1; -; mRNA. DR EMBL; AY225225; AAO67710.1; -; Genomic_DNA. DR EMBL; AL136096; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AK313908; BAG36631.1; -; mRNA. DR EMBL; CH471051; EAW48574.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48575.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48576.1; -; Genomic_DNA. DR EMBL; BC074811; AAH74811.1; -; mRNA. DR EMBL; BC074812; AAH74812.1; -; mRNA. DR EMBL; BC095513; AAH95513.1; -; mRNA. DR EMBL; BC100968; AAI00969.1; -; mRNA. DR EMBL; BC100969; AAI00970.1; -; mRNA. DR EMBL; BC100970; AAI00971.1; -; mRNA. DR EMBL; BC100971; AAI00972.1; -; mRNA. DR CCDS; CCDS5015.1; -. [P21554-1] DR CCDS; CCDS5016.2; -. [P21554-3] DR PIR; S17595; S17595. DR RefSeq; NP_001153698.1; NM_001160226.3. [P21554-1] DR RefSeq; NP_001153730.1; NM_001160258.3. [P21554-1] DR RefSeq; NP_001153731.1; NM_001160259.3. [P21554-1] DR RefSeq; NP_001352798.1; NM_001365869.2. [P21554-1] DR RefSeq; NP_001352799.1; NM_001365870.2. [P21554-1] DR RefSeq; NP_001352801.1; NM_001365872.2. [P21554-1] DR RefSeq; NP_001352803.1; NM_001365874.3. [P21554-1] DR RefSeq; NP_001357474.1; NM_001370545.1. [P21554-1] DR RefSeq; NP_001357475.1; NM_001370546.1. [P21554-1] DR RefSeq; NP_001357476.1; NM_001370547.1. [P21554-1] DR RefSeq; NP_001411023.1; NM_001424094.1. [P21554-1] DR RefSeq; NP_001411024.1; NM_001424095.1. [P21554-1] DR RefSeq; NP_001411025.1; NM_001424096.1. [P21554-1] DR RefSeq; NP_001411026.1; NM_001424097.1. [P21554-1] DR RefSeq; NP_001411027.1; NM_001424098.1. [P21554-1] DR RefSeq; NP_057167.2; NM_016083.4. [P21554-1] DR RefSeq; NP_149421.2; NM_033181.4. [P21554-3] DR RefSeq; XP_047274127.1; XM_047418171.1. [P21554-1] DR RefSeq; XP_047274128.1; XM_047418172.1. [P21554-1] DR RefSeq; XP_047274129.1; XM_047418173.1. [P21554-1] DR RefSeq; XP_054210179.1; XM_054354204.1. [P21554-1] DR RefSeq; XP_054210180.1; XM_054354205.1. [P21554-1] DR RefSeq; XP_054210181.1; XM_054354206.1. [P21554-1] DR PDB; 1LVQ; NMR; -; A=338-346. DR PDB; 1LVR; NMR; -; A=338-346. DR PDB; 2B0Y; NMR; -; A=400-414. DR PDB; 2KOE; NMR; -; A=377-414. DR PDB; 2MZ2; NMR; -; A=400-414. DR PDB; 2MZ3; NMR; -; A=400-414. DR PDB; 2MZA; NMR; -; A=400-414. DR PDB; 5TGZ; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 5U09; X-ray; 2.60 A; A=90-301, A=333-421. DR PDB; 5XR8; X-ray; 2.95 A; A=99-306, A=332-414. DR PDB; 5XRA; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 6KPG; EM; 3.00 A; R=71-425. DR PDB; 6KQI; X-ray; 3.25 A; A=94-301, A=334-413. DR PDB; 6N4B; EM; 3.00 A; R=1-472. DR PDB; 7FEE; X-ray; 2.70 A; A=74-305, A=333-414. DR PDB; 7V3Z; X-ray; 3.29 A; A=102-306, A=336-414. DR PDB; 7WV9; EM; 3.36 A; R=1-472. DR PDB; 8GAG; EM; 3.30 A; R=1-472. DR PDB; 8GHV; EM; 2.80 A; D=1-472. DR PDB; 8IKG; EM; 3.40 A; R=99-408. DR PDB; 8IKH; EM; 3.30 A; R=99-408. DR PDB; 8K8J; EM; 2.88 A; R=71-425. DR PDB; 8WRZ; EM; 3.60 A; R=71-432. DR PDB; 8WU1; EM; 3.20 A; R=1-413. DR PDB; 9B54; EM; 2.86 A; R=1-472. DR PDB; 9B65; EM; 3.03 A; R=1-472. DR PDB; 9B9Y; EM; 3.50 A; R=96-301, R=334-416. DR PDB; 9B9Z; EM; 3.30 A; R=96-301, R=334-416. DR PDB; 9BA0; EM; 3.13 A; R=96-301, R=334-416. DR PDB; 9DGI; EM; 3.35 A; R=1-472. DR PDB; 9EGO; EM; 3.20 A; R=1-472. DR PDB; 9ERX; EM; 2.90 A; R=2-472. DR PDBsum; 1LVQ; -. DR PDBsum; 1LVR; -. DR PDBsum; 2B0Y; -. DR PDBsum; 2KOE; -. DR PDBsum; 2MZ2; -. DR PDBsum; 2MZ3; -. DR PDBsum; 2MZA; -. DR PDBsum; 5TGZ; -. DR PDBsum; 5U09; -. DR PDBsum; 5XR8; -. DR PDBsum; 5XRA; -. DR PDBsum; 6KPG; -. DR PDBsum; 6KQI; -. DR PDBsum; 6N4B; -. DR PDBsum; 7FEE; -. DR PDBsum; 7V3Z; -. DR PDBsum; 7WV9; -. DR PDBsum; 8GAG; -. DR PDBsum; 8GHV; -. DR PDBsum; 8IKG; -. DR PDBsum; 8IKH; -. DR PDBsum; 8K8J; -. DR PDBsum; 8WRZ; -. DR PDBsum; 8WU1; -. DR PDBsum; 9B54; -. DR PDBsum; 9B65; -. DR PDBsum; 9B9Y; -. DR PDBsum; 9B9Z; -. DR PDBsum; 9BA0; -. DR PDBsum; 9DGI; -. DR PDBsum; 9EGO; -. DR PDBsum; 9ERX; -. DR AlphaFoldDB; P21554; -. DR EMDB; EMD-0339; -. DR EMDB; EMD-0745; -. DR EMDB; EMD-19929; -. DR EMDB; EMD-29898; -. DR EMDB; EMD-32850; -. DR EMDB; EMD-35511; -. DR EMDB; EMD-35512; -. DR EMDB; EMD-36951; -. DR EMDB; EMD-37795; -. DR EMDB; EMD-40052; -. DR EMDB; EMD-44199; -. DR EMDB; EMD-44247; -. DR EMDB; EMD-44392; -. DR EMDB; EMD-44393; -. DR EMDB; EMD-44394; -. DR EMDB; EMD-46828; -. DR EMDB; EMD-47992; -. DR SMR; P21554; -. DR BioGRID; 107668; 11. DR CORUM; P21554; -. DR DIP; DIP-61575N; -. DR FunCoup; P21554; 1275. DR IntAct; P21554; 12. DR STRING; 9606.ENSP00000358513; -. DR BindingDB; P21554; -. DR ChEMBL; CHEMBL218; -. DR DrugBank; DB09061; Cannabidiol. DR DrugBank; DB14737; Cannabinol. DR DrugBank; DB05750; Drinabant. DR DrugBank; DB00470; Dronabinol. DR DrugBank; DB14009; Medical Cannabis. DR DrugBank; DB00486; Nabilone. DR DrugBank; DB14011; Nabiximols. DR DrugBank; DB16495; Oleic monoethanolamide. DR DrugBank; DB01083; Orlistat. DR DrugBank; DB11745; Otenabant. DR DrugBank; DB13495; Paraoxon. DR DrugBank; DB09288; Propacetamol. DR DrugBank; DB02955; Ricinoleic acid. DR DrugBank; DB06155; Rimonabant. DR DrugBank; DB05077; SLV319. DR DrugBank; DB13070; Surinabant. DR DrugBank; DB06624; Taranabant. DR DrugBank; DB11755; Tetrahydrocannabivarin. DR DrugBank; DB05201; V24343. DR DrugBank; DB13950; WIN 55212-2. DR DrugCentral; P21554; -. DR GuidetoPHARMACOLOGY; 56; -. DR SwissLipids; SLP:000001607; -. DR TCDB; 9.A.14.2.2; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P21554; 2 sites, No reported glycans. DR GlyGen; P21554; 2 sites. DR iPTMnet; P21554; -. DR PhosphoSitePlus; P21554; -. DR SwissPalm; P21554; -. DR BioMuta; CNR1; -. DR DMDM; 115562; -. DR MassIVE; P21554; -. DR PaxDb; 9606-ENSP00000358513; -. DR PeptideAtlas; P21554; -. DR ProteomicsDB; 53875; -. [P21554-1] DR ProteomicsDB; 53876; -. [P21554-2] DR ProteomicsDB; 53877; -. [P21554-3] DR ABCD; P21554; 62 sequenced antibodies. DR Antibodypedia; 3355; 718 antibodies from 42 providers. DR DNASU; 1268; -. DR Ensembl; ENST00000369499.3; ENSP00000358511.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000369501.3; ENSP00000358513.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000428600.3; ENSP00000412192.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000468898.2; ENSP00000420188.1; ENSG00000118432.14. [P21554-3] DR Ensembl; ENST00000549890.2; ENSP00000446819.1; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000551417.2; ENSP00000446702.2; ENSG00000118432.14. [P21554-1] DR GeneID; 1268; -. DR KEGG; hsa:1268; -. DR MANE-Select; ENST00000369501.3; ENSP00000358513.2; NM_016083.6; NP_057167.2. DR AGR; HGNC:2159; -. DR ClinPGx; PA26681; -. DR CTD; 1268; -. DR DisGeNET; 1268; -. DR GeneCards; CNR1; -. DR HGNC; HGNC:2159; CNR1. DR HPA; ENSG00000118432; Tissue enhanced (adipose tissue, pituitary gland). DR MIM; 114610; gene. DR MIM; 601665; phenotype. DR OpenTargets; ENSG00000118432; -. DR VEuPathDB; HostDB:ENSG00000118432; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT01140000282530; -. DR HOGENOM; CLU_009579_7_0_1; -. DR InParanoid; P21554; -. DR OMA; HKHANSA; -. DR OrthoDB; 5966748at2759; -. DR PAN-GO; P21554; 6 GO annotations based on evolutionary models. DR PhylomeDB; P21554; -. DR PathwayCommons; P21554; -. DR Reactome; R-HSA-373076; Class A/1 (Rhodopsin-like receptors). DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR SignaLink; P21554; -. DR SIGNOR; P21554; -. DR Agora; ENSG00000118432; -. DR BioGRID-ORCS; 1268; 19 hits in 1157 CRISPR screens. DR ChiTaRS; CNR1; human. DR EvolutionaryTrace; P21554; -. DR GeneWiki; Cannabinoid_receptor_type_1; -. DR GenomeRNAi; 1268; -. DR Pharos; P21554; Tclin. DR PRO; PR:P21554; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P21554; protein. DR Bgee; ENSG00000118432; Expressed in ganglionic eminence and 150 other cell types or tissues. DR ExpressionAtlas; P21554; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0030426; C:growth cone; IEA:Ensembl. DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0004949; F:cannabinoid receptor activity; IDA:UniProtKB. DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0007413; P:axonal fasciculation; IEA:Ensembl. DR GO; GO:0038171; P:cannabinoid signaling pathway; IDA:UniProtKB. DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc. DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl. DR GO; GO:0099509; P:regulation of presynaptic cytosolic calcium ion concentration; IEA:Ensembl. DR GO; GO:0098921; P:retrograde trans-synaptic signaling by endocannabinoid; IEA:Ensembl. DR CDD; cd15340; 7tmA_CB1; 1. DR FunFam; 1.20.1070.10:FF:000072; Cannabinoid receptor 1; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000810; Canbinoid_rcpt_1. DR InterPro; IPR002230; Cnbnoid_rcpt. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR PANTHER; PTHR22750; G-PROTEIN COUPLED RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PIRSF; PIRSF037995; Cnoid_rcpt_1; 1. DR PRINTS; PR00522; CANABINOID1R. DR PRINTS; PR00362; CANNABINOIDR. DR PRINTS; PR00237; GPCRRHODOPSN. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; KW Mitochondrion; Mitochondrion outer membrane; Neurodegeneration; Obesity; KW Palmitate; Phosphoprotein; Proteomics identification; Receptor; KW Reference proteome; Synapse; Transducer; Transmembrane; KW Transmembrane helix. FT CHAIN 1..472 FT /note="Cannabinoid receptor 1" FT /id="PRO_0000069314" FT TOPO_DOM 1..116 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 117..142 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 143..154 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 155..175 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 176..187 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 188..212 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 213..232 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 233..255 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 256..273 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 274..299 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 300..344 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 345..365 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 366..377 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 378..399 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 400..472 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT REGION 2..23 FT /note="Required for mitochondrial localization" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 425 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 429 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT LIPID 415 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:21895628" FT CARBOHYD 77 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 83 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..89 FT /note="MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTS FT FRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF -> MALQIPPSAPSPLTSCTW FT AQMTFSTKTS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7876112" FT /id="VSP_001868" FT VAR_SEQ 22..54 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15620723" FT /id="VSP_016529" FT MUTAGEN 155 FT /note="F->V: Enhanced G(i) signaling activation ability." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 155 FT /note="F->W: Reduced agonist-induced receptor activation." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 210 FT /note="T->A: 7-fold lower affinity for a synthetic agonist, FT CP55940, possibly due the stabilization of an inactive FT conformation." FT /evidence="ECO:0000269|PubMed:27851727" FT MUTAGEN 341..342 FT /note="LA->AL: Loss of activity, when assayed for GNAI1 FT GTPase stimulatory activity." FT /evidence="ECO:0000269|PubMed:12237474" FT MUTAGEN 415 FT /note="C->A: Loss of palmitoylation, marked loss of FT association with lipid rafts on the plasma membrane and FT loss of activity, when assayed for downstream GTP-binding FT and reduction in cAMP levels." FT /evidence="ECO:0000269|PubMed:21895628" FT CONFLICT 94 FT /note="E -> G (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 103 FT /note="M -> I (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 149 FT /note="C -> R (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 200 FT /note="F -> L (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 216 FT /note="I -> V (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 246 FT /note="V -> A (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 298 FT /note="L -> P (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 332 FT /note="P -> S (in Ref. 12; AAI00972)" FT /evidence="ECO:0000305" FT STRAND 100..102 FT /evidence="ECO:0007829|PDB:7FEE" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 113..143 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 145..148 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 151..153 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 154..178 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 186..219 FT /evidence="ECO:0007829|PDB:5U09" FT TURN 221..223 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 224..227 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 230..249 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 250..253 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 257..260 FT /evidence="ECO:0007829|PDB:5U09" FT STRAND 266..268 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 273..300 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 302..305 FT /evidence="ECO:0007829|PDB:6KPG" FT HELIX 306..309 FT /evidence="ECO:0007829|PDB:8K8J" FT HELIX 334..367 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 375..400 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 402..409 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 411..415 FT /evidence="ECO:0007829|PDB:2B0Y" SQ SEQUENCE 472 AA; 52858 MW; 1D2E49061D12ABF2 CRC64; MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE KMTAGDNPQL VPADQVNITE FYNKSLSSFK ENEENIQCGE NFMDIECFMV LNPSQQLAIA VLSLTLGTFT VLENLLVLCV ILHSRSLRCR PSYHFIGSLA VADLLGSVIF VYSFIDFHVF HRKDSRNVFL FKLGGVTASF TASVGSLFLT AIDRYISIHR PLAYKRIVTR PKAVVAFCLM WTIAIVIAVL PLLGWNCEKL QSVCSDIFPH IDETYLMFWI GVTSVLLLFI VYAYMYILWK AHSHAVRMIQ RGTQKSIIIH TSEDGKVQVT RPDQARMDIR LAKTLVLILV VLIICWGPLL AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR SKDLRHAFRS MFPSCEGTAQ PLDNSMGDSD CLHKHANNAA SVHRAAESCI KSTVKIAKVT MSVSTDTSAE AL // ID HRH2_HUMAN Reviewed; 359 AA. AC P25021; B5BUP7; Q14464; Q7Z5R9; DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1992, sequence version 1. DT 28-JAN-2026, entry version 203. DE RecName: Full=Histamine H2 receptor; DE Short=H2R; DE Short=HH2R; DE AltName: Full=Gastric receptor I; GN Name=HRH2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=1714721; DOI=10.1016/0006-291x(91)91047-g; RA Gantz I., Munzert G., Tashiro T., Schaeffer M., Wang L.-D., DelValle J., RA Yamada T.; RT "Molecular cloning of the human histamine H2 receptor."; RL Biochem. Biophys. Res. Commun. 178:1386-1392(1991). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Liver; RX PubMed=7755641; DOI=10.1006/bbrc.1995.1703; RA Nishi T., Koike T., Oka T., Maeda M., Futai M.; RT "Identification of the promoter region of the human histamine H2-receptor RT gene."; RL Biochem. Biophys. Res. Commun. 210:616-623(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10371214; DOI=10.1016/s0014-5793(99)00618-3; RA Murakami H., Sun-Wada G., Matsumoto M., Nishi T., Wada Y., Futai M.; RT "Human histamine H2 receptor gene: multiple transcription initiation and RT tissue-specific expression."; RL FEBS Lett. 451:327-331(1999). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=15014171; DOI=10.1093/molbev/msh100; RA Kitano T., Liu Y.-H., Ueda S., Saitou N.; RT "Human-specific amino acid changes found in 103 protein-coding genes."; RL Mol. Biol. Evol. 21:936-944(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Stomach; RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=19054851; DOI=10.1038/nmeth.1273; RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R., RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y., RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B., RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H., Maruyama Y., RA Matsuo K., Minami K., Mitsubori M., Mori M., Morishita R., Murase A., RA Nishikawa A., Nishikawa S., Okamoto T., Sakagami N., Sakamoto Y., RA Sasaki Y., Seki T., Sono S., Sugiyama A., Sumiya T., Takayama T., RA Takayama Y., Takeda H., Togashi T., Yahata K., Yamada H., Yanagisawa Y., RA Endo Y., Imamoto F., Kisu Y., Tanaka S., Isogai T., Imai J., Watanabe S., RA Nomura N.; RT "Human protein factory for converting the transcriptome into an in vitro- RT expressed proteome."; RL Nat. Methods 5:1011-1017(2008). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 4-351, AND POLYMORPHISM. RC TISSUE=Brain; RX PubMed=8817552; DOI=10.1097/00001756-199605170-00015; RA Orange P.R., Heath P.R., Wright S.R., Pearson R.C.A.; RT "Allelic variations of the human histamine H2 receptor gene."; RL NeuroReport 7:1293-1296(1996). RN [10] RP REVIEW. RX PubMed=9374694; DOI=10.1152/ajpgi.1997.273.5.g987; RA DelValle J., Gantz I.; RT "Novel insights into histamine H2 receptor biology."; RL Am. J. Physiol. 273:G987-G996(1997). RN [11] {ECO:0007744|PDB:8YUT} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF 2-359, DISULFIDE RP BONDS, FUNCTION, AND INTERACTION WITH GNAS. RX PubMed=38647423; DOI=10.1002/advs.202310120; RA Shen Q., Tang X., Wen X., Cheng S., Xiao P., Zang S.K., Shen D.D., RA Jiang L., Zheng Y., Zhang H., Xu H., Mao C., Zhang M., Hu W., Sun J.P., RA Zhang Y., Chen Z.; RT "Molecular Determinant Underlying Selective Coupling of Primary G-Protein RT by Class A GPCRs."; RL Adv. Sci. 11:e2310120-e2310120(2024). RN [12] {ECO:0007744|PDB:8POK} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), DISULFIDE BONDS, AND RP TOPOLOGY. RX PubMed=38418462; DOI=10.1038/s41467-024-46096-z; RA Kock Z., Schnelle K., Persechino M., Umbach S., Schihada H., Januliene D., RA Parey K., Pockes S., Kolb P., Dotsch V., Moller A., Hilger D., Bernhard F.; RT "Cryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs RT complex in nanodisc environment."; RL Nat. Commun. 15:1831-1831(2024). RN [13] {ECO:0007744|PDB:8YN3, ECO:0007744|PDB:8YN4} RP STRUCTURE BY ELECTRON MICROSCOPY (2.56 ANGSTROMS) OF 1-312, DISULFIDE RP BONDS, AND FUNCTION. RX PubMed=39333117; DOI=10.1038/s41467-024-52585-y; RA Zhang X., Liu G., Zhong Y.N., Zhang R., Yang C.C., Niu C., Pu X., Sun J., RA Zhang T., Yang L., Zhang C., Li X., Shen X., Xiao P., Sun J.P., Gong W.; RT "Structural basis of ligand recognition and activation of the histamine RT receptor family."; RL Nat. Commun. 15:8296-8296(2024). CC -!- FUNCTION: G-protein coupled receptor for histamine, primarily mediating CC gastric acid secretion. Predominantly expressed in the gastric mucosa, CC couples to G(s) G alpha proteins upon histamine binding, leading to CC activation of adenylate cyclase and increased intracellular cyclic AMP CC (cAMP) levels (PubMed:38647423, PubMed:39333117). This signaling CC cascade stimulates parietal cells to secrete hydrochloric acid, playing CC a key role in digestive physiology. Also expressed in other tissues, CC including the heart and central nervous system, where it may contribute CC to cardiac stimulation and modulate neurotransmitter release (By CC similarity). {ECO:0000250|UniProtKB:P97292, CC ECO:0000269|PubMed:38647423, ECO:0000269|PubMed:39333117}. CC -!- SUBUNIT: Interacts with GNAS. {ECO:0000269|PubMed:38647423}. CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P25021-1; Sequence=Displayed; CC Name=2; CC IsoId=P25021-2; Sequence=VSP_043594; CC -!- MISCELLANEOUS: Antagonists for this receptor have proven to be CC effective therapy for acid peptic disorders of the gastrointestinal CC tract. Certain antagonists are used in the treatment of CC neuropsychiatric and neurological diseases such as schizophrenia, CC Alzheimer disease and Parkinson disease. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=H2 receptor entry; CC URL="https://en.wikipedia.org/wiki/H2_receptor"; 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; M64799; AAA58647.1; -; Genomic_DNA. DR EMBL; D49783; BAA08618.1; -; Genomic_DNA. DR EMBL; AB023486; BAA84279.1; -; Genomic_DNA. DR EMBL; AB041384; BAA94469.1; -; Genomic_DNA. DR EMBL; AY136744; AAN01270.1; -; mRNA. DR EMBL; AB451483; BAG70297.1; -; mRNA. DR EMBL; CH471062; EAW61369.1; -; Genomic_DNA. DR EMBL; BC054510; AAH54510.1; -; mRNA. DR EMBL; X98133; CAA66832.1; -; Genomic_DNA. DR CCDS; CCDS47344.1; -. [P25021-2] DR PIR; JH0449; JH0449. DR RefSeq; NP_001124527.1; NM_001131055.2. [P25021-2] DR PDB; 7UL3; EM; 3.00 A; A=1-199, A=248-359. DR PDB; 8POK; EM; 3.40 A; A=1-359. DR PDB; 8YN3; EM; 2.56 A; R=1-312. DR PDB; 8YN4; EM; 2.97 A; R=1-312. DR PDB; 8YUT; EM; 2.70 A; R=2-359. DR PDB; 9IXJ; EM; 2.92 A; R=1-359. DR PDBsum; 7UL3; -. DR PDBsum; 8POK; -. DR PDBsum; 8YN3; -. DR PDBsum; 8YN4; -. DR PDBsum; 8YUT; -. DR PDBsum; 9IXJ; -. DR AlphaFoldDB; P25021; -. DR EMDB; EMD-17793; -. DR EMDB; EMD-26590; -. DR EMDB; EMD-39413; -. DR EMDB; EMD-39414; -. DR EMDB; EMD-39582; -. DR EMDB; EMD-60971; -. DR SMR; P25021; -. DR BioGRID; 109510; 1. DR CORUM; P25021; -. DR FunCoup; P25021; 1004. DR STRING; 9606.ENSP00000366506; -. DR BindingDB; P25021; -. DR ChEMBL; CHEMBL1941; -. DR DrugBank; DB00321; Amitriptyline. DR DrugBank; DB01238; Aripiprazole. DR DrugBank; DB06216; Asenapine. DR DrugBank; DB00972; Azelastine. DR DrugBank; DB00272; Betazole. DR DrugBank; DB00501; Cimetidine. DR DrugBank; DB00434; Cyproheptadine. DR DrugBank; DB01142; Doxepin. DR DrugBank; DB00751; Epinastine. DR DrugBank; DB00927; Famotidine. DR DrugBank; DB05381; Histamine. DR DrugBank; DB05369; HZT-501. DR DrugBank; DB12884; Lavoltidine. DR DrugBank; DB00408; Loxapine. DR DrugBank; DB00940; Methantheline. DR DrugBank; DB08805; Metiamide. DR DrugBank; DB13760; Niperotidine. DR DrugBank; DB00585; Nizatidine. DR DrugBank; DB00768; Olopatadine. DR DrugBank; DB01069; Promethazine. DR DrugBank; DB00863; Ranitidine. DR DrugBank; DB08806; Roxatidine acetate. DR DrugBank; DB00797; Tolazoline. DR DrugBank; DB09185; Viloxazine. DR DrugCentral; P25021; -. DR GuidetoPHARMACOLOGY; 263; -. DR GlyCosmos; P25021; 1 site, No reported glycans. DR GlyGen; P25021; 1 site. DR PhosphoSitePlus; P25021; -. DR BioMuta; HRH2; -. DR DMDM; 123120; -. DR PaxDb; 9606-ENSP00000366506; -. DR PeptideAtlas; P25021; -. DR Antibodypedia; 2931; 339 antibodies from 38 providers. DR DNASU; 3274; -. DR Ensembl; ENST00000377291.2; ENSP00000366506.2; ENSG00000113749.9. [P25021-2] DR GeneID; 3274; -. DR KEGG; hsa:3274; -. DR UCSC; uc003mdc.5; human. [P25021-1] DR AGR; HGNC:5183; -. DR ClinPGx; PA29457; -. DR CTD; 3274; -. DR DisGeNET; 3274; -. DR GeneCards; HRH2; -. DR HGNC; HGNC:5183; HRH2. DR HPA; ENSG00000113749; Tissue enhanced (bone marrow, heart muscle). DR MIM; 142703; gene. DR OpenTargets; ENSG00000113749; -. DR VEuPathDB; HostDB:ENSG00000113749; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT00940000158761; -. DR HOGENOM; CLU_009579_11_0_1; -. DR InParanoid; P25021; -. DR OMA; CGNVMVC; -. DR OrthoDB; 5951059at2759; -. DR PAN-GO; P25021; 6 GO annotations based on evolutionary models. DR PhylomeDB; P25021; -. DR PathwayCommons; P25021; -. DR Reactome; R-HSA-390650; Histamine receptors. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; P25021; -. DR SIGNOR; P25021; -. DR Agora; ENSG00000113749; -. DR BioGRID-ORCS; 3274; 15 hits in 1155 CRISPR screens. DR GeneWiki; Histamine_H2_receptor; -. DR GenomeRNAi; 3274; -. DR Pharos; P25021; Tclin. DR PRO; PR:P25021; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; P25021; protein. DR Bgee; ENSG00000113749; Expressed in monocyte and 116 other cell types or tissues. DR ExpressionAtlas; P25021; baseline and differential. DR GO; GO:0030425; C:dendrite; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0045202; C:synapse; IEA:GOC. DR GO; GO:0004969; F:histamine receptor activity; IDA:UniProt. DR GO; GO:0030594; F:neurotransmitter receptor activity; IBA:GO_Central. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; TAS:UniProt. DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; IBA:GO_Central. DR GO; GO:0001696; P:gastric acid secretion; IEA:InterPro. DR GO; GO:0006955; P:immune response; TAS:ProtInc. DR GO; GO:0045907; P:positive regulation of vasoconstriction; IEA:InterPro. DR CDD; cd15051; 7tmA_Histamine_H2R; 1. DR FunFam; 1.20.1070.10:FF:000121; Histamine H2 receptor; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR000503; Histamine_H2_rcpt. DR PANTHER; PTHR24247; 5-HYDROXYTRYPTAMINE RECEPTOR; 1. DR PANTHER; PTHR24247:SF278; HISTAMINE H2 RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR00531; HISTAMINEH2R. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Disulfide bond; KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; Palmitate; KW Proteomics identification; Receptor; Reference proteome; Transducer; KW Transmembrane; Transmembrane helix. FT CHAIN 1..359 FT /note="Histamine H2 receptor" FT /id="PRO_0000069684" FT TOPO_DOM 1..20 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 21..44 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 45..53 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 54..75 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 76..91 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 92..114 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 115..133 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 134..156 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 157..174 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 175..202 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 203..232 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 233..259 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 260..268 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 269..291 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 292..359 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT REGION 316..340 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 317..327 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 328..340 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 98 FT /note="Essential for histamine binding" FT /evidence="ECO:0000250" FT SITE 186 FT /note="Essential for tiotidine binding and implicated in H2 FT selectivity" FT /evidence="ECO:0000250" FT SITE 190 FT /note="Implicated in histamine binding" FT /evidence="ECO:0000250" FT LIPID 305 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT CARBOHYD 4 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 91..174 FT /evidence="ECO:0000269|PubMed:38418462, FT ECO:0000269|PubMed:38647423, ECO:0000269|PubMed:39333117" FT VAR_SEQ 359 FT /note="R -> RPWLCLPECWSVELTHSFIHLFIHSFANIHPIPTTCQEL (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043594" FT VARIANT 217 FT /note="N -> D" FT /id="VAR_009958" FT VARIANT 231 FT /note="K -> R" FT /id="VAR_009959" FT VARIANT 268 FT /note="V -> M" FT /id="VAR_009960" FT CONFLICT 133 FT /note="V -> A (in Ref. 9; CAA66832)" FT /evidence="ECO:0000305" FT CONFLICT 175 FT /note="K -> N (in Ref. 9; CAA66832)" FT /evidence="ECO:0000305" FT CONFLICT 207 FT /note="K -> R (in Ref. 9; CAA66832)" FT /evidence="ECO:0000305" FT HELIX 15..45 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 52..54 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 55..70 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 72..81 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 88..121 FT /evidence="ECO:0007829|PDB:8YN3" FT TURN 123..125 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 126..129 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 132..155 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 180..190 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 192..217 FT /evidence="ECO:0007829|PDB:8YN3" FT STRAND 221..223 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 231..260 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 267..287 FT /evidence="ECO:0007829|PDB:8YN3" FT TURN 288..291 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 293..301 FT /evidence="ECO:0007829|PDB:8YN3" SQ SEQUENCE 359 AA; 40098 MW; 9835AE2BA60B9B0F CRC64; MAPNGTASSF CLDSTACKIT ITVVLAVLIL ITVAGNVVVC LAVGLNRRLR NLTNCFIVSL AITDLLLGLL VLPFSAIYQL SCKWSFGKVF CNIYTSLDVM LCTASILNLF MISLDRYCAV MDPLRYPVLV TPVRVAISLV LIWVISITLS FLSIHLGWNS RNETSKGNHT TSKCKVQVNE VYGLVDGLVT FYLPLLIMCI TYYRIFKVAR DQAKRINHIS SWKAATIREH KATVTLAAVM GAFIICWFPY FTAFVYRGLR GDDAINEVLE AIVLWLGYAN SALNPILYAA LNRDFRTGYQ QLFCCRLANR NSHKTSLRSN ASQLSRTQSR EPRQQEEKPL KLQVWSGTEV TAPQGATDR // ID PAWR_HUMAN Reviewed; 340 AA. AC Q96IZ0; O75796; Q6FHY9; Q8N700; DT 24-MAY-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 183. DE RecName: Full=PRKC apoptosis WT1 regulator protein; DE AltName: Full=Prostate apoptosis response 4 protein; DE Short=Par-4; GN Name=PAWR; Synonyms=PAR4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND RP INTERACTION WITH WT1. RX PubMed=8943350; DOI=10.1128/mcb.16.12.6945; RA Johnstone R.W., See R.H., Sells S.F., Wang J., Muthukkumar S., Englert C., RA Haber D.A., Licht J.D., Sugrue S.P., Roberts T., Rangnekar V.M., Shi Y.; RT "A novel repressor, par-4, modulates transcription and growth suppression RT functions of the Wilms' tumor suppressor WT1."; RL Mol. Cell. Biol. 16:6945-6956(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-78. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-42; ARG-78; ALA-137 AND RP ALA-202. RG NIEHS SNPs program; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-64. RC TISSUE=Blood; RX PubMed=12242017; DOI=10.1016/s0378-1119(02)00826-0; RA Hsu S.-C., Kirschenbaum F., Miller J., Cordell B., McCarthy J.V.; RT "Structural and functional characterization of the upstream regulatory RT region of the human gene encoding prostate apoptosis response factor-4."; RL Gene 295:109-116(2002). RN [6] RP FUNCTION IN APOPTOSIS AND TUMOR REGRESSION. RX PubMed=11585763; RA Chakraborty M., Qiu S.G., Vasudevan K.M., Rangnekar V.M.; RT "Par-4 drives trafficking and activation of Fas and Fasl to induce prostate RT cancer cell apoptosis and tumor regression."; RL Cancer Res. 61:7255-7263(2001). RN [7] RP INTERACTION WITH SQSTM1 AND PRKCZ. RX PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0; RA Chang S., Kim J.H., Shin J.; RT "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4- RT induced PKCzeta inhibition."; RL FEBS Lett. 510:57-61(2002). RN [8] RP SUBCELLULAR LOCATION, AND INTERACTION WITH THAP1. RX PubMed=12717420; DOI=10.1038/sj.onc.1206271; RA Roussigne M., Cayrol C., Clouaire T., Amalric F., Girard J.-P.; RT "THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis- RT response-4 (Par-4) to PML nuclear bodies."; RL Oncogene 22:2432-2442(2003). RN [9] RP INTERACTION WITH AATF. RX PubMed=14627703; DOI=10.1074/jbc.m309811200; RA Guo Q., Xie J.; RT "AATF inhibits aberrant production of amyloid beta peptide 1-42 by RT interacting directly with Par-4."; RL J. Biol. Chem. 279:4596-4603(2004). RN [10] RP INTERACTION WITH BACE1. RX PubMed=15671026; DOI=10.1074/jbc.m411933200; RA Xie J., Guo Q.; RT "PAR-4 is involved in regulation of beta-secretase cleavage of the RT Alzheimer amyloid precursor protein."; RL J. Biol. Chem. 280:13824-13832(2005). RN [11] RP INTERACTION WITH SPSB1 AND SPSB2, AND MUTAGENESIS OF ASN-72. RX PubMed=17189197; DOI=10.1016/j.molcel.2006.11.009; RA Woo J.S., Suh H.Y., Park S.Y., Oh B.H.; RT "Structural basis for protein recognition by B30.2/SPRY domains."; RL Mol. Cell 24:967-976(2006). RN [12] RP REVIEW ON FUNCTION IN APOPTOSIS AND NEURODEGENERATIVE DISEASES. RX PubMed=12565819; DOI=10.1016/s0014-4827(02)00016-2; RA El-Guendy N., Rangnekar V.M.; RT "Apoptosis by Par-4 in cancer and neurodegenerative diseases."; RL Exp. Cell Res. 283:51-66(2003). RN [13] RP REVIEW. RX PubMed=14755681; DOI=10.1002/jcb.20000; RA Gurumurthy S., Rangnekar V.M.; RT "Par-4 inducible apoptosis in prostate cancer cells."; RL J. Cell. Biochem. 91:504-512(2004). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-231, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [20] {ECO:0007744|PDB:2JK9} RP X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) OF 67-74 IN COMPLEX WITH SPSB1, RP INTERACTION WITH SPSB1; SPSB2 AND SPSB4, MUTAGENESIS OF ALA-66; GLU-68; RP LEU-69; ASN-71 AND ASN-72, AND MOTIF. RX PubMed=20561531; DOI=10.1016/j.jmb.2010.06.017; RA Filippakopoulos P., Low A., Sharpe T.D., Uppenberg J., Yao S., Kuang Z., RA Savitsky P., Lewis R.S., Nicholson S.E., Norton R.S., Bullock A.N.; RT "Structural basis for Par-4 recognition by the SPRY domain- and SOCS box- RT containing proteins SPSB1, SPSB2, and SPSB4."; RL J. Mol. Biol. 401:389-402(2010). CC -!- FUNCTION: Pro-apoptotic protein capable of selectively inducing CC apoptosis in cancer cells, sensitizing the cells to diverse apoptotic CC stimuli and causing regression of tumors in animal models. Induces CC apoptosis in certain cancer cells by activation of the Fas prodeath CC pathway and coparallel inhibition of NF-kappa-B transcriptional CC activity. Inhibits the transcriptional activation and augments the CC transcriptional repression mediated by WT1. Down-regulates the anti- CC apoptotic protein BCL2 via its interaction with WT1. Also seems to be a CC transcriptional repressor by itself. May be directly involved in CC regulating the amyloid precursor protein (APP) cleavage activity of CC BACE1. {ECO:0000269|PubMed:11585763}. CC -!- SUBUNIT: Homooligomer. Interacts (via the C-terminal region) with WT1 CC (PubMed:8943350). Interacts with THAP1 (PubMed:12717420). Interacts CC with AATF (PubMed:14627703). Interacts with BACE1 (PubMed:15671026). CC Interacts with SPSB1 (via B30.2/SPRY domain); this interaction is CC direct and occurs in association with the Elongin BC complex CC (PubMed:17189197, PubMed:20561531). Interacts with SPSB2 (via CC B30.2/SPRY domain); this interaction occurs in association with the CC Elongin BC complex (PubMed:17189197, PubMed:20561531). Interacts with CC SPSB4 (via B30.2/SPRY domain) (PubMed:20561531); this interaction CC occurs in association with the Elongin BC complex (PubMed:20561531). CC Component of a ternary complex composed of SQSTM1 and PRKCZ CC (PubMed:11755531). Interacts with actin (By similarity). CC {ECO:0000250|UniProtKB:Q62627, ECO:0000250|UniProtKB:Q925B0, CC ECO:0000269|PubMed:11755531, ECO:0000269|PubMed:12717420, CC ECO:0000269|PubMed:14627703, ECO:0000269|PubMed:15671026, CC ECO:0000269|PubMed:17189197, ECO:0000269|PubMed:20561531, CC ECO:0000269|PubMed:8943350}. CC -!- INTERACTION: CC Q96IZ0; Q01094: E2F1; NbExp=2; IntAct=EBI-595869, EBI-448924; CC Q96IZ0; P11021: HSPA5; NbExp=8; IntAct=EBI-595869, EBI-354921; CC Q96IZ0; Q96BD6: SPSB1; NbExp=2; IntAct=EBI-595869, EBI-2659201; CC Q96IZ0; Q99619: SPSB2; NbExp=2; IntAct=EBI-595869, EBI-2323209; CC Q96IZ0; Q96A44: SPSB4; NbExp=2; IntAct=EBI-595869, EBI-2323233; CC Q96IZ0; P08670: VIM; NbExp=2; IntAct=EBI-595869, EBI-353844; CC Q96IZ0; Q9D5L7: Spsb1; Xeno; NbExp=2; IntAct=EBI-595869, EBI-8821912; CC Q96IZ0; O88838: Spsb2; Xeno; NbExp=6; IntAct=EBI-595869, EBI-8820410; CC Q96IZ0; Q8R5B6: Spsb4; Xeno; NbExp=3; IntAct=EBI-595869, EBI-8821982; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Mainly cytoplasmic in CC absence of apoptosis signal and in normal cells. Nuclear in most cancer CC cell lines. Nuclear entry seems to be essential but not sufficient for CC apoptosis (By similarity). Nuclear localization includes nucleoplasm CC and PML nuclear bodies. {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Widely expressed. Expression is elevated in various CC neurodegenerative diseases such as amyotrophic lateral sclerosis, CC Alzheimer, Parkinson and Huntington diseases and stroke. Down-regulated CC in several cancers. {ECO:0000269|PubMed:8943350}. CC -!- INDUCTION: By apoptosis. CC -!- DOMAIN: The leucine-zipper domain is not essential for apoptosis, but CC is required for sensitization of cells to exogenous apoptotic insults CC and for interaction with its partners. {ECO:0000250}. CC -!- DOMAIN: The SAC domain is a death-inducing domain selective for CC apoptosis induction in cancer cells. This domain is essential for CC nuclear entry, Fas activation, inhibition of NF-kappa-B activity and CC induction of apoptosis in cancer cells (By similarity). {ECO:0000250}. CC -!- DOMAIN: The B30.2/SPRY domain-binding motif mediates recognition by CC proteins containing a B30.2/SPRY domain. {ECO:0000269|PubMed:20561531}. CC -!- PTM: Preferentially phosphorylated at the Thr-163 by PKC in cancer CC cells. {ECO:0000250}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41641/PAWR"; CC --------------------------------------------------------------------------- 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; U63809; AAC24947.1; -; mRNA. DR EMBL; CR536549; CAG38786.1; -; mRNA. DR EMBL; AY300794; AAP43693.1; -; Genomic_DNA. DR EMBL; BC007018; AAH07018.1; -; mRNA. DR EMBL; AF503628; AAM27453.1; -; Genomic_DNA. DR CCDS; CCDS31863.1; -. DR RefSeq; NP_001341661.1; NM_001354732.2. DR RefSeq; NP_002574.2; NM_002583.4. DR RefSeq; XP_047284872.1; XM_047428916.1. DR RefSeq; XP_054228126.1; XM_054372151.1. DR PDB; 2JK9; X-ray; 1.79 A; B=67-81. DR PDBsum; 2JK9; -. DR AlphaFoldDB; Q96IZ0; -. DR SMR; Q96IZ0; -. DR BioGRID; 111108; 137. DR CORUM; Q96IZ0; -. DR DIP; DIP-29003N; -. DR ELM; Q96IZ0; -. DR FunCoup; Q96IZ0; 1301. DR IntAct; Q96IZ0; 40. DR MINT; Q96IZ0; -. DR STRING; 9606.ENSP00000328088; -. DR BindingDB; Q96IZ0; -. DR DrugBank; DB14942; BMS-986141. DR GlyGen; Q96IZ0; 12 sites, 1 O-linked glycan (12 sites). DR iPTMnet; Q96IZ0; -. DR PhosphoSitePlus; Q96IZ0; -. DR BioMuta; PAWR; -. DR DMDM; 66773935; -. DR jPOST; Q96IZ0; -. DR MassIVE; Q96IZ0; -. DR PaxDb; 9606-ENSP00000328088; -. DR PeptideAtlas; Q96IZ0; -. DR ProteomicsDB; 76870; -. DR Pumba; Q96IZ0; -. DR TopDownProteomics; Q96IZ0; -. DR Antibodypedia; 1824; 392 antibodies from 41 providers. DR DNASU; 5074; -. DR Ensembl; ENST00000328827.9; ENSP00000328088.4; ENSG00000177425.12. DR GeneID; 5074; -. DR KEGG; hsa:5074; -. DR MANE-Select; ENST00000328827.9; ENSP00000328088.4; NM_002583.4; NP_002574.2. DR UCSC; uc001syx.4; human. DR AGR; HGNC:8614; -. DR ClinPGx; PA32954; -. DR CTD; 5074; -. DR DisGeNET; 5074; -. DR GeneCards; PAWR; -. DR HGNC; HGNC:8614; PAWR. DR HPA; ENSG00000177425; Low tissue specificity. DR MIM; 601936; gene. DR OpenTargets; ENSG00000177425; -. DR VEuPathDB; HostDB:ENSG00000177425; -. DR eggNOG; ENOG502QVUF; Eukaryota. DR GeneTree; ENSGT00390000000406; -. DR HOGENOM; CLU_076619_0_0_1; -. DR InParanoid; Q96IZ0; -. DR OMA; NCIPLAR; -. DR OrthoDB; 6286739at2759; -. DR PAN-GO; Q96IZ0; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q96IZ0; -. DR PathwayCommons; Q96IZ0; -. DR SignaLink; Q96IZ0; -. DR SIGNOR; Q96IZ0; -. DR Agora; ENSG00000177425; -. DR BioGRID-ORCS; 5074; 29 hits in 1161 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR ChiTaRS; PAWR; human. DR EvolutionaryTrace; Q96IZ0; -. DR GeneWiki; PAWR; -. DR GenomeRNAi; 5074; -. DR Pharos; Q96IZ0; Tbio. DR PRO; PR:Q96IZ0; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q96IZ0; protein. DR Bgee; ENSG00000177425; Expressed in germinal epithelium of ovary and 186 other cell types or tissues. DR ExpressionAtlas; Q96IZ0; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0005884; C:actin filament; IBA:GO_Central. DR GO; GO:0000785; C:chromatin; IEA:Ensembl. DR GO; GO:0097542; C:ciliary tip; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0003779; F:actin binding; ISS:UniProtKB. DR GO; GO:0019899; F:enzyme binding; IDA:UniProtKB. DR GO; GO:0043522; F:leucine zipper domain binding; IPI:UniProtKB. DR GO; GO:0003714; F:transcription corepressor activity; TAS:ProtInc. DR GO; GO:0051017; P:actin filament bundle assembly; ISS:UniProtKB. DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB. DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0030889; P:negative regulation of B cell proliferation; IEA:Ensembl. DR GO; GO:0048147; P:negative regulation of fibroblast proliferation; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl. DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:ProtInc. DR GO; GO:0042986; P:positive regulation of amyloid precursor protein biosynthetic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IBA:GO_Central. DR GO; GO:2000774; P:positive regulation of cellular senescence; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl. DR GO; GO:1901300; P:positive regulation of hydrogen peroxide-mediated programmed cell death; IEA:Ensembl. DR DisProt; DP01603; -. DR IDEAL; IID00177; -. DR InterPro; IPR026117; Par-4. DR PANTHER; PTHR15093:SF1; PRKC APOPTOSIS WT1 REGULATOR PROTEIN; 1. DR PANTHER; PTHR15093; PROSTATE APOPTOSIS RESPONSE PROTEIN PAR-4; 1. PE 1: Evidence at protein level; KW 3D-structure; Apoptosis; Coiled coil; Cytoplasm; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Transcription; KW Transcription regulation. FT CHAIN 1..340 FT /note="PRKC apoptosis WT1 regulator protein" FT /id="PRO_0000058236" FT REGION 1..253 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..203 FT /note="Selective for apoptosis induction in cancer cells FT (SAC)" FT REGION 300..340 FT /note="Leucine-zipper" FT COILED 186..206 FT /evidence="ECO:0000255" FT MOTIF 68..72 FT /note="B30.2/SPRY domain-binding motif" FT /evidence="ECO:0000269|PubMed:20561531" FT MOTIF 145..161 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250" FT COMPBIAS 1..18 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 47..82 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 182..192 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 193..203 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 242..253 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 108 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 163 FT /note="Phosphothreonine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q62627" FT MOD_RES 231 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VARIANT 42 FT /note="P -> L (in dbSNP:rs8176804)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_022465" FT VARIANT 78 FT /note="P -> R (in dbSNP:rs8176805)" FT /evidence="ECO:0000269|Ref.2, ECO:0000269|Ref.3" FT /id="VAR_022466" FT VARIANT 137 FT /note="G -> A (in dbSNP:rs8176806)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_022467" FT VARIANT 202 FT /note="E -> A (in dbSNP:rs8176870)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_022468" FT MUTAGEN 66 FT /note="A->D: No loss of interaction with SPSB1, SPSB2 and FT SPSB4." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 68 FT /note="E->D: Increased interaction with SPSB2. Only FT slightly increased interaction with SPSB4. Increased FT interaction with SPSB1, SPSB2 and SPSB4; when associated FT with A-69." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 69 FT /note="L->I: Only slightly increased interaction with FT SPSB2. Only slightly increased interaction with SPSB4. FT Increased interaction with SPSB1, SPSB2 and SPSB4; when FT associated with A-68." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 71 FT /note="N->A: Loss of interaction with SPSB1, SPSB2 and FT SPSB4." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 72 FT /note="N->A: Loss of interaction with SPSB1-Elongin BC FT complex and SPSB2 and SPSB4." FT /evidence="ECO:0000269|PubMed:17189197, FT ECO:0000269|PubMed:20561531" FT CONFLICT 102..103 FT /note="AP -> PPAR (in Ref. 1; AAC24947)" FT /evidence="ECO:0000305" FT CONFLICT 199 FT /note="I -> M (in Ref. 2; CAG38786)" FT /evidence="ECO:0000305" FT CONFLICT 281 FT /note="R -> T (in Ref. 1; AAC24947)" FT /evidence="ECO:0000305" SQ SEQUENCE 340 AA; 36568 MW; 7E7515455402DBF8 CRC64; MATGGYRTSS GLGGSTTDFL EEWKAKREKM RAKQNPPGPA PPGGGSSDAA GKPPAGALGT PAAAAANELN NNLPGGAPAA PAVPGPGGVN CAVGSAMLTR AAPGPRRSED EPPAASASAA PPPQRDEEEP DGVPEKGKSS GPSARKGKGQ IEKRKLREKR RSTGVVNIPA AECLDEYEDD EAGQKERKRE DAITQQNTIQ NEAVNLLDPG SSYLLQEPPR TVSGRYKSTT SVSEEDVSSR YSRTDRSGFP RYNRDANVSG TLVSSSTLEK KIEDLEKEVV RERQENLRLV RLMQDKEEMI GKLKEEIDLL NRDLDDIEDE NEQLKQENKT LLKVVGQLTR // ID PCS1N_HUMAN Reviewed; 260 AA. AC Q9UHG2; Q4VC04; DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 165. DE RecName: Full=ProSAAS; DE AltName: Full=Proprotein convertase subtilisin/kexin type 1 inhibitor; DE Short=Proprotein convertase 1 inhibitor; DE AltName: Full=pro-SAAS; DE Contains: DE RecName: Full=KEP; DE Contains: DE RecName: Full=Big SAAS; DE Short=b-SAAS; DE Contains: DE RecName: Full=Little SAAS; DE Short=l-SAAS; DE AltName: Full=N-proSAAS; DE Contains: DE RecName: Full=Big PEN-LEN; DE Short=b-PEN-LEN; DE AltName: Full=SAAS CT(1-49); DE Contains: DE RecName: Full=PEN; DE Contains: DE RecName: Full=Little LEN; DE Short=l-LEN; DE Contains: DE RecName: Full=Big LEN; DE Short=b-LEN; DE AltName: Full=SAAS CT(25-40); DE Flags: Precursor; GN Name=PCSK1N; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RX PubMed=10632593; DOI=10.1523/jneurosci.20-02-00639.2000; RA Fricker L., McKinzie A.A., Sun J., Curran E., Qian Y., Yan L., RA Patterson S.D., Courchesne P.L., Richards B., Levin N., Mzhavia N., RA Devi L.A., Douglass J.; RT "Identification and characterization of proSAAS, a granin-like RT neuroendocrine peptide precursor that inhibits prohormone processing."; RL J. Neurosci. 20:639-648(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-31. RC TISSUE=Brain, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP MUTAGENESIS OF VAL-235; LEU-236; GLY-237; LEU-240; ARG-241; VAL-242; RP LYS-243; ARG-244; LEU-245 AND GLU-246. RX PubMed=11435430; DOI=10.1074/jbc.m104064200; RA Basak A., Koch P., Dupelle M., Fricker L.D., Devi L.A., Chretien M., RA Seidah N.G.; RT "Inhibitory specificity and potency of proSAAS-derived peptides toward RT proprotein convertase 1."; RL J. Biol. Chem. 276:32720-32728(2001). RN [4] RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS), AND PROTEOLYTIC PROCESSING. RX PubMed=12914799; DOI=10.1016/s0006-291x(03)01391-3; RA Kikuchi K., Arawaka S., Koyama S., Kimura H., Ren C.H., Wada M., RA Kawanami T., Kurita K., Daimon M., Kawakatsu S., Kadoya T., Goto K., RA Kato T.; RT "An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide RT precursor) is associated with tau inclusions in Pick's disease."; RL Biochem. Biophys. Res. Commun. 308:646-654(2003). RN [5] RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS). RX PubMed=14746899; DOI=10.1016/j.neulet.2003.11.028; RA Wada M., Ren C.H., Koyama S., Arawaka S., Kawakatsu S., Kimura H., RA Nagasawa H., Kawanami T., Kurita K., Daimon M., Hirano A., Kato T.; RT "A human granin-like neuroendocrine peptide precursor (proSAAS) RT immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism- RT dementia complex on Guam."; RL Neurosci. Lett. 356:49-52(2004). RN [6] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-53 AND THR-247, AND STRUCTURE RP OF CARBOHYDRATES. RC TISSUE=Cerebrospinal fluid; RX PubMed=19838169; DOI=10.1038/nmeth.1392; RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., RA Larson G.; RT "Enrichment of glycopeptides for glycan structure and attachment site RT identification."; RL Nat. Methods 6:809-811(2009). RN [7] RP GLYCOSYLATION AT THR-53; SER-228 AND THR-247, STRUCTURE OF CARBOHYDRATES, RP AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22171320; DOI=10.1074/mcp.m111.013649; RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.; RT "Human urinary glycoproteomics; attachment site specific analysis of N- and RT O-linked glycosylations by CID and ECD."; RL Mol. Cell. Proteomics 11:1-17(2012). RN [8] RP GLYCOSYLATION AT SER-228, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=23234360; DOI=10.1021/pr300963h; RA Halim A., Ruetschi U., Larson G., Nilsson J.; RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures RT of human cerebrospinal fluid glycoproteins."; RL J. Proteome Res. 12:573-584(2013). CC -!- FUNCTION: May function in the control of the neuroendocrine secretory CC pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS CC and Big PEN-LEN, both containing the C-terminal inhibitory domain, but CC not the further processed peptides reduce PCSK1 activity in the CC endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa CC form but not the autocatalytically derived 66 kDa form of PCSK1. CC Subsequent processing of proSAAS may eliminate the inhibition. Slows CC down convertase-mediated processing of proopiomelanocortin and CC proenkephalin. May control the intracellular timing of PCSK1 rather CC than its total level of activity (By similarity). CC {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- FUNCTION: [Big LEN]: Endogenous ligand for GPR171. Neuropeptide CC involved in the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- FUNCTION: [PEN]: Endogenous ligand for GPR83. Neuropeptide involved in CC the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- SUBUNIT: Interacts via the C-terminal inhibitory domain with PCSK1 66 CC kDa form. {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9QXV0}. Golgi CC apparatus, trans-Golgi network {ECO:0000250|UniProtKB:Q9QXV0}. Note=A CC N-terminal processed peptide, probably Big SAAS or Little SAAS, is CC accumulated in cytoplasmic protein tau deposits in frontotemporal CC dementia and parkinsonism linked to chromosome 17 (Pick disease), CC Alzheimer disease and amyotrophic lateral sclerosis- CC parkinsonism/dementia complex 1 (Guam disease). CC {ECO:0000269|PubMed:12914799, ECO:0000269|PubMed:14746899}. CC -!- TISSUE SPECIFICITY: Expressed in brain and pancreas. CC {ECO:0000269|PubMed:10632593}. CC -!- DOMAIN: ProSAAS(1-180) increases secretion of enzymatically inactive CC PCSK1. {ECO:0000250}. CC -!- DOMAIN: The C-terminal inhibitory domain is involved in inhibition of CC PCSK1. It corresponds to the probable processing intermediate Big PEN- CC LEN, binds to PCSK1 in vitro and contains the hexapeptide L-L-R-V-K-R, CC which, as a synthetic peptide, is sufficient for PCSK1 inhibition (By CC similarity). {ECO:0000250}. CC -!- DOMAIN: [Big LEN]: The four C-terminal amino acids of Big LEN are CC sufficient to bind and activate GPR171. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- PTM: Proteolytically cleaved in the Golgi. CC {ECO:0000269|PubMed:12914799}. CC -!- PTM: O-glycosylated with a core 1 or possibly core 8 glycan. CC {ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:22171320, CC ECO:0000269|PubMed:23234360}. 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; AF181562; AAF22643.1; -; mRNA. DR EMBL; BC002851; AAH02851.1; -; mRNA. DR CCDS; CCDS14307.1; -. DR RefSeq; NP_037403.1; NM_013271.5. DR AlphaFoldDB; Q9UHG2; -. DR SMR; Q9UHG2; -. DR BioGRID; 118156; 18. DR FunCoup; Q9UHG2; 287. DR IntAct; Q9UHG2; 17. DR MINT; Q9UHG2; -. DR STRING; 9606.ENSP00000218230; -. DR MEROPS; I49.001; -. DR GlyConnect; 743; 1 O-Linked glycan (3 sites). DR GlyCosmos; Q9UHG2; 3 sites, 2 glycans. DR GlyGen; Q9UHG2; 4 sites, 4 O-linked glycans (4 sites). DR iPTMnet; Q9UHG2; -. DR PhosphoSitePlus; Q9UHG2; -. DR BioMuta; PCSK1N; -. DR DMDM; 74735013; -. DR jPOST; Q9UHG2; -. DR MassIVE; Q9UHG2; -. DR PaxDb; 9606-ENSP00000218230; -. DR PeptideAtlas; Q9UHG2; -. DR ProteomicsDB; 84349; -. DR Antibodypedia; 579; 87 antibodies from 19 providers. DR DNASU; 27344; -. DR Ensembl; ENST00000218230.6; ENSP00000218230.5; ENSG00000102109.10. DR GeneID; 27344; -. DR KEGG; hsa:27344; -. DR MANE-Select; ENST00000218230.6; ENSP00000218230.5; NM_013271.5; NP_037403.1. DR UCSC; uc004dkz.6; human. DR AGR; HGNC:17301; -. DR ClinPGx; PA33090; -. DR CTD; 27344; -. DR DisGeNET; 27344; -. DR GeneCards; PCSK1N; -. DR HGNC; HGNC:17301; PCSK1N. DR HPA; ENSG00000102109; Group enriched (brain, pituitary gland). DR MIM; 300399; gene. DR OpenTargets; ENSG00000102109; -. DR VEuPathDB; HostDB:ENSG00000102109; -. DR eggNOG; ENOG502RYS0; Eukaryota. DR GeneTree; ENSGT00390000013488; -. DR HOGENOM; CLU_100077_0_0_1; -. DR InParanoid; Q9UHG2; -. DR OMA; VWGAPRT; -. DR OrthoDB; 8962476at2759; -. DR PAN-GO; Q9UHG2; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q9UHG2; -. DR PathwayCommons; Q9UHG2; -. DR SignaLink; Q9UHG2; -. DR Agora; ENSG00000102109; -. DR BioGRID-ORCS; 27344; 8 hits in 764 CRISPR screens. DR GenomeRNAi; 27344; -. DR Pharos; Q9UHG2; Tbio. DR PRO; PR:Q9UHG2; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; Q9UHG2; protein. DR Bgee; ENSG00000102109; Expressed in adenohypophysis and 138 other cell types or tissues. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0030141; C:secretory granule; IEA:Ensembl. DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl. DR GO; GO:0004866; F:endopeptidase inhibitor activity; IBA:GO_Central. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:Ensembl. DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc. DR GO; GO:0007218; P:neuropeptide signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0016486; P:peptide hormone processing; IEA:Ensembl. DR GO; GO:0009409; P:response to cold; IEA:Ensembl. DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl. DR InterPro; IPR010832; ProSAAS. DR PANTHER; PTHR15531; PROSAAS; 1. DR PANTHER; PTHR15531:SF0; PROSAAS; 1. DR Pfam; PF07259; ProSAAS; 1. PE 1: Evidence at protein level; KW Cleavage on pair of basic residues; Glycoprotein; Golgi apparatus; KW Neuropeptide; Proteomics identification; Reference proteome; Secreted; KW Signal. FT SIGNAL 1..33 FT /evidence="ECO:0000255" FT CHAIN 34..260 FT /note="ProSAAS" FT /id="PRO_0000259673" FT PEPTIDE 34..59 FT /note="Big SAAS" FT /evidence="ECO:0000250" FT /id="PRO_0000259675" FT PEPTIDE 34..40 FT /note="KEP" FT /evidence="ECO:0000250" FT /id="PRO_0000259674" FT PEPTIDE 42..59 FT /note="Little SAAS" FT /evidence="ECO:0000250" FT /id="PRO_0000259676" FT PEPTIDE 221..260 FT /note="Big PEN-LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259677" FT PEPTIDE 221..242 FT /note="PEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259678" FT PEPTIDE 245..260 FT /note="Big LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259679" FT PEPTIDE 245..254 FT /note="Little LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259680" FT REGION 34..215 FT /note="ProSAAS(1-180)" FT /evidence="ECO:0000250" FT REGION 165..188 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 221..260 FT /note="C-terminal inhibitory domain; interacts with PCSK1" FT /evidence="ECO:0000250" FT MOTIF 239..244 FT /note="Sufficient for inhibition of PCSK1" FT COMPBIAS 179..188 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 53 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:22171320" FT CARBOHYD 228 FT /note="O-linked (GalNAc...) serine" FT /evidence="ECO:0000269|PubMed:22171320, FT ECO:0000269|PubMed:23234360" FT CARBOHYD 247 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:22171320" FT VARIANT 31 FT /note="A -> T (in dbSNP:rs11538176)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_028971" FT MUTAGEN 235 FT /note="V->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 236 FT /note="L->A: Greatly reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 237 FT /note="G->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 240 FT /note="L->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 241 FT /note="R->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 242 FT /note="V->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 243 FT /note="K->A: Abolishes inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 244 FT /note="R->A: Abolishes inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 245 FT /note="L->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 246 FT /note="E->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" SQ SEQUENCE 260 AA; 27372 MW; FF8E2722784B7A5C CRC64; MAGSPLLWGP RAGGVGLLVL LLLGLFRPPP ALCARPVKEP RGLSAASPPL AETGAPRRFR RSVPRGEAAG AVQELARALA HLLEAERQER ARAEAQEAED QQARVLAQLL RVWGAPRNSD PALGLDDDPD APAAQLARAL LRARLDPAAL AAQLVPAPVP AAALRPRPPV YDDGPAGPDA EEAGDETPDV DPELLRYLLG RILAGSADSE GVAAPRRLRR AADHDVGSEL PPEGVLGALL RVKRLETPAP QVPARRLLPP // ID PIEZ1_HUMAN Reviewed; 2521 AA. AC Q92508; A6NHT9; A7E2B7; Q0KKZ9; DT 18-OCT-2001, integrated into UniProtKB/Swiss-Prot. DT 11-JAN-2011, sequence version 4. DT 28-JAN-2026, entry version 190. DE RecName: Full=Piezo-type mechanosensitive ion channel component 1 {ECO:0000305}; DE AltName: Full=Membrane protein induced by beta-amyloid treatment; DE Short=Mib; DE AltName: Full=Protein FAM38A; GN Name=PIEZO1 {ECO:0000312|HGNC:HGNC:28993}; Synonyms=FAM38A, KIAA0233; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] OF 432-2521, AND TISSUE SPECIFICITY. RX PubMed=16854388; DOI=10.1016/j.brainres.2006.06.050; RA Satoh K., Hata M., Takahara S., Tsuzaki H., Yokota H., Akatsu H., RA Yamamoto T., Kosaka K., Yamada T.; RT "A novel membrane protein, encoded by the gene covering KIAA0233, is RT transcriptionally induced in senile plaque-associated astrocytes."; RL Brain Res. 1108:19-27(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 486-2521. RC TISSUE=Bone marrow; RX PubMed=9039502; DOI=10.1093/dnares/3.5.321; RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O., RA Tanaka A., Kotani H., Miyajima N., Nomura N.; RT "Prediction of the coding sequences of unidentified human genes. VI. The RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of RT cDNA clones from cell line KG-1 and brain."; RL DNA Res. 3:321-329(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 486-2521. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP PROTEIN SEQUENCE OF 955-972; 1324-1334; 1548-1562 AND 1656-1671, VARIANTS RP DHS1 ARG-2225 AND HIS-2456, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=22529292; DOI=10.1182/blood-2012-04-422253; RA Zarychanski R., Schulz V.P., Houston B.L., Maksimova Y., Houston D.S., RA Smith B., Rinehart J., Gallagher P.G.; RT "Mutations in the mechanotransduction protein PIEZO1 are associated with RT hereditary xerocytosis."; RL Blood 120:1908-1915(2012). RN [6] RP IDENTIFICATION BY 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 [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1391; SER-1646 AND THR-1854, RP AND 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 [8] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-2294. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1646, 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 [10] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=20016066; DOI=10.1242/jcs.056424; RA McHugh B.J., Buttery R., Lad Y., Banks S., Haslett C., Sethi T.; RT "Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to RT the endoplasmic reticulum."; RL J. Cell Sci. 123:51-61(2010). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1391 AND SER-1646, 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 [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-734; SER-758; SER-1391; RP SER-1396; SER-1636; SER-1646 AND THR-1854, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1646, 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 [14] RP SUBCELLULAR LOCATION. RX PubMed=25119035; DOI=10.1038/nature13701; RA Li J., Hou B., Tumova S., Muraki K., Bruns A., Ludlow M.J., Sedo A., RA Hyman A.J., McKeown L., Young R.S., Yuldasheva N.Y., Majeed Y., RA Wilson L.A., Rode B., Bailey M.A., Kim H.R., Fu Z., Carter D.A., Bilton J., RA Imrie H., Ajuh P., Dear T.N., Cubbon R.M., Kearney M.T., Prasad R.K., RA Evans P.C., Ainscough J.F., Beech D.J.; RT "Piezo1 integration of vascular architecture with physiological force."; RL Nature 515:279-282(2014). RN [15] RP FUNCTION, TRANSPORTER ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=25955826; DOI=10.1371/journal.pone.0125503; RA Gnanasambandam R., Bae C., Gottlieb P.A., Sachs F.; RT "Ionic Selectivity and Permeation Properties of Human PIEZO1 Channels."; RL PLoS ONE 10:e0125503-e0125503(2015). RN [16] RP FUNCTION, ACTIVITY REGULATION, AND TISSUE SPECIFICITY. RX PubMed=29799007; DOI=10.1038/s41467-018-04436-w; RA Tsuchiya M., Hara Y., Okuda M., Itoh K., Nishioka R., Shiomi A., Nagao K., RA Mori M., Mori Y., Ikenouchi J., Suzuki R., Tanaka M., Ohwada T., Aoki J., RA Kanagawa M., Toda T., Nagata Y., Matsuda R., Takayama Y., Tominaga M., RA Umeda M.; RT "Cell surface flip-flop of phosphatidylserine is critical for PIEZO1- RT mediated myotube formation."; RL Nat. Commun. 9:2049-2049(2018). RN [17] RP FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND INTERACTION WITH MDFIC AND RP MDFI. RX PubMed=37590348; DOI=10.1126/science.adh8190; RA Zhou Z., Ma X., Lin Y., Cheng D., Bavi N., Secker G.A., Li J.V., RA Janbandhu V., Sutton D.L., Scott H.S., Yao M., Harvey R.P., Harvey N.L., RA Corry B., Zhang Y., Cox C.D.; RT "MyoD-family inhibitor proteins act as auxiliary subunits of Piezo RT channels."; RL Science 381:799-804(2023). RN [18] RP VARIANTS DHS1 SER-718; SER-782; GLN-808; LEU-1117; ASP-2003; VAL-2020; RP MET-2127; 2166-LYS--LYS-2169 DEL; HIS-2456 AND GLN-2488, CHARACTERIZATION RP OF VARIANTS DHS1 HIS-2456 AND GLN-2488, FUNCTION, SUBCELLULAR LOCATION, RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=23479567; DOI=10.1182/blood-2013-02-482489; RA Andolfo I., Alper S.L., De Franceschi L., Auriemma C., Russo R., RA De Falco L., Vallefuoco F., Esposito M.R., Vandorpe D.H., Shmukler B.E., RA Narayan R., Montanaro D., D'Armiento M., Vetro A., Limongelli I., RA Zuffardi O., Glader B.E., Schrier S.L., Brugnara C., Stewart G.W., RA Delaunay J., Iolascon A.; RT "Multiple clinical forms of dehydrated hereditary stomatocytosis arise from RT mutations in PIEZO1."; RL Blood 121:3925-3935(2013). RN [19] RP VARIANTS DHS1 PRO-1358; THR-2020; MET-2127 AND LEU-GLU-2496 INS, RP CHARACTERIZATION OF VARIANTS DHS1 PRO-1358; THR-2020; MET-2127; RP LEU-GLU-2496 INS; ARG-2225 AND HIS-2456, FUNCTION, AND SUBCELLULAR RP LOCATION. RX PubMed=23695678; DOI=10.1038/ncomms2899; RA Albuisson J., Murthy S.E., Bandell M., Coste B., Louis-Dit-Picard H., RA Mathur J., Feneant-Thibault M., Tertian G., de Jaureguiberry J.P., RA Syfuss P.Y., Cahalan S., Garcon L., Toutain F., Simon Rohrlich P., RA Delaunay J., Picard V., Jeunemaitre X., Patapoutian A.; RT "Dehydrated hereditary stomatocytosis linked to gain-of-function mutations RT in mechanically activated PIEZO1 ion channels."; RL Nat. Commun. 4:1884-1884(2013). RN [20] RP VARIANTS DHS1 ARG-2225 AND HIS-2456, CHARACTERIZATION OF VARIANTS DHS1 RP ARG-2225 AND HIS-2456, AND MUTAGENESIS OF ARG-2456. RX PubMed=23487776; DOI=10.1073/pnas.1219777110; RA Bae C., Gnanasambandam R., Nicolai C., Sachs F., Gottlieb P.A.; RT "Xerocytosis is caused by mutations that alter the kinetics of the RT mechanosensitive channel PIEZO1."; RL Proc. Natl. Acad. Sci. U.S.A. 110:E1162-1168(2013). RN [21] RP VARIANT DHS1 HIS-2456. RX PubMed=23973043; DOI=10.1016/j.bcmd.2013.07.015; RA Shmukler B.E., Vandorpe D.H., Rivera A., Auerbach M., Brugnara C., RA Alper S.L.; RT "Dehydrated stomatocytic anemia due to the heterozygous mutation R2456H in RT the mechanosensitive cation channel PIEZO1: a case report."; RL Blood Cells Mol. Dis. 52:53-54(2014). RN [22] RP VARIANT DHS1 HIS-2456. RX PubMed=23581886; DOI=10.1111/cge.12147; RA Beneteau C., Thierry G., Blesson S., Le Vaillant C., Picard V., Bene M.C., RA Eveillard M., Le Caignec C.; RT "Recurrent mutation in the PIEZO1 gene in two families of hereditary RT xerocytosis with fetal hydrops."; RL Clin. Genet. 85:293-295(2014). RN [23] RP INVOLVEMENT IN LMPHM6, AND VARIANTS LMPHM6 MET-939; LEU-2430; CYS-2456 AND RP LEU-2458. RX PubMed=26333996; DOI=10.1038/ncomms9085; RA Fotiou E., Martin-Almedina S., Simpson M.A., Lin S., Gordon K., Brice G., RA Atton G., Jeffery I., Rees D.C., Mignot C., Vogt J., Homfray T., RA Snyder M.P., Rockson S.G., Jeffery S., Mortimer P.S., Mansour S., RA Ostergaard P.; RT "Novel mutations in PIEZO1 cause an autosomal recessive generalized RT lymphatic dysplasia with non-immune hydrops fetalis."; RL Nat. Commun. 6:8085-8085(2015). RN [24] RP POLYMORPHISM, INVOLVEMENT IN ER BLOOD GROUP SYSTEM, AND VARIANTS RP 1763-TYR--GLU-2521 DEL; GLN-2245; LYS-2392; SER-2394; GLN-2407 AND RP LYS-2407. RX PubMed=36122374; DOI=10.1182/blood.2022016504; RA Karamatic Crew V., Tilley L.A., Satchwell T.J., AlSubhi S.A., Jones B., RA Spring F.A., Walser P.J., Martins Freire C., Murciano N., Rotordam M.G., RA Woestmann S.J., Hamed M., Alradwan R., AlKhrousey M., Skidmore I., RA Lewis S., Hussain S., Jackson J., Latham T., Kilby M.D., Lester W., RA Becker N., Rapedius M., Toye A.M., Thornton N.M.; RT "Missense mutations in PIEZO1, which encodes the Piezo1 mechanosensor RT protein, define Er red blood cell antigens."; RL Blood 141:135-146(2023). RN [25] RP VARIANTS ARG-253 AND LEU-2195, AND CHARACTERIZATION OF VARIANT LEU-2195. RX PubMed=38184690; DOI=10.1038/s41467-023-44594-0; RA Amado N.G., Nosyreva E.D., Thompson D., Egeland T.J., Ogujiofor O.W., RA Yang M., Fusco A.N., Passoni N., Mathews J., Cantarel B., Baker L.A., RA Syeda R.; RT "PIEZO1 loss-of-function compound heterozygous mutations in the rare RT congenital human disorder Prune Belly Syndrome."; RL Nat. Commun. 15:339-339(2024). CC -!- FUNCTION: Pore-forming subunit of the mechanosensitive non-specific CC cation Piezo channel required for rapidly adapting mechanically CC activated (MA) currents and has a key role in sensing touch and tactile CC pain (PubMed:23479567, PubMed:23695678, PubMed:25955826, CC PubMed:37590348). Piezo channels are homotrimeric three-blade CC propeller-shaped structures that utilize a cap-motion and plug-and- CC latch mechanism to gate their ion-conducting pathways CC (PubMed:37590348). Generates currents characterized by a linear CC current-voltage relationship that are sensitive to ruthenium red and CC gadolinium (By similarity). Conductance to monovalent alkali ions is CC highest for K(+), intermediate for Na(+) and lowest for Li(+) CC (PubMed:25955826). Divalent ions except for Mn(2+) permeate the channel CC but more slowly than the monovalent ions and they also reduce K(+) CC currents (PubMed:25955826). Plays a key role in epithelial cell CC adhesion by maintaining integrin activation through R-Ras recruitment CC to the ER, most probably in its activated state, and subsequent CC stimulation of calpain signaling (PubMed:20016066). In inner ear hair CC cells, PIEZO1/2 subunits may constitute part of the mechanotransducer CC (MET) non-selective cation channel complex where they may act as pore- CC forming ion-conducting component in the complex (By similarity). In the CC kidney, may contribute to the detection of intraluminal pressure CC changes and to urine flow sensing (By similarity). Acts as a shear- CC stress sensor that promotes endothelial cell organization and alignment CC in the direction of blood flow through calpain activation CC (PubMed:25119035). Plays a key role in blood vessel formation and CC vascular structure in both development and adult physiology (By CC similarity). Acts as a sensor of phosphatidylserine (PS) flipping at CC the plasma membrane and governs morphogenesis of muscle cells (By CC similarity). In myoblasts, flippase-mediated PS enrichment at the inner CC leaflet of plasma membrane triggers channel activation and Ca2+ influx CC followed by Rho GTPases signal transduction, leading to assembly of CC cortical actomyosin fibers and myotube formation (PubMed:29799007). CC {ECO:0000250|UniProtKB:E2JF22, ECO:0000250|UniProtKB:Q91X60, CC ECO:0000269|PubMed:25955826, ECO:0000269|PubMed:29799007}. CC -!- CATALYTIC ACTIVITY: CC Reaction=K(+)(in) = K(+)(out); Xref=Rhea:RHEA:29463, ChEBI:CHEBI:29103; CC Evidence={ECO:0000269|PubMed:25955826}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Na(+)(in) = Na(+)(out); Xref=Rhea:RHEA:34963, CC ChEBI:CHEBI:29101; Evidence={ECO:0000269|PubMed:25955826}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Ca(2+)(in) = Ca(2+)(out); Xref=Rhea:RHEA:29671, CC ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:25955826}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Mg(2+)(in) = Mg(2+)(out); Xref=Rhea:RHEA:29827, CC ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:25955826}; CC -!- ACTIVITY REGULATION: Regulated by auxillary subunits MDFIC and MDFI CC (PubMed:37590348). Down-regulated by phosphatidylserines exposed on the CC cell surface. Divalent ions decrease the single-channel permeability of CC K(+) (PubMed:25955826). {ECO:0000269|PubMed:25955826, CC ECO:0000269|PubMed:29799007, ECO:0000269|PubMed:37590348}. CC -!- SUBUNIT: Homotrimer; the homotrimer forms a propeller-shaped Piezo CC channel with a cation-ion conducting pore (PubMed:37590348). CC Heterotrimeric interaction may occur between PIEZO1 and PIEZO2 (By CC similarity). Interacts with PKD2 (By similarity). Interacts with STOML3 CC (By similarity). Interacts with TMC1, TMC2, PCDH15 and CIB2; the CC interaction may be part of the MET complex (By similarity). Interacts CC with MDFIC (via C-terminus); the interaction prolongs Piezo channel CC inactivation (PubMed:37590348). Interacts with MDFI (via C-terminus); CC the interaction prolongs Piezo channel inactivation (PubMed:37590348). CC {ECO:0000250|UniProtKB:E2JF22}. CC -!- INTERACTION: CC Q92508; Q6UW02: CYP20A1; NbExp=2; IntAct=EBI-10986212, EBI-11066876; CC Q92508; P04155: TFF1; NbExp=5; IntAct=EBI-10986212, EBI-743871; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:20016066}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:E2JF22}. Endoplasmic reticulum-Golgi CC intermediate compartment membrane {ECO:0000250|UniProtKB:Q0KL00}. Cell CC membrane {ECO:0000269|PubMed:22529292, ECO:0000269|PubMed:23479567}; CC Multi-pass membrane protein {ECO:0000250|UniProtKB:E2JF22}. Cell CC projection, lamellipodium membrane {ECO:0000269|PubMed:25119035}. CC Note=In erythrocytes, located in the plasma membrane (PubMed:22529292, CC PubMed:23479567). Accumulates at the leading apical lamellipodia of CC endothelial cells in response to shear stress (PubMed:25119035). CC Colocalizes with F-actin and MYH9 at the actomyosin cortex in CC myoblasts. {ECO:0000250|UniProtKB:E2JF22, ECO:0000269|PubMed:22529292, CC ECO:0000269|PubMed:23479567, ECO:0000269|PubMed:25119035}. CC -!- TISSUE SPECIFICITY: Expressed in numerous tissues. In normal brain, CC expressed exclusively in neurons, not in astrocytes. In Alzheimer CC disease brains, expressed in about half of the activated astrocytes CC located around classical senile plaques. In Parkinson disease CC substantia nigra, not detected in melanin-containing neurons nor in CC activated astrocytes. Expressed in erythrocytes (at protein level). CC Expressed in myoblasts (at protein level). CC {ECO:0000269|PubMed:16854388, ECO:0000269|PubMed:22529292, CC ECO:0000269|PubMed:23479567, ECO:0000269|PubMed:29799007}. CC -!- DEVELOPMENTAL STAGE: At 17 weeks of gestation, strongly expressed in CC hepatic erythroblasts. At that stage, also expressed in fetal splenic CC plasma cells and in lymphatic vessel of fetal peritoneum. In vitro, up- CC regulated during the erythroid differentiation of CD34+ cells from CC healthy donors (at protein level). {ECO:0000269|PubMed:23479567}. CC -!- POLYMORPHISM: PIEZO1 is responsible for the Er blood group system (ER) CC [MIM:620207]. At least five antigens have been identified: Er(a), CC Er(b), Er(3), Er(4), and Er(5). The molecular basis of the Er(a)/Er(b) CC polymorphism is a single variation at position 2394; Gly-2394 CC corresponds to Er(a) and Ser-2394 to Er(b), while the Er(3) antigen is CC recognized by antibodies produced by Er(a-b-) individuals. The Er(4) CC and Er(5) antigens are defined by Glu-2407 and Arg-2245, respectively. CC Alloantibodies against Er(4) and Er(5) are associated with hemolytic CC disease of the fetus and newborn. {ECO:0000269|PubMed:36122374}. CC -!- DISEASE: Dehydrated hereditary stomatocytosis 1 with or without CC pseudohyperkalemia and/or perinatal edema (DHS1) [MIM:194380]: An CC autosomal dominant hemolytic anemia characterized by primary CC erythrocyte dehydration. DHS erythrocytes exhibit decreased total CC cation and potassium content that are not accompanied by a proportional CC net gain of sodium and water. DHS patients typically exhibit mild to CC moderate compensated hemolytic anemia, with an increased erythrocyte CC mean corpuscular hemoglobin concentration and a decreased osmotic CC fragility, both of which reflect cellular dehydration. Patients may CC also show perinatal edema and pseudohyperkalemia due to loss of CC potassium from red cells stored at room temperature. A minor proportion CC of red cells appear as stomatocytes on blood films. Complications such CC as splenomegaly and cholelithiasis, resulting from increased red cell CC trapping in the spleen and elevated bilirubin levels, respectively, may CC occur. The course of DHS is frequently associated with iron overload, CC which may lead to hepatosiderosis. {ECO:0000269|PubMed:22529292, CC ECO:0000269|PubMed:23479567, ECO:0000269|PubMed:23487776, CC ECO:0000269|PubMed:23581886, ECO:0000269|PubMed:23695678, CC ECO:0000269|PubMed:23973043}. Note=The disease is caused by variants CC affecting the gene represented in this entry. All disease-causing CC mutations characterized so far produce a gain-of-function phenotype, CC mutated channels exhibiting increased cation transport in erythroid CC cells, that could be due to slower channel inactivation rate compared CC to the wild-type protein. CC -!- DISEASE: Lymphatic malformation 6 (LMPHM6) [MIM:616843]: A form of CC primary lymphedema, a disease characterized by swelling of body parts CC due to developmental anomalies and functional defects of the lymphatic CC system. Patients with lymphedema may suffer from recurrent local CC infections. LMPHM6 is an autosomal recessive, severe form manifesting CC as generalized lymphatic dysplasia. It is characterized by uniform, CC widespread swelling of all segments of the body, with systemic CC involvement such as intestinal and/or pulmonary lymphangiectasia, CC pleural effusions, chylothoraces and/or pericardial effusions, and with CC a high incidence of non- immune hydrops fetalis. CC {ECO:0000269|PubMed:26333996}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Piezo comes from the Greek 'piesi' meaning pressure. CC -!- SIMILARITY: Belongs to the PIEZO (TC 1.A.75) 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; AC138028; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AB161230; BAF03565.1; -; mRNA. DR EMBL; D87071; BAA13240.1; -; mRNA. DR EMBL; BC150271; AAI50272.1; -; mRNA. DR CCDS; CCDS54058.1; -. DR RefSeq; NP_001136336.2; NM_001142864.4. DR PDB; 8YEZ; EM; 3.30 A; A/B/C=1-2521. DR PDB; 8YFC; EM; 3.20 A; A/B/D=1-2521. DR PDB; 8YFG; EM; 4.50 A; A/B/D=1-2521. DR PDB; 8ZU3; EM; 3.10 A; A/B/D=1-2521. DR PDB; 8ZU8; EM; 3.90 A; A/B/C=570-2521. DR PDB; 9VMX; EM; 3.20 A; A/B/D=1-2521. DR PDBsum; 8YEZ; -. DR PDBsum; 8YFC; -. DR PDBsum; 8YFG; -. DR PDBsum; 8ZU3; -. DR PDBsum; 8ZU8; -. DR PDBsum; 9VMX; -. DR AlphaFoldDB; Q92508; -. DR EMDB; EMD-39205; -. DR EMDB; EMD-39219; -. DR EMDB; EMD-39223; -. DR EMDB; EMD-60479; -. DR EMDB; EMD-60481; -. DR EMDB; EMD-65195; -. DR SMR; Q92508; -. DR BioGRID; 115124; 73. DR FunCoup; Q92508; 1077. DR IntAct; Q92508; 60. DR MINT; Q92508; -. DR STRING; 9606.ENSP00000301015; -. DR BindingDB; Q92508; -. DR ChEMBL; CHEMBL5169186; -. DR GuidetoPHARMACOLOGY; 2945; -. DR TCDB; 1.A.75.1.1; the mechanical nociceptor, piezo (piezo) family. DR GlyCosmos; Q92508; 2 sites, No reported glycans. DR GlyGen; Q92508; 6 sites, 10 N-linked glycans (2 sites), 1 O-linked glycan (1 site). DR iPTMnet; Q92508; -. DR PhosphoSitePlus; Q92508; -. DR SwissPalm; Q92508; -. DR BioMuta; PIEZO1; -. DR DMDM; 317373533; -. DR jPOST; Q92508; -. DR MassIVE; Q92508; -. DR PaxDb; 9606-ENSP00000301015; -. DR PeptideAtlas; Q92508; -. DR ProteomicsDB; 75277; -. DR Pumba; Q92508; -. DR Antibodypedia; 44957; 186 antibodies from 24 providers. DR DNASU; 9780; -. DR Ensembl; ENST00000301015.14; ENSP00000301015.9; ENSG00000103335.23. DR GeneID; 9780; -. DR KEGG; hsa:9780; -. DR MANE-Select; ENST00000301015.14; ENSP00000301015.9; NM_001142864.4; NP_001136336.2. DR UCSC; uc010vpb.3; human. DR AGR; HGNC:28993; -. DR CTD; 9780; -. DR DisGeNET; 9780; -. DR GeneCards; PIEZO1; -. DR HGNC; HGNC:28993; PIEZO1. DR HPA; ENSG00000103335; Low tissue specificity. DR MalaCards; PIEZO1; -. DR MIM; 194380; phenotype. DR MIM; 611184; gene. DR MIM; 616843; phenotype. DR MIM; 620207; phenotype. DR OpenTargets; ENSG00000103335; -. DR Orphanet; 3202; Dehydrated hereditary stomatocytosis. DR Orphanet; 568062; PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis. DR VEuPathDB; HostDB:ENSG00000103335; -. DR eggNOG; KOG1893; Eukaryota. DR GeneTree; ENSGT00940000157348; -. DR HOGENOM; CLU_000512_0_0_1; -. DR InParanoid; Q92508; -. DR OMA; KTTFQMA; -. DR OrthoDB; 303066at2759; -. DR PAN-GO; Q92508; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q92508; -. DR PathwayCommons; Q92508; -. DR Reactome; R-HSA-9856530; High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells. DR Reactome; R-HSA-9856532; Mechanical load activates signaling by PIEZO1 and integrins in osteocytes. DR Reactome; R-HSA-9860927; Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells. DR SignaLink; Q92508; -. DR SIGNOR; Q92508; -. DR Agora; ENSG00000103335; -. DR BioGRID-ORCS; 9780; 24 hits in 1164 CRISPR screens. DR ChiTaRS; PIEZO1; human. DR GenomeRNAi; 9780; -. DR Pharos; Q92508; Tchem. DR PRO; PR:Q92508; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q92508; protein. DR Bgee; ENSG00000103335; Expressed in muscle layer of sigmoid colon and 94 other cell types or tissues. DR ExpressionAtlas; Q92508; baseline and differential. DR GO; GO:0032437; C:cuticular plate; ISS:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IEA:UniProtKB-SubCell. DR GO; GO:0031258; C:lamellipodium membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0032420; C:stereocilium; ISS:UniProtKB. DR GO; GO:0140135; F:mechanosensitive monoatomic cation channel activity; IDA:UniProtKB. DR GO; GO:0008381; F:mechanosensitive monoatomic ion channel activity; IBA:GO_Central. DR GO; GO:0005261; F:monoatomic cation channel activity; ISS:UniProtKB. DR GO; GO:0071260; P:cellular response to mechanical stimulus; IBA:GO_Central. DR GO; GO:0050982; P:detection of mechanical stimulus; IBA:GO_Central. DR GO; GO:0006812; P:monoatomic cation transport; ISS:UniProtKB. DR GO; GO:0033634; P:positive regulation of cell-cell adhesion mediated by integrin; IMP:UniProtKB. DR GO; GO:0033625; P:positive regulation of integrin activation; IMP:UniProtKB. DR GO; GO:0010831; P:positive regulation of myotube differentiation; IMP:UniProtKB. DR GO; GO:0042391; P:regulation of membrane potential; IBA:GO_Central. DR InterPro; IPR027272; Piezo. DR InterPro; IPR031334; Piezo_cap_dom. DR InterPro; IPR056770; Piezo_THU9_anchor. DR InterPro; IPR056769; Piezo_TM1-24. DR InterPro; IPR031805; Piezo_TM25-28. DR InterPro; IPR056768; THU_Piezo. DR PANTHER; PTHR47049:SF5; PIEZO-TYPE MECHANOSENSITIVE ION CHANNEL COMPONENT; 1. DR PANTHER; PTHR47049; PIEZO-TYPE MECHANOSENSITIVE ION CHANNEL HOMOLOG; 1. DR Pfam; PF12166; Piezo_cap; 1. DR Pfam; PF24874; Piezo_THU9_anchor; 1. DR Pfam; PF24871; Piezo_TM1-24; 1. DR Pfam; PF15917; Piezo_TM25-28; 1. DR Pfam; PF23188; THU_Piezo1; 1. PE 1: Evidence at protein level; KW 3D-structure; Blood group antigen; Cell membrane; Cell projection; KW Coiled coil; Direct protein sequencing; Disease variant; Disulfide bond; KW Endoplasmic reticulum; Glycoprotein; Hereditary hemolytic anemia; KW Ion channel; Ion transport; Membrane; Phosphoprotein; KW Proteomics identification; Reference proteome; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..2521 FT /note="Piezo-type mechanosensitive ion channel component 1" FT /id="PRO_0000186817" FT TOPO_DOM 1..12 FT /note="Cytoplasmic" FT TRANSMEM 13..25 FT /note="Helical; Name=1" FT TOPO_DOM 26..28 FT /note="Extracellular" FT TRANSMEM 29..44 FT /note="Helical; Name=2" FT TOPO_DOM 45..58 FT /note="Cytoplasmic" FT TRANSMEM 59..81 FT /note="Helical; Name=3" FT TOPO_DOM 82..121 FT /note="Extracellular" FT TRANSMEM 122..138 FT /note="Helical; Name=4" FT TOPO_DOM 139..194 FT /note="Cytoplasmic" FT TRANSMEM 195..214 FT /note="Helical; Name=5" FT TOPO_DOM 215..216 FT /note="Extracellular" FT TRANSMEM 217..236 FT /note="Helical; Name=6" FT TOPO_DOM 237..247 FT /note="Cytoplasmic" FT TRANSMEM 248..268 FT /note="Helical; Name=7" FT TOPO_DOM 269..309 FT /note="Extracellular" FT TRANSMEM 310..330 FT /note="Helical; Name=8" FT TOPO_DOM 331..417 FT /note="Cytoplasmic" FT TRANSMEM 418..438 FT /note="Helical; Name=9" FT TOPO_DOM 439..440 FT /note="Extracellular" FT TRANSMEM 441..456 FT /note="Helical; Name=10" FT TOPO_DOM 457..461 FT /note="Cytoplasmic" FT TRANSMEM 462..484 FT /note="Helical; Name=11" FT TOPO_DOM 485..512 FT /note="Extracellular" FT TRANSMEM 513..530 FT /note="Helical; Name=12" FT TOPO_DOM 531..574 FT /note="Cytoplasmic" FT TRANSMEM 575..595 FT /note="Helical; Name=13" FT TOPO_DOM 596 FT /note="Extracellular" FT TRANSMEM 597..617 FT /note="Helical; Name=14" FT TOPO_DOM 618..627 FT /note="Cytoplasmic" FT TRANSMEM 628..649 FT /note="Helical; Name=15" FT TOPO_DOM 650..679 FT /note="Extracellular" FT TRANSMEM 680..696 FT /note="Helical; Name=16" FT TOPO_DOM 697..816 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 817..828 FT /note="Helical; Name=17" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 829..831 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 832..845 FT /note="Helical; Name=18" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 846..859 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 860..874 FT /note="Helical; Name=19" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 875..926 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 927..954 FT /note="Helical; Name=20" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 955..994 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 995..1010 FT /note="Helical; Name=21" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1011..1012 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1013..1028 FT /note="Helical; Name=22" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1029..1041 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1042..1057 FT /note="Helical; Name=23" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1058..1096 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1097..1118 FT /note="Helical; Name=24" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1119..1153 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1154..1180 FT /note="Helical; Name=25" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1181..1185 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1186..1204 FT /note="Helical; Name=26" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1205..1217 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1218..1236 FT /note="Helical; Name=27" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1237..1285 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1286..1302 FT /note="Helical; Name=28" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1303..1656 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1657..1700 FT /note="Helical; Name=29" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1701..1704 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1705..1720 FT /note="Helical; Name=30" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1721..1728 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1729..1747 FT /note="Helical; Name=31" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1748..1779 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1780..1801 FT /note="Helical; Name=32" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1802..1960 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 1961..1980 FT /note="Helical; Name=33" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 1981..2000 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 2001..2017 FT /note="Helical; Name=34" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 2018..2031 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 2032..2052 FT /note="Helical; Name=35" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 2053..2060 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 2061..2076 FT /note="Helical; Name=36" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 2077..2176 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 2177..2197 FT /note="Helical; Name=37" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 2198..2431 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TRANSMEM 2432..2452 FT /note="Helical; Name=38" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT TOPO_DOM 2453..2521 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT REGION 738..769 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1356..1402 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1462..1498 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1576..1630 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1811..1921 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 1339..1368 FT /evidence="ECO:0000255" FT COMPBIAS 749..759 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1385..1398 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1811..1822 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1859..1868 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1869..1878 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1890..1903 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1904..1913 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 734 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 758 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1391 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 1396 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1636 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1646 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 1854 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT CARBOHYD 295 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 2294 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT DISULFID 2411..2415 FT /evidence="ECO:0000250|UniProtKB:E2JF22" FT VARIANT 253 FT /note="G -> R (found in a patient with prune belly FT syndrome; uncertain significance; dbSNP:rs142027562)" FT /evidence="ECO:0000269|PubMed:38184690" FT /id="VAR_089217" FT VARIANT 718 FT /note="G -> S (in DHS1; dbSNP:rs755885744)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069822" FT VARIANT 782 FT /note="G -> S (in DHS1; dbSNP:rs200970763)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069823" FT VARIANT 808 FT /note="R -> Q (in DHS1; dbSNP:rs202103485)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069824" FT VARIANT 939 FT /note="L -> M (in LMPHM6; uncertain significance; FT dbSNP:rs201226914)" FT /evidence="ECO:0000269|PubMed:26333996" FT /id="VAR_076407" FT VARIANT 1117 FT /note="S -> L (in DHS1; dbSNP:rs587777765)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069825" FT VARIANT 1358 FT /note="R -> P (in DHS1; gives rise to mechanically FT activated currents that inactivate more slowly than wild- FT type currents; dbSNP:rs587776990)" FT /evidence="ECO:0000269|PubMed:23695678" FT /id="VAR_069826" FT VARIANT 1763..2521 FT /note="Missing (found in Er(a-b-) blood group phenotype; FT dbSNP:rs72811487)" FT /evidence="ECO:0000269|PubMed:36122374" FT /id="VAR_088145" FT VARIANT 2003 FT /note="A -> D (in DHS1)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069827" FT VARIANT 2020 FT /note="A -> T (in DHS1; gives rise to mechanically FT activated currents that inactivate more slowly than wild- FT type currents; dbSNP:rs587776989)" FT /evidence="ECO:0000269|PubMed:23695678" FT /id="VAR_069828" FT VARIANT 2020 FT /note="A -> V (in DHS1; dbSNP:rs587777764)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069829" FT VARIANT 2127 FT /note="T -> M (in DHS1; gives rise to mechanically FT activated currents that inactivate more slowly than wild- FT type currents; dbSNP:rs587776991)" FT /evidence="ECO:0000269|PubMed:23479567, FT ECO:0000269|PubMed:23695678" FT /id="VAR_069830" FT VARIANT 2166..2169 FT /note="Missing (in DHS1)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069831" FT VARIANT 2195 FT /note="S -> L (found in a patient with prune belly FT syndrome; uncertain significance; the orthologous mouse FT mutation affects channel gating properties without FT affecting channel conductance; dbSNP:rs766429217)" FT /evidence="ECO:0000269|PubMed:38184690" FT /id="VAR_089218" FT VARIANT 2225 FT /note="M -> R (in DHS1; gives rise to mechanically FT activated currents that inactivate more slowly than wild- FT type currents; dbSNP:rs587776987)" FT /evidence="ECO:0000269|PubMed:22529292, FT ECO:0000269|PubMed:23487776, ECO:0000269|PubMed:23695678" FT /id="VAR_069832" FT VARIANT 2245 FT /note="R -> Q (found in Er(5-) blood group phenotype; FT dbSNP:rs2290901)" FT /evidence="ECO:0000269|PubMed:36122374" FT /id="VAR_088146" FT VARIANT 2392 FT /note="E -> K (found in Er(a-b+) and Er(a-b-) blood group FT phenotypes; dbSNP:rs528448732)" FT /evidence="ECO:0000269|PubMed:36122374" FT /id="VAR_088147" FT VARIANT 2394 FT /note="G -> S (found in Er(a-b+) blood group phenotype; FT dbSNP:rs201950081)" FT /evidence="ECO:0000269|PubMed:36122374" FT /id="VAR_088148" FT VARIANT 2407 FT /note="E -> K (found in Er(4-) blood group phenotype; FT dbSNP:rs200291894)" FT /evidence="ECO:0000269|PubMed:36122374" FT /id="VAR_088149" FT VARIANT 2407 FT /note="E -> Q (found in Er(4-) blood group phenotype; FT dbSNP:rs200291894)" FT /evidence="ECO:0000269|PubMed:36122374" FT /id="VAR_088150" FT VARIANT 2430 FT /note="P -> L (in LMPHM6; uncertain significance; FT dbSNP:rs869025601)" FT /evidence="ECO:0000269|PubMed:26333996" FT /id="VAR_076408" FT VARIANT 2456 FT /note="R -> C (in LMPHM6; uncertain significance)" FT /evidence="ECO:0000269|PubMed:26333996" FT /id="VAR_076409" FT VARIANT 2456 FT /note="R -> H (in DHS1; gives rise to mechanically FT activated currents that inactivate more slowly than wild- FT type currents; dbSNP:rs587776988)" FT /evidence="ECO:0000269|PubMed:22529292, FT ECO:0000269|PubMed:23479567, ECO:0000269|PubMed:23487776, FT ECO:0000269|PubMed:23581886, ECO:0000269|PubMed:23695678, FT ECO:0000269|PubMed:23973043" FT /id="VAR_069833" FT VARIANT 2458 FT /note="F -> L (in LMPHM6; uncertain significance; FT dbSNP:rs577860843)" FT /evidence="ECO:0000269|PubMed:26333996" FT /id="VAR_076410" FT VARIANT 2488 FT /note="R -> Q (in DHS1; increased cation transport in FT erythroid cells; dbSNP:rs749288233)" FT /evidence="ECO:0000269|PubMed:23479567" FT /id="VAR_069834" FT VARIANT 2496 FT /note="E -> ELE (in DHS1; gives rise to mechanically FT activated currents that inactivate more slowly than wild- FT type currents)" FT /evidence="ECO:0000269|PubMed:23695678" FT /id="VAR_069835" FT MUTAGEN 2456 FT /note="R->K: Does not inactivate the protein. gives rise to FT mechanically activated currents that inactivate more slowly FT than wild-type currents, suggesting it could shift the FT channel kinetics from phasic to tonic." FT /evidence="ECO:0000269|PubMed:23487776" FT CONFLICT 750 FT /note="Missing (in Ref. 3; BAA13240 and 4; AAI50272)" FT /evidence="ECO:0000305" FT HELIX 571..578 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 581..591 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 594..596 FT /evidence="ECO:0007829|PDB:8YEZ" FT HELIX 599..603 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 605..617 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 622..624 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 627..642 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 679..699 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 703..706 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 791..807 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 810..813 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 815..823 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 824..826 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 827..829 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 833..836 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 837..840 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 841..844 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 848..850 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 851..870 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 873..876 FT /evidence="ECO:0007829|PDB:8YEZ" FT HELIX 926..929 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 932..954 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 971..977 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 979..988 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 990..1008 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1014..1026 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1031..1035 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1038..1056 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1097..1116 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 1117..1119 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1155..1162 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1166..1180 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1184..1198 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1202..1205 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 1206..1210 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1213..1230 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1286..1301 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1306..1319 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1321..1369 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1409..1413 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1418..1421 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1514..1539 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 1542..1544 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 1560..1566 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 1650..1652 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 1656..1658 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1659..1661 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1662..1668 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 1669..1672 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1673..1685 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1687..1701 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 1706..1709 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1710..1716 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 1719..1724 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1728..1745 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 1781..1784 FT /evidence="ECO:0007829|PDB:8YEZ" FT HELIX 1786..1802 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1942..1951 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 1961..1977 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2000..2023 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2027..2043 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 2044..2046 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2061..2083 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2093..2095 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2101..2111 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2115..2126 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2133..2158 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2169..2199 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2210..2215 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2218..2220 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2222..2228 FT /evidence="ECO:0007829|PDB:8YEZ" FT TURN 2229..2231 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2232..2234 FT /evidence="ECO:0007829|PDB:8YEZ" FT HELIX 2237..2246 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2251..2259 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 2262..2264 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2265..2271 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2282..2293 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2302..2307 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2311..2313 FT /evidence="ECO:0007829|PDB:8YEZ" FT STRAND 2318..2328 FT /evidence="ECO:0007829|PDB:8YEZ" FT HELIX 2333..2343 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2350..2352 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2358..2360 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2364..2366 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 2372..2374 FT /evidence="ECO:0007829|PDB:8YEZ" FT STRAND 2375..2382 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2385..2391 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2402..2408 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 2414..2416 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2417..2422 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 2436..2438 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2439..2456 FT /evidence="ECO:0007829|PDB:8ZU3" FT STRAND 2459..2461 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2462..2464 FT /evidence="ECO:0007829|PDB:8ZU3" FT TURN 2466..2468 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2475..2489 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2493..2506 FT /evidence="ECO:0007829|PDB:8ZU3" FT HELIX 2510..2516 FT /evidence="ECO:0007829|PDB:8ZU3" SQ SEQUENCE 2521 AA; 286790 MW; 127A3DA3E7CBD2DD CRC64; MEPHVLGAVL YWLLLPCALL AACLLRFSGL SLVYLLFLLL LPWFPGPTRC GLQGHTGRLL RALLGLSLLF LVAHLALQIC LHIVPRLDQL LGPSCSRWET LSRHIGVTRL DLKDIPNAIR LVAPDLGILV VSSVCLGICG RLARNTRQSP HPRELDDDER DVDASPTAGL QEAATLAPTR RSRLAARFRV TAHWLLVAAG RVLAVTLLAL AGIAHPSALS SVYLLLFLAL CTWWACHFPI STRGFSRLCV AVGCFGAGHL ICLYCYQMPL AQALLPPAGI WARVLGLKDF VGPTNCSSPH ALVLNTGLDW PVYASPGVLL LLCYATASLR KLRAYRPSGQ RKEAAKGYEA RELELAELDQ WPQERESDQH VVPTAPDTEA DNCIVHELTG QSSVLRRPVR PKRAEPREAS PLHSLGHLIM DQSYVCALIA MMVWSITYHS WLTFVLLLWA CLIWTVRSRH QLAMLCSPCI LLYGMTLCCL RYVWAMDLRP ELPTTLGPVS LRQLGLEHTR YPCLDLGAML LYTLTFWLLL RQFVKEKLLK WAESPAALTE VTVADTEPTR TQTLLQSLGE LVKGVYAKYW IYVCAGMFIV VSFAGRLVVY KIVYMFLFLL CLTLFQVYYS LWRKLLKAFW WLVVAYTMLV LIAVYTFQFQ DFPAYWRNLT GFTDEQLGDL GLEQFSVSEL FSSILVPGFF LLACILQLHY FHRPFMQLTD MEHVSLPGTR LPRWAHRQDA VSGTPLLREE QQEHQQQQQE EEEEEEDSRD EGLGVATPHQ ATQVPEGAAK WGLVAERLLE LAAGFSDVLS RVQVFLRRLL ELHVFKLVAL YTVWVALKEV SVMNLLLVVL WAFALPYPRF RPMASCLSTV WTCVIIVCKM LYQLKVVNPQ EYSSNCTEPF PNSTNLLPTE ISQSLLYRGP VDPANWFGVR KGFPNLGYIQ NHLQVLLLLV FEAIVYRRQE HYRRQHQLAP LPAQAVFASG TRQQLDQDLL GCLKYFINFF FYKFGLEICF LMAVNVIGQR MNFLVTLHGC WLVAILTRRH RQAIARLWPN YCLFLALFLL YQYLLCLGMP PALCIDYPWR WSRAVPMNSA LIKWLYLPDF FRAPNSTNLI SDFLLLLCAS QQWQVFSAER TEEWQRMAGV NTDRLEPLRG EPNPVPNFIH CRSYLDMLKV AVFRYLFWLV LVVVFVTGAT RISIFGLGYL LACFYLLLFG TALLQRDTRA RLVLWDCLIL YNVTVIISKN MLSLLACVFV EQMQTGFCWV IQLFSLVCTV KGYYDPKEMM DRDQDCLLPV EEAGIIWDSV CFFFLLLQRR VFLSHYYLHV RADLQATALL ASRGFALYNA ANLKSIDFHR RIEEKSLAQL KRQMERIRAK QEKHRQGRVD RSRPQDTLGP KDPGLEPGPD SPGGSSPPRR QWWRPWLDHA TVIHSGDYFL FESDSEEEEE AVPEDPRPSA QSAFQLAYQA WVTNAQAVLR RRQQEQEQAR QEQAGQLPTG GGPSQEVEPA EGPEEAAAGR SHVVQRVLST AQFLWMLGQA LVDELTRWLQ EFTRHHGTMS DVLRAERYLL TQELLQGGEV HRGVLDQLYT SQAEATLPGP TEAPNAPSTV SSGLGAEEPL SSMTDDMGSP LSTGYHTRSG SEEAVTDPGE REAGASLYQG LMRTASELLL DRRLRIPELE EAELFAEGQG RALRLLRAVY QCVAAHSELL CYFIIILNHM VTASAGSLVL PVLVFLWAML SIPRPSKRFW MTAIVFTEIA VVVKYLFQFG FFPWNSHVVL RRYENKPYFP PRILGLEKTD GYIKYDLVQL MALFFHRSQL LCYGLWDHEE DSPSKEHDKS GEEEQGAEEG PGVPAATTED HIQVEARVGP TDGTPEPQVE LRPRDTRRIS LRFRRRKKEG PARKGAAAIE AEDREEEEGE EEKEAPTGRE KRPSRSGGRV RAAGRRLQGF CLSLAQGTYR PLRRFFHDIL HTKYRAATDV YALMFLADVV DFIIIIFGFW AFGKHSAATD ITSSLSDDQV PEAFLVMLLI QFSTMVVDRA LYLRKTVLGK LAFQVALVLA IHLWMFFILP AVTERMFNQN VVAQLWYFVK CIYFALSAYQ IRCGYPTRIL GNFLTKKYNH LNLFLFQGFR LVPFLVELRA VMDWVWTDTT LSLSSWMCVE DIYANIFIIK CSRETEKKYP QPKGQKKKKI VKYGMGGLII LFLIAIIWFP LLFMSLVRSV VGVVNQPIDV TVTLKLGGYE PLFTMSAQQP SIIPFTAQAY EELSRQFDPQ PLAMQFISQY SPEDIVTAQI EGSSGALWRI SPPSRAQMKR ELYNGTADIT LRFTWNFQRD LAKGGTVEYA NEKHMLALAP NSTARRQLAS LLEGTSDQSV VIPNLFPKYI RAPNGPEANP VKQLQPNEEA DYLGVRIQLR REQGAGATGF LEWWVIELQE CRTDCNLLPM VIFSDKVSPP SLGFLAGYGI MGLYVSIVLV IGKFVRGFFS EISHSIMFEE LPCVDRILKL CQDIFLVRET RELELEEELY AKLIFLYRSP ETMIKWTREK E // ID PSN1_HUMAN Reviewed; 467 AA. AC P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 263. DE RecName: Full=Presenilin-1 {ECO:0000303|PubMed:9144240}; DE Short=PS-1 {ECO:0000303|PubMed:9298817}; DE EC=3.4.23.- {ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:26280335}; DE AltName: Full=Protein S182 {ECO:0000303|PubMed:7550356}; DE Contains: DE RecName: Full=Presenilin-1 NTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF12 {ECO:0000305|PubMed:9485372}; DE Short=PS1-CTF12; GN Name=PSEN1 {ECO:0000312|HGNC:HGNC:9508}; Synonyms=AD3, PS1, PSNL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANTS AD3 RP LEU-146; ARG-163; GLU-246 AND VAL-286, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=7596406; DOI=10.1038/375754a0; RA Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M., RA Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.-F., RA Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L., RA Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W., RA da Silva H.A.R., Haines J.L., Pericak-Vance M.A., Tanzi R.E., Roses A.D., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Cloning of a gene bearing missense mutations in early-onset familial RT Alzheimer's disease."; RL Nature 375:754-760(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND TISSUE SPECIFICITY. RC TISSUE=Blood, and Brain; RX PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3; RA Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M., RA Shirasawa T., Mori H.; RT "Identification and characterization of presenilin I-467, I-463 and I- RT 374."; RL FEBS Lett. 381:7-11(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RA Powell C.S., Gegg M.E., Palmer M.S.; RT "Human presenilin 1 gene encodes an alternative protein-minilin."; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A., Madan A., RA Dickhoff R., Shaffer T., James R., Lasky S., Hood L.; RT "Complete sequence of the gene for presenilin 1."; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RA Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.; RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Tongue; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113. RX PubMed=9070286; DOI=10.1006/bbrc.1996.6043; RA Tsujimura A., Yasojima K., Hashimoto-Gotoh T.; RT "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential RT expression in oogenesis and embryogenesis."; RL Biochem. Biophys. Res. Commun. 231:392-396(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING (ISOFORMS 6 RP AND 7). RC TISSUE=Megakaryocyte, and Platelet; RX PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9; RA Vidal R., Ghiso J., Wisniewski T., Frangione B.; RT "Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. RT Identification of a novel splice variant."; RL FEBS Lett. 393:19-23(1996). RN [12] RP PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; RP 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, RP IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, RP AND SUBCELLULAR LOCATION. RX PubMed=15274632; DOI=10.1021/bi0494976; RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J., RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.; RT "Purification and characterization of the human gamma-secretase complex."; RL Biochemistry 43:9774-9789(2004). RN [13] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=8574969; DOI=10.1038/nm0296-224; RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E., RA Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., RA Tanzi R.E., Wasco W.; RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and RT localization to intracellular membranes in mammalian cells."; RL Nat. Med. 2:224-229(1996). RN [14] RP PROTEOLYTIC PROCESSING. RX PubMed=9173929; DOI=10.1006/nbdi.1997.0129; RA Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., RA Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P., RA St George-Hyslop P.H., Teplow D.B., Selkoe D.J.; RT "Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 RT and Ala299 and occur as stable N- and C-terminal fragments in normal and RT Alzheimer brain tissue."; RL Neurobiol. Dis. 3:325-337(1997). RN [15] RP PHOSPHORYLATION. RX PubMed=9144240; DOI=10.1073/pnas.94.10.5349; RA Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M., RA Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C.; RT "Proteolytic processing of the Alzheimer disease-associated presenilin-1 RT generates an in vivo substrate for protein kinase C."; RL Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997). RN [16] RP CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385. RX PubMed=9485372; DOI=10.1021/bi972106l; RA Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C.; RT "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa RT C-terminal fragment are death substrates for proteases of the caspase RT family."; RL Biochemistry 37:2263-2270(1998). RN [17] RP FUNCTION, INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=9738936; DOI=10.1016/s0014-5793(98)00886-2; RA Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X., RA Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.; RT "Direct association of presenilin-1 with beta-catenin."; RL FEBS Lett. 433:73-77(1998). RN [18] RP INTERACTION WITH FLNA AND FLNB. RX PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998; RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.; RT "Interaction of presenilins with the filamin family of actin-binding RT proteins."; RL J. Neurosci. 18:914-922(1998). RN [19] RP FUNCTION, MUTAGENESIS OF MET-292, AND PROTEOLYTIC PROCESSING. RX PubMed=10545183; DOI=10.1021/bi9914210; RA Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., RA Loetscher H., Jacobsen H., Haass C.; RT "Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 RT in the absence of endoproteolysis."; RL Biochemistry 38:14600-14605(1999). RN [20] RP INTERACTION WITH MTCH1. RX PubMed=10551805; DOI=10.1074/jbc.274.46.32543; RA Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.; RT "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting RT with the C terminus of presenilin-1."; RL J. Biol. Chem. 274:32543-32546(1999). RN [21] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NOTCH. RX PubMed=10593990; DOI=10.1074/jbc.274.51.36801; RA Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M., RA Selkoe D.J., Kopan R., Goate A.M.; RT "Cell surface presenilin-1 participates in the gamma-secretase-like RT proteolysis of Notch."; RL J. Biol. Chem. 274:36801-36807(1999). RN [22] RP INTERACTION WITH CTNND2 AND CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x; RA Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D., RA Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L., RA VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E., RA St George-Hyslop P.H.; RT "Presenilins interact with armadillo proteins including neural-specific RT plakophilin-related protein and beta-catenin."; RL J. Neurochem. 72:999-1008(1999). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10206644; DOI=10.1038/19077; RA Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T., RA Selkoe D.J.; RT "Two transmembrane aspartates in presenilin-1 required for presenilin RT endoproteolysis and gamma-secretase activity."; RL Nature 398:513-517(1999). RN [24] RP INTERACTION WITH DOCK3. RX PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x; RA Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R., RA Schubert D., Kimura H.; RT "Isolation and characterization of novel presenilin binding protein."; RL J. Neurochem. 75:109-116(2000). RN [25] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x; RA Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W., RA Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.; RT "Aspartate mutations in presenilin and gamma-secretase inhibitors both RT impair notch1 proteolysis and nuclear translocation with relative RT preservation of notch1 signaling."; RL J. Neurochem. 75:583-593(2000). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LEU-286. RX PubMed=10811883; DOI=10.1073/pnas.100049897; RA Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H., RA Capell A., Steiner H., Haass C.; RT "Separation of presenilin function in amyloid beta-peptide generation and RT endoproteolysis of Notch."; RL Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000). RN [27] RP INTERACTION WITH PARL. RX PubMed=12214059; DOI=10.3233/jad-2001-3203; RA Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K., RA Fowlkes B.J., Koonin E.V., D'Adamio L.; RT "PAMP and PARL, two novel putative metalloproteases interacting with the RT COOH-terminus of presenilin-1 and -2."; RL J. Alzheimers Dis. 3:181-190(2001). RN [28] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=11987239; DOI=10.1006/bcmd.2002.0486; RA Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L., RA Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.; RT "Identification of the presenilins in hematopoietic cells with localization RT of presenilin 1 to neutrophil and platelet granules."; RL Blood Cells Mol. Dis. 28:28-38(2002). RN [29] RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH CDH1 RP AND CTNNB1. RX PubMed=11953314; DOI=10.1093/emboj/21.8.1948; RA Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V., RA Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K.; RT "A presenilin-1/gamma-secretase cleavage releases the E-cadherin RT intracellular domain and regulates disassembly of adherens junctions."; RL EMBO J. 21:1948-1956(2002). RN [30] RP INTERACTION WITH HERPUD1. RX PubMed=11799129; DOI=10.1074/jbc.m112372200; RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., RA Yanagisawa K., Komano H.; RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin- RT mediated generation of amyloid beta-protein."; RL J. Biol. Chem. 277:12915-12920(2002). RN [31] RP INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; RP 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF VARIANTS RP AD3 VAL-79 AND LEU-82. RX PubMed=12058025; DOI=10.1074/jbc.m112121200; RA Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P., RA Jorgensen A.L.; RT "A new splice variant of glial fibrillary acidic protein GFAPepsilon, RT interacts with the presenilin proteins."; RL J. Biol. Chem. 277:29983-29991(2002). RN [32] RP INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-385. RX PubMed=14515347; DOI=10.1002/jnr.10753; RA Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K., RA Shibasaki H., Shimohama S.; RT "Presenilin 1 is involved in maturation and trafficking of N-cadherin to RT the plasma membrane."; RL J. Neurosci. Res. 74:184-191(2003). RN [33] RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, CATALYTIC ACTIVITY, FUNCTION, RP AND SUBUNIT. RX PubMed=12679784; DOI=10.1038/ncb960; RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.; RT "Reconstitution of gamma-secretase activity."; RL Nat. Cell Biol. 5:486-488(2003). RN [34] RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN. RX PubMed=12740439; DOI=10.1073/pnas.1037392100; RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., RA Selkoe D.J.; RT "Gamma-secretase is a membrane protein complex comprised of presenilin, RT nicastrin, Aph-1, and Pen-2."; RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003). RN [35] RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S). RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8; RA Hillman R.T., Green R.E., Brenner S.E.; RT "An unappreciated role for RNA surveillance."; RL Genome Biol. 5:R8.1-R8.16(2004). RN [36] RP FUNCTION, SUBCELLULAR LOCATION, VARIANT AD3 SER-117, AND CHARACTERIZATION RP OF VARIANTS AD3 LEU-117 AND SER-117. RX PubMed=15004326; DOI=10.3233/jad-2004-6105; RA Dowjat W.K., Kuchna I., Wisniewski T., Wegiel J.; RT "A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 RT (Pro117Ser): Comparison of clinical, neuropathological and cell culture RT phenotypes of Pro117Leu and Pro117Ser mutations."; RL J. Alzheimers Dis. 6:31-43(2004). RN [37] RP PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND RP SER-346. RX PubMed=14576165; DOI=10.1074/jbc.m306653200; RA Fluhrer R., Friedlein A., Haass C., Walter J.; RT "Phosphorylation of presenilin 1 at the caspase recognition site regulates RT its proteolytic processing and the progression of apoptosis."; RL J. Biol. Chem. 279:1585-1593(2004). RN [38] RP TOPOLOGY. RX PubMed=15385547; DOI=10.1074/jbc.m407898200; RA Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G., RA Martoglio B.; RT "Consensus analysis of signal peptide peptidase and homologous human RT aspartic proteases reveals opposite topology of catalytic domains compared RT with presenilins."; RL J. Biol. Chem. 279:50790-50798(2004). RN [39] RP FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF TYR-256; RP ASP-257; ASP-385 AND TYR-389. RX PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x; RA Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A., RA De Strooper B., Shearman M.S., Beher D.; RT "Conserved residues within the putative active site of gamma-secretase RT differentially influence enzyme activity and inhibitor binding."; RL J. Neurochem. 90:1312-1320(2004). RN [40] RP INTERACTION WITH CDH1 AND CTNNB1. RX PubMed=16126725; DOI=10.1074/jbc.m507503200; RA Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J., RA Robakis N.K.; RT "Cadherins mediate both the association between PS1 and beta-catenin and RT the effects of PS1 on beta-catenin stability."; RL J. Biol. Chem. 280:36007-36012(2005). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [42] RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD3 VAL-146. RX PubMed=16959576; DOI=10.1016/j.cell.2006.06.059; RA Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H., RA Serneels L., De Strooper B., Yu G., Bezprozvanny I.; RT "Presenilins form ER Ca2+ leak channels, a function disrupted by familial RT Alzheimer's disease-linked mutations."; RL Cell 126:981-993(2006). RN [43] RP FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435, AND RP CHARACTERIZATION OF VARIANT AD3 PHE-435. RX PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x; RA Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.; RT "C-terminal PAL motif of presenilin and presenilin homologues required for RT normal active site conformation."; RL J. Neurochem. 96:218-227(2006). RN [44] RP VARIANTS AD3 ILE-139 AND CYS-289. RX PubMed=8875251; DOI=10.1093/hmg/5.supplement_1.1449; RA Cruts M., Hendriks L., Van Broeckhoven C.; RT "The presenilin genes: a new gene family involved in Alzheimer disease RT pathology."; RL Hum. Mol. Genet. 5:1449-1455(1996). RN [45] RP REVIEW ON VARIANTS. RX PubMed=9521418; RX DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j; RA Cruts M., van Broeckhoven C.; RT "Presenilin mutations in Alzheimer's disease."; RL Hum. Mutat. 11:183-190(1998). RN [46] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [47] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [49] RP IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, AND INTERACTION WITH CRB2. RX PubMed=20299451; DOI=10.1074/jbc.m109.038760; RA Mitsuishi Y., Hasegawa H., Matsuo A., Araki W., Suzuki T., Tagami S., RA Okochi M., Takeda M., Roepman R., Nishimura M.; RT "Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein RT by binding to the presenilin complex."; RL J. Biol. Chem. 285:14920-14931(2010). RN [50] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [51] RP INVOLVEMENT IN ACNINV3. RX PubMed=20929727; DOI=10.1126/science.1196284; RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y., RA Qu T., Chen M., Sun M., Shen Y., Zhang X.; RT "Gamma-secretase gene mutations in familial acne inversa."; RL Science 330:1065-1065(2010). RN [52] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [53] RP SUBCELLULAR LOCATION, AND INTERACTION WITH UBQLN1. RX PubMed=21143716; DOI=10.1111/j.1600-0854.2010.01149.x; RA Viswanathan J., Haapasalo A., Bottcher C., Miettinen R., Kurkinen K.M., RA Lu A., Thomas A., Maynard C.J., Romano D., Hyman B.T., Berezovska O., RA Bertram L., Soininen H., Dantuma N.P., Tanzi R.E., Hiltunen M.; RT "Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 RT accumulation and aggresome formation."; RL Traffic 12:330-348(2011). RN [54] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [55] RP FUNCTION, INTERACTION WITH APH1A/APH1B AND PEN2, SUBCELLULAR LOCATION, AND RP CHARACTERIZATION OF VARIANT AD3 ASP-206. RX PubMed=25394380; DOI=10.1007/s12035-014-8969-1; RA Chen W.T., Hsieh Y.F., Huang Y.J., Lin C.C., Lin Y.T., Liu Y.C., Lien C.C., RA Cheng I.H.; RT "G206D mutation of presenilin-1 reduces Pen2 interaction, increases RT Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation."; RL Mol. Neurobiol. 52:1835-1849(2015). RN [56] {ECO:0007744|PDB:2KR6} RP STRUCTURE BY NMR OF 292-467. RA Doetsch V.; RT "Solution structure of presenilin-1 CTF subunit."; RL Submitted (DEC-2009) to the PDB data bank. RN [57] RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, SUBUNIT, AND TOPOLOGY. RX PubMed=25043039; DOI=10.1038/nature13567; RA Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R., RA Scheres S.H., Shi Y.; RT "Three-dimensional structure of human gamma-secretase."; RL Nature 512:166-170(2014). RN [58] {ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5} RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, AND TOPOLOGY. RX PubMed=26623517; DOI=10.7554/elife.11182; RA Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.; RT "Sampling the conformational space of the catalytic subunit of human gamma- RT secretase."; RL Elife 4:0-0(2015). RN [59] {ECO:0007744|PDB:5A63} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, RP TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF RP VARIANTS AD3 LEU-213; ILE-237 AND PHE-261, AND MUTAGENESIS OF ILE-202; RP LEU-226; LEU-248 AND LEU-424. RX PubMed=26280335; DOI=10.1038/nature14892; RA Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H., RA Shi Y.; RT "An atomic structure of human gamma-secretase."; RL Nature 525:212-217(2015). RN [60] {ECO:0007744|PDB:4UIS} RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 81-463, SUBUNIT, AND RP TOPOLOGY. RX PubMed=25918421; DOI=10.1073/pnas.1506242112; RA Sun L., Zhao L., Yang G., Yan C., Zhou R., Zhou X., Xie T., Zhao Y., Wu S., RA Li X., Shi Y.; RT "Structural basis of human gamma-secretase assembly."; RL Proc. Natl. Acad. Sci. U.S.A. 112:6003-6008(2015). RN [61] RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH NOTCH1; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, CATALYTIC RP ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF GLN-112; 288-TYR--SER-290; RP 377-ARG--LEU-381; ASP-385; LEU-432 AND 432-LEU--ALA-434, AND DOMAIN. RX PubMed=30598546; DOI=10.1038/s41586-018-0813-8; RA Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.; RT "Structural basis of Notch recognition by human gamma-secretase."; RL Nature 565:192-197(2019). RN [62] RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH APP CHAIN C83; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, RP CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF RP GLN-112; 288-TYR--SER-290; 377-ARG--LEU-381; ASP-385; LEU-432 AND RP 432-LEU--ALA-434. RX PubMed=30630874; DOI=10.1126/science.aaw0930; RA Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.; RT "Recognition of the amyloid precursor protein by human gamma-secretase."; RL Science 0:0-0(2019). RN [63] RP VARIANTS AD3 THR-143 AND ALA-384. RX PubMed=8634711; DOI=10.1093/hmg/4.12.2363; RA Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J., RA de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M., RA Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L., RA Van Broeckhoven C.; RT "Molecular genetic analysis of familial early-onset Alzheimer's disease RT linked to chromosome 14q24.3."; RL Hum. Mol. Genet. 4:2363-2372(1995). RN [64] RP VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392 RP AND TYR-410. RX PubMed=8634712; DOI=10.1093/hmg/4.12.2373; RA Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C., RA Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M., RA Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M., RA Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T.; RT "Mutations of the presenilin I gene in families with early-onset RT Alzheimer's disease."; RL Hum. Mol. Genet. 4:2373-2377(1995). RN [65] RP VARIANTS AD3 VAL-260; VAL-285 AND VAL-392. RX PubMed=7651536; DOI=10.1038/376775a0; RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., RA Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., RA Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Familial Alzheimer's disease in kindreds with missense mutations in a gene RT on chromosome 1 related to the Alzheimer's disease type 3 gene."; RL Nature 376:775-778(1995). RN [66] RP VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280. RX PubMed=7550356; DOI=10.1038/ng1095-219; RA Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C., RA Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A., RA Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J., RA Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J., RA Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L., RA Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R., RA Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L., RA Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B., RA Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D., RA Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D., RA Hardy J., Goate A.M.; RT "The structure of the presenilin 1 (S182) gene and identification of six RT novel mutations in early onset AD families."; RL Nat. Genet. 11:219-222(1995). RN [67] RP VARIANT AD3 ALA-280, AND INVOLVEMENT IN AD3. RX PubMed=8837617; DOI=10.1038/nm1096-1146; RA Lemere C.A., Lopera F., Kosik K.S., Lendon C.L., Ossa J., Saido T.C., RA Yamaguchi H., Ruiz A., Martinez A., Madrigal L., Hincapie L., Arango J.C., RA Anthony D.C., Koo E.H., Goate A.M., Selkoe D.J., Arango J.C.; RT "The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 RT deposition and severe cerebellar pathology."; RL Nat. Med. 2:1146-1150(1996). RN [68] RP VARIANTS AD3 PHE-96; ARG-163 AND THR-213. RX PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8; RA Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H., RA Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T.; RT "Three different mutations of presenilin 1 gene in early-onset Alzheimer's RT disease families."; RL Neurosci. Lett. 208:195-198(1996). RN [69] RP VARIANT AD3 ASP-135. RX PubMed=9225696; DOI=10.1002/ana.410420121; RA Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M., RA Hutton M., Haltia T., Hardy J., Galasko D.; RT "Early-onset Alzheimer's disease with a presenilin-1 mutation at the site RT corresponding to the Volga German presenilin-2 mutation."; RL Ann. Neurol. 42:124-128(1997). RN [70] RP VARIANT AD3 ALA-280. RX PubMed=9298817; RX DOI=10.1002/(sici)1098-1004(1997)10:3<186::aid-humu2>3.0.co;2-h; RA Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J., RA Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C., RA Ossa J., Ruiz A., Goate A.M., Lopera F.; RT "E280A PS-1 mutation causes Alzheimer's disease but age of onset is not RT modified by ApoE alleles."; RL Hum. Mutat. 10:186-195(1997). RN [71] RP VARIANTS AD3 THR-233 AND THR-278. RX PubMed=9172170; DOI=10.1097/00001756-199704140-00043; RA Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A., RA Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H., RA Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E., RA Schofield P.R., Martins R.N.; RT "Two novel (M233T and R278T) presenilin-1 mutations in early-onset RT Alzheimer's disease pedigrees and preliminary evidence for association of RT presenilin-1 mutations with a novel phenotype."; RL NeuroReport 8:1537-1542(1997). RN [72] RP VARIANT AD3 PRO-171. RX PubMed=9833068; RA Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C., RA Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H., RA Cantu J.M.; RT "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with RT early onset Alzheimer disease."; RL Ann. Genet. 41:149-153(1998). RN [73] RP VARIANT GLY-318. RX PubMed=9851443; DOI=10.1002/ana.410440617; RA Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M., RA Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L.; RT "The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause RT Alzheimer's disease."; RL Ann. Neurol. 44:965-967(1998). RN [74] RP VARIANT GLY-318. RX PubMed=9851450; DOI=10.1002/ana.410440624; RA Aldudo J., Bullido M.J., Frank A., Valdivieso F.; RT "Missense mutation E318G of the presenilin-1 gene appears to be a RT nonpathogenic polymorphism."; RL Ann. Neurol. 44:985-986(1998). RN [75] RP VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318. RX PubMed=9384602; DOI=10.1093/hmg/7.1.43; RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A., RA Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H., RA Hofman A., van Broeckhoven C.; RT "Estimation of the genetic contribution of presenilin-1 and -2 mutations in RT a population-based study of presenile Alzheimer disease."; RL Hum. Mol. Genet. 7:43-51(1998). RN [76] RP VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND RP PRO-426. RX PubMed=9521423; RX DOI=10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f; RA Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H., RA White J., Heston L., Bird T.D., Schellenberg G.D.; RT "Missense mutations in the chromosome 14 familial Alzheimer's disease RT presenilin 1 gene."; RL Hum. Mutat. 11:216-221(1998). RN [77] RP VARIANT AD3 GLU-378. RX PubMed=10200054; RX DOI=10.1002/(sici)1098-1004(1998)11:6<481::aid-humu12>3.0.co;2-q; RA Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E., RA Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A.; RT "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a RT French family with early-onset Alzheimer's disease and transmission study RT by mismatch enhanced allele specific amplification."; RL Hum. Mutat. 11:481-481(1998). RN [78] RP VARIANT AD3 LYS-139. RX PubMed=9719376; DOI=10.1136/jmg.35.8.672; RA Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V., RA Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.; RT "De novo presenilin 1 mutations are rare in clinically sporadic, early RT onset Alzheimer's disease cases."; RL J. Med. Genet. 35:672-673(1998). RN [79] RP VARIANT AD3 LEU-117. RX PubMed=9507958; DOI=10.1097/00001756-199801260-00008; RA Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S., RA Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B.; RT "A novel Polish presenilin-1 mutation (P117L) is associated with familial RT Alzheimer's disease and leads to death as early as the age of 28 years."; RL NeuroReport 9:217-221(1998). RN [80] RP VARIANTS AD3 LEU-169 AND GLN-436. RX PubMed=9831473; DOI=10.1097/00001756-199810050-00034; RA Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M., RA Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R., RA Martins R.N.; RT "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with RT very early onset Alzheimer's disease."; RL NeuroReport 9:3335-3339(1998). RN [81] RP VARIANT GLY-318. RX PubMed=9915968; DOI=10.1086/302200; RA Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C., RA Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A., RA van Duijn C.M., van Broeckhoven C.; RT "The Glu318Gly substitution in presenilin 1 is not causally related to RT Alzheimer disease."; RL Am. J. Hum. Genet. 64:290-292(1999). RN [82] RP VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163; RP CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND RP TYR-410, AND VARIANT GLY-318. RX PubMed=10441572; DOI=10.1086/302553; RA Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., RA Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G., RA Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F., RA Brice A., Frebourg T.; RT "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic RT heterogeneity, and mutation spectrum."; RL Am. J. Hum. Genet. 65:664-670(1999). RN [83] RP VARIANTS AD3 PHE-143 AND SER-436. RX PubMed=10090481; RX DOI=10.1002/(sici)1098-1004(1999)13:3<256::aid-humu11>3.0.co;2-p; RA Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K., RA Fox N.C., Harvey R., Rossor M.N., Collinge J.; RT "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset RT Alzheimer's disease in the UK."; RL Hum. Mutat. 13:256-256(1999). RN [84] RP VARIANT AD3 ARG-209. RX PubMed=10447269; RX DOI=10.1002/(sici)1098-1004(1999)14:1<90::aid-humu19>3.0.co;2-s; RA Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y., RA Iseki E., Kosaka K.; RT "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a RT Japanese family with presenile familial Alzheimer's disease."; RL Hum. Mutat. 14:90-90(1999). RN [85] RP VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318. RX PubMed=10533070; RX DOI=10.1002/(sici)1098-1004(199911)14:5<433::aid-humu10>3.0.co;2-k; RA Aldudo J., Bullido M.J., Valdivieso F.; RT "DGGE method for the mutational analysis of the coding and proximal RT promoter regions of the Alzheimer's disease presenilin-1 gene: two novel RT mutations."; RL Hum. Mutat. 14:433-439(1999). RN [86] RP VARIANT AD3 PRO-169. RX PubMed=10025789; DOI=10.1212/wnl.52.3.566; RA Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.; RT "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and RT myoclonic seizures."; RL Neurology 52:566-570(1999). RN [87] RP VARIANT AD3 PRO-219. RX PubMed=10208579; DOI=10.1097/00001756-199902250-00011; RA Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K., RA Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.; RT "Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of RT the presenilin-1 gene."; RL NeuroReport 10:503-507(1999). RN [88] RP VARIANT AD3 ASN-116. RX PubMed=10439444; DOI=10.1097/00001756-199908020-00006; RA Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D., RA Havsager A.-M., Joergensen A.L.; RT "A presenilin-1 Thr116Asn substitution in a family with early-onset RT Alzheimer's disease."; RL NeuroReport 10:2255-2260(1999). RN [89] RP VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [90] RP VARIANT AD3 SER-405. RX PubMed=10644793; DOI=10.1136/jnnp.68.2.220; RA Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S., RA Maeda K., Tanaka C.; RT "Novel presenilin-1 mutation with widespread cortical amyloid deposition RT but limited cerebral amyloid angiopathy."; RL J. Neurol. Neurosurg. Psych. 68:220-223(2000). RN [91] RP VARIANT AD3 SER-92. RX PubMed=11027672; DOI=10.1006/bbrc.2000.3646; RA Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.; RT "The presenilin 1 C92S mutation increases abeta 42 production."; RL Biochem. Biophys. Res. Commun. 277:261-263(2000). RN [92] RP VARIANT FTD1 PRO-113. RX PubMed=11094121; DOI=10.1212/wnl.55.10.1577; RA Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P., RA Hannequin D., Brice A., Frebourg T., Campion D.; RT "Dementia with prominent frontotemporal features associated with L113P RT presenilin 1 mutation."; RL Neurology 55:1577-1578(2000). RN [93] RP VARIANTS AD3 MET-94; THR-143 AND ALA-280, AND VARIANT GLY-318. RX PubMed=11568920; RX DOI=10.1002/1096-8628(20011001)103:2<138::aid-ajmg1529>3.0.co;2-8; RA Arango D., Cruts M., Torres O., Backhovens H., Serrano M.L., Villareal E., RA Montanes P., Matallana D., Cano C., Van Broeckhoven C., Jacquier M.; RT "Systematic genetic study of Alzheimer disease in Latin America: mutation RT frequencies of the amyloid beta precursor protein and presenilin genes in RT Colombia."; RL Am. J. Med. Genet. 103:138-143(2001). RN [94] RP VARIANT AD3 VAL-282, AND CHARACTERIZATION OF VARIANT AD3 VAL-282. RX PubMed=11701593; DOI=10.1093/brain/124.12.2383; RA Dermaut B., Kumar-Singh S., De Jonghe C., Cruts M., Loefgren A., Luebke U., RA Cras P., Dom R., De Deyn P.P., Martin J.J., Van Broeckhoven C.; RT "Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease RT due to a novel presenilin 1 mutation."; RL Brain 124:2383-2392(2001). RN [95] RP ERRATUM OF PUBMED:11701593, AND VARIANT AD3 GLU-431. RA Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.; RL Hum. Genet. 109:242-242(2001). RN [96] RP VARIANT AD3 ALA-206. RX PubMed=11710891; DOI=10.1001/jama.286.18.2257; RA Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H., RA Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E., RA Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K., RA Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.; RT "A founder mutation in presenilin 1 causing early-onset Alzheimer disease RT in unrelated Caribbean Hispanic families."; RL JAMA 286:2257-2263(2001). RN [97] RP VARIANT AD3 ILE-237. RX PubMed=11561050; DOI=10.1136/jnnp.71.4.556; RA Sodeyama N., Iwata T., Ishikawa K., Mizusawa H., Yamada M., Itoh Y., RA Otomo E., Matsushita M., Komatsuzaki Y.; RT "Very early onset Alzheimer's disease with spastic paraparesis associated RT with a novel presenilin 1 mutation (Phe237Ile)."; RL J. Neurol. Neurosurg. Psych. 71:556-557(2001). RN [98] RP VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; RP VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; RP ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; RP PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; RP GLU-431; PHE-435 AND VAL-439, AND VARIANT GLY-318. RX PubMed=11524469; DOI=10.1212/wnl.57.4.621; RA Rogaeva E.A., Fafel K.C., Song Y.Q., Medeiros H., Sato C., Liang Y., RA Richard E., Rogaev E.I., Frommelt P., Sadovnick A.D., Meschino W., RA Rockwood K., Boss M.A., Mayeux R., St George-Hyslop P.; RT "Screening for PS1 mutations in a referral-based series of AD cases: 21 RT novel mutations."; RL Neurology 57:621-625(2001). RN [99] RP VARIANT AD3 SER-266. RX PubMed=11920851; DOI=10.1002/ajmg.10250; RA Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K., RA Kohara K., Miyoshi K., Miki T.; RT "Molecular evidence of presenilin 1 mutation in familial early onset RT dementia."; RL Am. J. Med. Genet. 114:292-298(2002). RN [100] RP VARIANT AD3 LEU-89. RX PubMed=11796781; DOI=10.1136/jnnp.72.2.266; RA Queralt R., Ezquerra M., Lleo A., Castellvi M., Gelpi J., Ferrer I., RA Acarin N., Pasarin L., Blesa R., Oliva R.; RT "A novel mutation (V89L) in the presenilin 1 gene in a family with early RT onset Alzheimer's disease and marked behavioural disturbances."; RL J. Neurol. Neurosurg. Psych. 72:266-269(2002). RN [101] RP VARIANT AD3 GLY-280. RX PubMed=12370477; DOI=10.1212/wnl.59.7.1108; RA O'Riordan S., McMonagle P., Janssen J.C., Fox N.C., Farrell M., RA Collinge J., Rossor M.N., Hutchinson M.; RT "Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white- RT matter abnormalities."; RL Neurology 59:1108-1110(2002). RN [102] RP VARIANT AD3 PRO-166. RX PubMed=12048239; DOI=10.1073/pnas.112686799; RA Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A., RA Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.; RT "Presenilin-1 mutations of leucine 166 equally affect the generation of the RT Notch and APP intracellular domains independent of their effect on Abeta 42 RT production."; RL Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002). RN [103] RP VARIANT AD3 MET-174. RX PubMed=12484344; DOI=10.1007/s10048-002-0136-6; RA Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J., RA Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M., RA van Duijn C.M., Heredero Baute L., Heutink P.; RT "A novel presenilin 1 mutation (L174 M) in a large Cuban family with early RT onset Alzheimer disease."; RL Neurogenetics 4:97-104(2002). RN [104] RP VARIANT AD3 VAL-271. RX PubMed=12493737; DOI=10.1074/jbc.m211827200; RA Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O., RA Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A., RA Gandy S.E., Schofield P.R.; RT "Presenilin-1 mutation L271V results in altered exon 8 splicing and RT Alzheimer's disease with non-cored plaques and no neuritic dystrophy."; RL J. Biol. Chem. 278:6748-6754(2003). RN [105] RP VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171; RP ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND RP VAL-378, AND VARIANT GLY-318. RX PubMed=12552037; DOI=10.1212/01.wnl.0000042088.22694.e3; RA Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C., RA Harvey R.J., Houlden H., Rossor M.N., Collinge J.; RT "Early onset familial Alzheimer's disease: Mutation frequency in 31 RT families."; RL Neurology 60:235-239(2003). RN [106] RP VARIANT PIDB VAL-183, CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282, RP AND CHARACTERIZATION OF VARIANT PIDB VAL-183. RX PubMed=15122701; DOI=10.1002/ana.20083; RA Dermaut B., Kumar-Singh S., Engelborghs S., Theuns J., Rademakers R., RA Saerens J., Pickut B.A., Peeters K., van den Broeck M., Vennekens K., RA Claes S., Cruts M., Cras P., Martin J.J., Van Broeckhoven C., De Deyn P.P.; RT "A novel presenilin 1 mutation associated with Pick's disease but not beta- RT amyloid plaques."; RL Ann. Neurol. 55:617-626(2004). RN [107] RP VARIANT AD3 PRO-85, AND CHARACTERIZATION OF VARIANT AD3 PRO-85. RX PubMed=15534188; DOI=10.1001/archneur.61.11.1773; RA Ataka S., Tomiyama T., Takuma H., Yamashita T., Shimada H., Tsutada T., RA Kawabata K., Mori H., Miki T.; RT "A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease RT with spastic paraparesis."; RL Arch. Neurol. 61:1773-1776(2004). RN [108] RP VARIANT AD3 ILE-278. RX PubMed=15534260; DOI=10.1212/01.wnl.0000143060.98164.1a; RA Godbolt A.K., Beck J.A., Collinge J., Garrard P., Warren J.D., Fox N.C., RA Rossor M.N.; RT "A presenilin 1 R278I mutation presenting with language impairment."; RL Neurology 63:1702-1704(2004). RN [109] RP VARIANT AD3 ASN-154. RX PubMed=15364419; DOI=10.1016/j.neulet.2004.07.057; RA Hattori S., Sakuma K., Wakutani Y., Wada K., Shimoda M., Urakami K., RA Kowa H., Nakashima K.; RT "A novel presenilin 1 mutation (Y154N) in a patient with early onset RT Alzheimer's disease with spastic paraparesis."; RL Neurosci. Lett. 368:319-322(2004). RN [110] RP VARIANT AD3 PHE-170. RX PubMed=16344340; DOI=10.1001/archneur.62.12.1821; RA Snider B.J., Norton J., Coats M.A., Chakraverty S., Hou C.E., Jervis R., RA Lendon C.L., Goate A.M., McKeel D.W. Jr., Morris J.C.; RT "Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy RT bodies in the third decade of life."; RL Arch. Neurol. 62:1821-1830(2005). RN [111] RP VARIANT AD3 LEU-97. RX PubMed=15851849; DOI=10.3233/jad-2005-7204; RA Jia J., Xu E., Shao Y., Jia J., Sun Y., Li D.; RT "One novel presenilin-1 gene mutation in a Chinese pedigree of familial RT Alzheimer's disease."; RL J. Alzheimers Dis. 7:119-124(2005). RN [112] RP VARIANT CMD1U GLY-333. RX PubMed=17186461; DOI=10.1086/509900; RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S., RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M., RA Hershberger R.E.; RT "Mutations of presenilin genes in dilated cardiomyopathy and heart RT failure."; RL Am. J. Hum. Genet. 79:1030-1039(2006). RN [113] RP CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262; RP PHE-263; VAL-282 AND ALA-384. RX PubMed=16752394; DOI=10.1002/humu.20336; RA Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K., RA Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.; RT "Mean age-of-onset of familial alzheimer disease caused by presenilin RT mutations correlates with both increased Abeta42 and decreased Abeta40."; RL Hum. Mutat. 27:686-695(2006). RN [114] RP VARIANT AD3 GLU-431. RX PubMed=16628450; DOI=10.1007/s10048-006-0043-3; RA Yescas P., Huertas-Vazquez A., Villarreal-Molina M.T., Rasmussen A., RA Tusie-Luna M.T., Lopez M., Canizales-Quinteros S., Alonso M.E.; RT "Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing RT early-onset Alzheimer's disease in Mexican families."; RL Neurogenetics 7:195-200(2006). RN [115] RP VARIANT AD3 GLU-431. RX PubMed=16897084; DOI=10.1007/s10048-006-0053-1; RA Murrell J., Ghetti B., Cochran E., Macias-Islas M.A., Medina L., RA Varpetian A., Cummings J.L., Mendez M.F., Kawas C., Chui H., Ringman J.M.; RT "The A431E mutation in PSEN1 causing familial Alzheimer's disease RT originating in Jalisco State, Mexico: an additional fifteen families."; RL Neurogenetics 7:277-279(2006). RN [116] RP VARIANT AD3 VAL-79, AND CHARACTERIZATION OF VARIANT AD3 VAL-79. RX PubMed=17366635; DOI=10.1002/ana.21099; RA Kauwe J.S., Jacquart S., Chakraverty S., Wang J., Mayo K., Fagan A.M., RA Holtzman D.M., Morris J.C., Goate A.M.; RT "Extreme cerebrospinal fluid amyloid beta levels identify family with late- RT onset Alzheimer's disease presenilin 1 mutation."; RL Ann. Neurol. 61:446-453(2007). RN [117] RP VARIANT AD3 PHE-170. RX PubMed=17502474; DOI=10.1001/archneur.64.5.738; RA Piccini A., Zanusso G., Borghi R., Noviello C., Monaco S., Russo R., RA Damonte G., Armirotti A., Gelati M., Giordano R., Zambenedetti P., RA Russo C., Ghetti B., Tabaton M.; RT "Association of a presenilin 1 S170F mutation with a novel Alzheimer RT disease molecular phenotype."; RL Arch. Neurol. 64:738-745(2007). RN [118] RP CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260; RP LEU-264 AND GLY-280, FUNCTION, AND MUTAGENESIS OF ASP-257. RX PubMed=17428795; DOI=10.1074/jbc.m611449200; RA Litterst C., Georgakopoulos A., Shioi J., Ghersi E., Wisniewski T., RA Wang R., Ludwig A., Robakis N.K.; RT "Ligand binding and calcium influx induce distinct ectodomain/gamma- RT secretase-processing pathways of EphB2 receptor."; RL J. Biol. Chem. 282:16155-16163(2007). RN [119] RP VARIANT GLY-318. RX PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014; RA Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F., RA Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J., RA Emans J.B., Turnpenny P.D., Pourquie O.; RT "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin RT syndrome."; RL Am. J. Hum. Genet. 82:1334-1341(2008). RN [120] RP CHARACTERIZATION OF VARIANT AD3 THR-213. RX PubMed=18430735; DOI=10.1074/jbc.m801279200; RA Shimojo M., Sahara N., Mizoroki T., Funamoto S., Morishima-Kawashima M., RA Kudo T., Takeda M., Ihara Y., Ichinose H., Takashima A.; RT "Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in RT cell models and knock-in mouse brains: familial Alzheimer disease-linked RT mutation impairs gamma-site cleavage of amyloid precursor protein C- RT terminal fragment beta."; RL J. Biol. Chem. 283:16488-16496(2008). RN [121] RP VARIANT AD3 VAL-381. RX PubMed=19797784; DOI=10.1177/1533317509341464; RA Dintchov Traykov L., Mehrabian S., Van den Broeck M., RA Radoslavova Raycheva M., Cruts M., Kirilova Jordanova A., RA Van Broeckhoven C.; RT "Novel PSEN1 mutation in a Bulgarian patient with very early-onset RT Alzheimer's disease, spastic paraparesis, and extrapyramidal signs."; RL Am. J. Alzheimers Dis. Other Demen. 24:404-407(2009). RN [122] RP VARIANT AD3 ARG-217, AND CHARACTERIZATION OF VARIANT AD3 ARG-217. RX PubMed=19667325; DOI=10.1212/wnl.0b013e3181b163ba; RA Norton J.B., Cairns N.J., Chakraverty S., Wang J., Levitch D., Galvin J.E., RA Goate A.; RT "Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool RT plaques."; RL Neurology 73:480-482(2009). RN [123] RP VARIANT AD3 LEU-146. RX PubMed=20164095; DOI=10.1212/wnl.0b013e3181d52785; RA Bruni A.C., Bernardi L., Colao R., Rubino E., Smirne N., Frangipane F., RA Terni B., Curcio S.A., Mirabelli M., Clodomiro A., Di Lorenzo R., RA Maletta R., Anfossi M., Gallo M., Geracitano S., Tomaino C., Muraca M.G., RA Leotta A., Lio S.G., Pinessi L., Rainero I., Sorbi S., Nee L., Milan G., RA Pappata S., Postiglione A., Abbamondi N., Forloni G., St George Hyslop P., RA Rogaeva E., Bugiani O., Giaccone G., Foncin J.F., Spillantini M.G., RA Puccio G.; RT "Worldwide distribution of PSEN1 Met146Leu mutation: a large variability RT for a founder mutation."; RL Neurology 74:798-806(2010). RN [124] RP VARIANT AD3 PHE-435, CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND RP SER-436, MUTAGENESIS OF PRO-433 AND LEU-435, AND FUNCTION. RX PubMed=20460383; DOI=10.1074/jbc.m110.116962; RA Heilig E.A., Xia W., Shen J., Kelleher R.J. III; RT "A presenilin-1 mutation identified in familial Alzheimer disease with RT cotton wool plaques causes a nearly complete loss of gamma-secretase RT activity."; RL J. Biol. Chem. 285:22350-22359(2010). RN [125] RP VARIANT AD3 ASP-206. RX PubMed=21335660; DOI=10.3233/jad-2011-102031; RA Wu Y.Y., Cheng I.H., Lee C.C., Chiu M.J., Lee M.J., Chen T.F., Hsu J.L.; RT "Clinical phenotype of G206D mutation in the presenilin 1 gene in RT pathologically confirmed familial Alzheimer's disease."; RL J. Alzheimers Dis. 25:145-150(2011). RN [126] RP VARIANT CYS-315. RX PubMed=21248752; DOI=10.1038/nature09639; RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H., RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J., RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M., RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L., RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J., RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A., RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K., RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.; RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene RT PBRM1 in renal carcinoma."; RL Nature 469:539-542(2011). RN [127] RP VARIANT AD3 ARG-235. RX PubMed=21501661; DOI=10.1016/j.neulet.2011.03.084; RA Antonell A., Balasa M., Oliva R., Llado A., Bosch B., Fabregat N., RA Fortea J., Molinuevo J.L., Sanchez-Valle R.; RT "A novel PSEN1 gene mutation (L235R) associated with familial early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 496:40-42(2011). RN [128] RP CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280. RX PubMed=22461631; DOI=10.1074/jbc.m111.300483; RA Chau D.M., Crump C.J., Villa J.C., Scheinberg D.A., Li Y.M.; RT "Familial Alzheimer disease presenilin-1 mutations alter the active site RT conformation of gamma-secretase."; RL J. Biol. Chem. 287:17288-17296(2012). RN [129] RP VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214. RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020; RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B., RA Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.; RT "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish RT dementia patients."; RL Neurobiol. Aging 33:1850.E17-1850.E27(2012). RN [130] RP VARIANT AD3 PHE-159. RX PubMed=23123781; DOI=10.1016/j.neulet.2012.10.037; RA Kerchner G.A., Holbrook K.; RT "Novel presenilin-1 Y159F sequence variant associated with early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 531:142-144(2012). RN [131] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166 AND GLN-436, AND MUTAGENESIS OF RP ASP-257 AND ASP-385. RX PubMed=22529981; DOI=10.1371/journal.pone.0035133; RA Cacquevel M., Aeschbach L., Houacine J., Fraering P.C.; RT "Alzheimer's disease-linked mutations in presenilin-1 result in a drastic RT loss of activity in purified gamma-secretase complexes."; RL PLoS ONE 7:E35133-E35133(2012). RN [132] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392; RP TYR-410 AND PHE-435. RX PubMed=23843529; DOI=10.1523/jneurosci.0954-13.2013; RA Heilig E.A., Gutti U., Tai T., Shen J., Kelleher R.J. III; RT "Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma- RT secretase activity and Abeta production."; RL J. Neurosci. 33:11606-11617(2013). RN [133] RP VARIANT AD3 PHE-381. RX PubMed=24121961; DOI=10.3233/jad-131340; RA Dolzhanskaya N., Gonzalez M.A., Sperziani F., Stefl S., Messing J., RA Wen G.Y., Alexov E., Zuchner S., Velinov M.; RT "A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very RT early onset and unusually fast progressing dementia as well as lysosomal RT inclusions typically seen in Kufs disease."; RL J. Alzheimers Dis. 39:23-27(2014). RN [134] RP VARIANT AD3 VAL-153. RX PubMed=24495933; DOI=10.1016/j.neulet.2014.01.016; RA Cornejo-Olivas M.R., Yu C.E., Mazzetti P., Mata I.F., Meza M., RA Lindo-Samanamud S., Leverenz J.B., Bird T.D.; RT "Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a RT Peruvian family with early-onset Alzheimer's disease."; RL Neurosci. Lett. 563:140-143(2014). RN [135] RP VARIANT AD3 VAL-275. RX PubMed=24582897; DOI=10.1016/j.neulet.2014.02.034; RA Luedecke D., Becktepe J.S., Lehmbeck J.T., Finckh U., Yamamoto R., Jahn H., RA Boelmans K.; RT "A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial RT Alzheimer disease."; RL Neurosci. Lett. 566:115-119(2014). RN [136] RP VARIANT AD3 THR-83. RX PubMed=26145164; DOI=10.1016/j.neurobiolaging.2015.06.007; RA Achouri-Rassas A., Ben Ali N., Fray S., Hadj Fredj S., Kechaou M., RA Zakraoui N.O., Cherif A., Chabbi S., Anane N., Messaoud T., Gouider R., RA Belal S.; RT "Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset RT Alzheimer's disease."; RL Neurobiol. Aging 36:2904.E09-2904.E11(2015). RN [137] RP VARIANTS AD3 ALA-206 AND VAL-378. RX PubMed=27073747; RA Ravenscroft T.A., Pottier C., Murray M.E., Baker M., Christopher E., RA Levitch D., Brown P.H., Barker W., Duara R., Greig-Custo M., Betancourt A., RA English M., Sun X., Ertekin-Taner N., Graff-Radford N.R., Dickson D.W., RA Rademakers R.; RT "The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset RT Alzheimer's disease in Hispanics in Florida."; RL Am. J. Neurodegener. Dis. 5:94-101(2016). RN [138] RP VARIANT AD3 THR-408. RX PubMed=26549787; DOI=10.1016/j.neulet.2015.11.004; RA Tedde A., Bartoli A., Piaceri I., Ferrara S., Bagnoli S., Serio A., RA Sorbi S., Nacmias B.; RT "Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late- RT onset Alzheimer's disease."; RL Neurosci. Lett. 610:150-153(2016). RN [139] RP VARIANT ARG-311, CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311, AND RP FUNCTION. RX PubMed=28269784; DOI=10.3233/jad-161188; RA Dong J., Qin W., Wei C., Tang Y., Wang Q., Jia J.; RT "A novel PSEN1 K311R mutation discovered in Chinese families with late- RT onset Alzheimer's disease affects amyloid-beta production and tau RT phosphorylation."; RL J. Alzheimers Dis. 57:613-623(2017). RN [140] RP CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; RP SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; RP ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; RP ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; RP LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; RP LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; RP PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; RP ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; RP ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; RP VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; RP THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439, RP CHARACTERIZATION OF VARIANT CMD1U GLY-333, AND MUTAGENESIS OF THR-99; RP PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; RP LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; RP LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; RP TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; RP ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437. RX PubMed=27930341; DOI=10.1073/pnas.1618657114; RA Sun L., Zhou R., Yang G., Shi Y.; RT "Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro RT production of Abeta42 and Abeta40 peptides by gamma-secretase."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017). RN [141] RP VARIANT AD3 ILE-116. RX PubMed=30200536; DOI=10.3390/ijms19092604; RA Bagyinszky E., Lee H.M., Van Giau V., Koh S.B., Jeong J.H., An S.S.A., RA Kim S.; RT "PSEN1 p.Thr116Ile variant in two Korean families with young onset RT Alzheimer's disease."; RL Int. J. Mol. Sci. 19:0-0(2018). RN [142] RP VARIANT AD3 ASN-116. RX PubMed=29404783; DOI=10.1007/s00702-018-1850-z; RA Sutovsky S., Smolek T., Turcani P., Petrovic R., Brandoburova P., RA Jadhav S., Novak P., Attems J., Zilka N.; RT "Neuropathology and biochemistry of early onset familial Alzheimer's RT disease caused by presenilin-1 missense mutation Thr116Asn."; RL J. Neural Transm. 125:965-976(2018). RN [143] RP VARIANTS AD3 PHE-142 AND ASP-206. RX PubMed=29175279; DOI=10.1016/j.neurobiolaging.2017.10.011; RA Wang J.C., Alinaghi S., Tafakhori A., Sikora E., Azcona L.J., RA Karkheiran S., Goate A., Paisan-Ruiz C., Darvish H.; RT "Genetic screening in two Iranian families with early-onset Alzheimer's RT disease identified a novel PSEN1 mutation."; RL Neurobiol. Aging 62:E15-E17(2018). RN [144] RP VARIANT AD3 ALA-417. RX PubMed=30180983; DOI=10.1016/j.neurobiolaging.2018.08.003; RA Giau V.V., Wang M.J., Bagyinszky E., Youn Y.C., An S.S.A., Kim S.; RT "Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset RT Alzheimer's disease with parkinsonism."; RL Neurobiol. Aging 72:E13-E17(2018). RN [145] RP VARIANT AD3 PHE-170. RX PubMed=29466804; DOI=10.1159/000485899; RA Tiedt H.O., Benjamin B., Niedeggen M., Lueschow A.; RT "Phenotypic variability in autosomal dominant familial Alzheimer disease RT due to the S170F mutation of presenilin-1."; RL Neurodegener. Dis. 18:57-68(2018). CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an CC endoprotease complex that catalyzes the intramembrane cleavage of CC integral membrane proteins such as Notch receptors and APP (amyloid- CC beta precursor protein) (PubMed:10206644, PubMed:10545183, CC PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039, CC PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). CC Requires the presence of the other members of the gamma-secretase CC complex for protease activity (PubMed:15274632, PubMed:25043039, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in CC Notch and Wnt signaling cascades and regulation of downstream processes CC via its role in processing key regulatory proteins, and by regulating CC cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883, CC PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its CC interaction with CDH1; this stabilizes the complexes between CDH1 (E- CC cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 CC and JUP (gamma-catenin) (PubMed:11953314). Under conditions of CC apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This CC promotes the disassembly of the complexes between CDH1 and CTNND1, JUP CC and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby CC negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936). CC Required for normal embryonic brain and skeleton development, and for CC normal angiogenesis (By similarity). Mediates the proteolytic cleavage CC of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The CC holoprotein functions as a calcium-leak channel that allows the passive CC movement of calcium from endoplasmic reticulum to cytosol and is CC therefore involved in calcium homeostasis (PubMed:16959576, CC PubMed:25394380). Involved in the regulation of neurite outgrowth CC (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic CC facilitation, spike transmission and synaptic vesicles replenishment in CC a process that depends on gamma-secretase activity. It acts through the CC control of SYT7 presynaptic expression (By similarity). CC {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644, CC ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15004326, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:28269784, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, CC ECO:0000269|PubMed:9738936}. CC -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed CC of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), CC nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:25394380, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Such minimal CC complex is sufficient for secretase activity (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:26280335, CC PubMed:30598546, PubMed:30630874). Other components which are CC associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 CC isoform 3. As part of the gamma-secretase complex, interacts with CRB2 CC (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer CC of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment CC (PubMed:15274632). Associates with proteolytic processed C-terminal CC fragments C83 and C99 of the amyloid precursor protein (APP) (via CC transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via CC transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates CC with cadherin/catenin adhesion complexes through direct binding to CDH1 CC or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). CC Interaction with CDH1 stabilizes the complex and stimulates cell-cell CC aggregation (PubMed:11953314). Interaction with CDH2 is essential for CC trafficking of CDH2 from the endoplasmic reticulum to the plasma CC membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, CC HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:10037471, CC PubMed:10551805, PubMed:11799129, PubMed:11953314, PubMed:12214059, CC PubMed:16126725, PubMed:9437013, PubMed:9738936). Interacts through its CC N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with CC DOCK3; this interaction mediates the membrane association of DOCK3 CC (PubMed:10854253). Interacts with isoform 1 and isoform 3 of UBQLN1 CC (PubMed:21143716). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10037471, ECO:0000269|PubMed:10551805, CC ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:14515347, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:16126725, CC ECO:0000269|PubMed:20299451, ECO:0000269|PubMed:21143716, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:9437013, CC ECO:0000269|PubMed:9738936}. CC -!- INTERACTION: CC P49768; Q02410: APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690; CC P49768; Q96BI3: APH1A; NbExp=3; IntAct=EBI-297277, EBI-2606935; CC P49768; P05067: APP; NbExp=6; IntAct=EBI-297277, EBI-77613; CC P49768; P05067-4: APP; NbExp=4; IntAct=EBI-297277, EBI-302641; CC P49768; P56817: BACE1; NbExp=6; IntAct=EBI-297277, EBI-2433139; CC P49768; Q16543: CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634; CC P49768; P12830: CDH1; NbExp=2; IntAct=EBI-297277, EBI-727477; CC P49768; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452; CC P49768; P21333: FLNA; NbExp=2; IntAct=EBI-297277, EBI-350432; CC P49768; O75369: FLNB; NbExp=2; IntAct=EBI-297277, EBI-352089; CC P49768; Q92542: NCSTN; NbExp=6; IntAct=EBI-297277, EBI-998440; CC P49768; Q99569: PKP4; NbExp=3; IntAct=EBI-297277, EBI-726447; CC P49768; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-297277, EBI-998468; CC P49768; P50502: ST13; NbExp=3; IntAct=EBI-297277, EBI-357285; CC P49768; P55061: TMBIM6; NbExp=12; IntAct=EBI-297277, EBI-1045825; CC P49768; P49755: TMED10; NbExp=4; IntAct=EBI-297277, EBI-998422; CC P49768; Q9NZC2: TREM2; NbExp=5; IntAct=EBI-297277, EBI-14036387; CC P49768; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-297277, EBI-741480; CC P49768; O35430: Apba1; Xeno; NbExp=2; IntAct=EBI-297277, EBI-704760; CC P49768; P98084: Apba2; Xeno; NbExp=2; IntAct=EBI-297277, EBI-81669; CC P49768; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-297277, EBI-7030357; CC P49768-2; P63010-2: AP2B1; NbExp=6; IntAct=EBI-11047108, EBI-11529439; CC P49768-2; P05067: APP; NbExp=6; IntAct=EBI-11047108, EBI-77613; CC P49768-2; P16870: CPE; NbExp=3; IntAct=EBI-11047108, EBI-711320; CC P49768-2; Q5D0E6-2: DALRD3; NbExp=3; IntAct=EBI-11047108, EBI-9090939; CC P49768-2; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-11047108, EBI-3508943; CC P49768-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-11047108, EBI-396453; CC P49768-2; Q06787-7: FMR1; NbExp=3; IntAct=EBI-11047108, EBI-25856644; CC P49768-2; P02792: FTL; NbExp=3; IntAct=EBI-11047108, EBI-713279; CC P49768-2; P68431: H3C12; NbExp=6; IntAct=EBI-11047108, EBI-79722; CC P49768-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-11047108, EBI-2806068; CC P49768-2; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-11047108, EBI-21911304; CC P49768-2; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-11047108, EBI-25871195; CC P49768-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-11047108, EBI-1044640; CC P49768-2; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-11047108, EBI-1108377; CC P49768-2; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-11047108, EBI-4397720; CC P49768-2; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-11047108, EBI-21250407; CC P49768-2; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-11047108, EBI-995714; CC P49768-2; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-11047108, EBI-25888682; CC P49768-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-11047108, EBI-1058491; CC P49768-2; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-11047108, EBI-716063; CC P49768-2; P53350: PLK1; NbExp=3; IntAct=EBI-11047108, EBI-476768; CC P49768-2; O14494: PLPP1; NbExp=3; IntAct=EBI-11047108, EBI-2865290; CC P49768-2; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-11047108, EBI-998468; CC P49768-2; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-11047108, EBI-21535400; CC P49768-2; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-11047108, EBI-25829984; CC P49768-2; Q8N488: RYBP; NbExp=6; IntAct=EBI-11047108, EBI-752324; CC P49768-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-11047108, EBI-10182463; CC P49768-2; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-11047108, EBI-358545; CC P49768-2; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11047108, EBI-18159983; CC P49768-2; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-11047108, EBI-11959123; CC P49768-2; O00300: TNFRSF11B; NbExp=3; IntAct=EBI-11047108, EBI-15481185; CC P49768-2; Q96NC0: ZMAT2; NbExp=6; IntAct=EBI-11047108, EBI-2682299; CC PRO_0000025591; Q63053: Arc; Xeno; NbExp=3; IntAct=EBI-2606326, EBI-5275794; CC PRO_0000025592; P35613: BSG; NbExp=6; IntAct=EBI-2606356, EBI-750709; CC PRO_0000025592; Q92542: NCSTN; NbExp=2; IntAct=EBI-2606356, EBI-998440; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum CC {ECO:0000269|PubMed:25394380}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:9738936, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Golgi CC apparatus membrane {ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:8574969, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cytoplasmic CC granule {ECO:0000269|PubMed:11987239}. Cell membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11953314, CC ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716}; Multi-pass CC membrane protein {ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Cell projection, growth cone CC {ECO:0000269|PubMed:15004326}. Early endosome CC {ECO:0000269|PubMed:25394380}. Early endosome membrane CC {ECO:0000305|PubMed:25394380}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cell CC projection, neuron projection {ECO:0000269|PubMed:15004326}. Cell CC projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Synapse CC {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1 CC from the endoplasmic reticulum and/or Golgi to the cell surface CC (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell CC contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the CC proximity of the plasma membrane (PubMed:9738936). Also present in CC azurophil granules of neutrophils (PubMed:11987239). Colocalizes with CC UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures CC called aggresomes (PubMed:21143716). Also highly enriched in CC mitochondria-associated endoplasmic reticulum membrane contact site (By CC similarity). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:9738936}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; Synonyms=I-467; CC IsoId=P49768-1; Sequence=Displayed; CC Name=2; Synonyms=I-463; CC IsoId=P49768-2; Sequence=VSP_005191; CC Name=3; Synonyms=I-374; CC IsoId=P49768-3; Sequence=VSP_005191, VSP_005192; CC Name=4; Synonyms=Minilin; CC IsoId=P49768-4; Sequence=VSP_007986, VSP_007987; CC Name=5; CC IsoId=P49768-5; Sequence=VSP_005192; CC Name=6; CC IsoId=P49768-6; Sequence=VSP_012288; CC Name=7; CC IsoId=P49768-7; Sequence=VSP_041440; CC -!- TISSUE SPECIFICITY: Detected in azurophile granules in neutrophils and CC in platelet cytoplasmic granules (at protein level) (PubMed:11987239). CC Expressed in a wide range of tissues including various regions of the CC brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8574969, CC PubMed:8641442). {ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:8641442}. CC -!- DOMAIN: The PAL motif is required for normal active site conformation. CC {ECO:0000269|PubMed:16305624}. CC -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between CC PSEN1 transmembrane domains and via the first lumenal loop and the CC cytoplasmic loop between the sixth and seventh transmembrane domains. CC Substrate binding causes a conformation change and formation of an CC intermolecular antiparallel beta-sheet between PSEN1 and its CC substrates. {ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF) CC and C-terminal (CTF) fragments of approximately 35 and 20 kDa, CC respectively. During apoptosis, the C-terminal fragment (CTF) is CC further cleaved by caspase-3 to produce the fragment, PS1-CTF12. CC {ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:15274632, CC ECO:0000269|PubMed:9173929, ECO:0000269|PubMed:9485372}. CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is CC phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on CC Ser-346 inhibits endoproteolysis. {ECO:0000269|PubMed:14576165, CC ECO:0000269|PubMed:9144240}. CC -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative CC disorder characterized by progressive dementia, loss of cognitive CC abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481, CC ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, CC ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, CC ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, CC ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, CC ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, CC ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920, CC ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891, CC ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851, CC ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344, CC ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037, CC ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701, CC ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188, CC ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340, CC ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394, CC ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795, CC ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735, CC ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784, CC ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661, CC ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161, CC ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781, CC ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961, CC ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897, CC ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, CC ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341, CC ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783, CC ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983, CC ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, CC ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, CC ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617, CC ECO:0000269|PubMed:8875251, ECO:0000269|PubMed:9172170, CC ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, CC ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, CC ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, CC ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, CC ECO:0000269|Ref.95}. Note=The disease is caused by variants affecting CC the gene represented in this entry. CC -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. In some cases, parkinsonian CC symptoms are prominent. Neuropathological changes include CC frontotemporal atrophy often associated with atrophy of the basal CC ganglia, substantia nigra, amygdala. In most cases, protein tau CC deposits are found in glial cells and/or neurons. CC {ECO:0000269|PubMed:11094121}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Cardiomyopathy, dilated, 1U (CMD1U) [MIM:613694]: A disorder CC characterized by ventricular dilation and impaired systolic function, CC resulting in congestive heart failure and arrhythmia. Patients are at CC risk of premature death. {ECO:0000269|PubMed:17186461, CC ECO:0000269|PubMed:27930341}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic CC relapsing inflammatory disease of the hair follicles characterized by CC recurrent draining sinuses, painful skin abscesses, and disfiguring CC scars. Manifestations typically appear after puberty. CC {ECO:0000269|PubMed:20929727}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of CC dementia pathologically defined by severe atrophy, neuronal loss and CC gliosis. It is characterized by the occurrence of tau-positive CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal CC inclusions known as Pick bodies that disproportionally affect the CC frontal and temporal cortical regions. Clinical features include CC aphasia, apraxia, confusion, anomia, memory loss and personality CC deterioration. {ECO:0000269|PubMed:15122701}. Note=The gene represented CC in this entry may be involved in disease pathogenesis. CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins CC mutations; CC URL="https://www.alzforum.org/mutations/psen-1"; 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; L42110; AAB46416.1; -; mRNA. DR EMBL; L76517; AAB46370.1; -; mRNA. DR EMBL; L76528; AAB46371.1; -; Genomic_DNA. DR EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; U40379; AAB05894.1; -; mRNA. DR EMBL; U40380; AAB05895.1; -; mRNA. DR EMBL; AJ008005; CAA07825.1; -; mRNA. DR EMBL; AF109907; AAC97960.1; -; Genomic_DNA. DR EMBL; AF416717; AAL16811.1; -; mRNA. DR EMBL; AK312531; BAG35430.1; -; mRNA. DR EMBL; AC004858; AAF19253.1; -; Genomic_DNA. DR EMBL; AC004858; AAF19254.1; -; Genomic_DNA. DR EMBL; CH471061; EAW81092.1; -; Genomic_DNA. DR EMBL; BC011729; AAH11729.1; -; mRNA. DR EMBL; D84149; BAA20883.1; -; Genomic_DNA. DR CCDS; CCDS9812.1; -. [P49768-1] DR CCDS; CCDS9813.1; -. [P49768-2] DR PIR; S58396; S58396. DR PIR; S63683; S63683. DR PIR; S63684; S63684. DR RefSeq; NP_000012.1; NM_000021.4. [P49768-1] DR RefSeq; NP_015557.2; NM_007318.3. [P49768-2] DR RefSeq; XP_005267921.1; XM_005267864.4. [P49768-1] DR RefSeq; XP_005267923.1; XM_005267866.3. [P49768-2] DR RefSeq; XP_011535274.1; XM_011536972.3. [P49768-1] DR RefSeq; XP_011535275.1; XM_011536973.3. [P49768-2] DR RefSeq; XP_011535276.1; XM_011536974.3. [P49768-2] DR RefSeq; XP_047287556.1; XM_047431600.1. [P49768-1] DR RefSeq; XP_047287557.1; XM_047431601.1. [P49768-1] DR RefSeq; XP_047287558.1; XM_047431602.1. [P49768-2] DR RefSeq; XP_054232388.1; XM_054376413.1. [P49768-1] DR RefSeq; XP_054232389.1; XM_054376414.1. [P49768-1] DR RefSeq; XP_054232390.1; XM_054376415.1. [P49768-1] DR RefSeq; XP_054232391.1; XM_054376416.1. [P49768-1] DR RefSeq; XP_054232392.1; XM_054376417.1. [P49768-2] DR RefSeq; XP_054232393.1; XM_054376418.1. [P49768-2] DR RefSeq; XP_054232394.1; XM_054376419.1. [P49768-2] DR RefSeq; XP_054232395.1; XM_054376420.1. [P49768-2] DR PDB; 2KR6; NMR; -; A=292-467. DR PDB; 4UIS; EM; 4.40 A; B=81-463. DR PDB; 5A63; EM; 3.40 A; B=1-467. DR PDB; 5FN2; EM; 4.20 A; B=1-467. DR PDB; 5FN3; EM; 4.10 A; B=1-467. DR PDB; 5FN4; EM; 4.00 A; B=1-467. DR PDB; 5FN5; EM; 4.30 A; B=1-467. DR PDB; 6IDF; EM; 2.70 A; B=1-467. DR PDB; 6IYC; EM; 2.60 A; B=1-467. DR PDB; 6LQG; EM; 3.10 A; B=1-467. DR PDB; 6LR4; EM; 3.00 A; B=1-467. DR PDB; 7C9I; EM; 3.10 A; B=1-467. DR PDB; 7D8X; EM; 2.60 A; B=1-467. DR PDB; 7Y5T; EM; 2.90 A; B=1-467. DR PDB; 8IM7; EM; 3.40 A; B=1-467. DR PDB; 8K8E; EM; 2.60 A; B=1-467. DR PDB; 8KCO; EM; 2.80 A; B=1-467. DR PDB; 8KCP; EM; 3.00 A; B=1-467. DR PDB; 8KCS; EM; 2.40 A; B=1-467. DR PDB; 8KCT; EM; 2.60 A; B=1-467. DR PDB; 8KCU; EM; 2.70 A; B=1-467. DR PDB; 8OQY; EM; 3.30 A; B=1-467. DR PDB; 8OQZ; EM; 3.40 A; B=1-467. DR PDB; 8X52; EM; 2.90 A; B=1-467. DR PDB; 8X53; EM; 3.00 A; B=1-467. DR PDB; 8X54; EM; 2.90 A; B=1-467. DR PDBsum; 2KR6; -. DR PDBsum; 4UIS; -. DR PDBsum; 5A63; -. DR PDBsum; 5FN2; -. DR PDBsum; 5FN3; -. DR PDBsum; 5FN4; -. DR PDBsum; 5FN5; -. DR PDBsum; 6IDF; -. DR PDBsum; 6IYC; -. DR PDBsum; 6LQG; -. DR PDBsum; 6LR4; -. DR PDBsum; 7C9I; -. DR PDBsum; 7D8X; -. DR PDBsum; 7Y5T; -. DR PDBsum; 8IM7; -. DR PDBsum; 8K8E; -. DR PDBsum; 8KCO; -. DR PDBsum; 8KCP; -. DR PDBsum; 8KCS; -. DR PDBsum; 8KCT; -. DR PDBsum; 8KCU; -. DR PDBsum; 8OQY; -. DR PDBsum; 8OQZ; -. DR PDBsum; 8X52; -. DR PDBsum; 8X53; -. DR PDBsum; 8X54; -. DR AlphaFoldDB; P49768; -. DR EMDB; EMD-0944; -. DR EMDB; EMD-0957; -. DR EMDB; EMD-17112; -. DR EMDB; EMD-17113; -. DR EMDB; EMD-2477; -. DR EMDB; EMD-2478; -. DR EMDB; EMD-30312; -. DR EMDB; EMD-30614; -. DR EMDB; EMD-33624; -. DR EMDB; EMD-35572; -. DR EMDB; EMD-36948; -. DR EMDB; EMD-37106; -. DR EMDB; EMD-37107; -. DR EMDB; EMD-37108; -. DR EMDB; EMD-37109; -. DR EMDB; EMD-37110; -. DR EMDB; EMD-38059; -. DR EMDB; EMD-38060; -. DR EMDB; EMD-38061; -. DR EMDB; EMD-9648; -. DR EMDB; EMD-9751; -. DR SMR; P49768; -. DR BioGRID; 111642; 203. DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant. DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant. DR CORUM; P49768; -. DR DIP; DIP-1134N; -. DR ELM; P49768; -. DR FunCoup; P49768; 2287. DR IntAct; P49768; 299. DR MINT; P49768; -. DR STRING; 9606.ENSP00000326366; -. DR BindingDB; P49768; -. DR ChEMBL; CHEMBL2473; -. DR DrugBank; DB11893; Avagacestat. DR DrugBank; DB12263; Begacestat. DR DrugBank; DB05171; E-2012. DR DrugBank; DB16159; Esflurbiprofen. DR DrugBank; DB12819; GSI-136. DR DrugBank; DB16825; Itanapraced. DR DrugBank; DB12852; MK-0752. DR DrugBank; DB12005; Nirogacestat. DR DrugBank; DB11870; RG-4733. DR DrugBank; DB12463; Semagacestat. DR DrugBank; DB05289; Tarenflurbil. DR GuidetoPHARMACOLOGY; 2402; -. DR MEROPS; A22.001; -. DR TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family. DR iPTMnet; P49768; -. DR PhosphoSitePlus; P49768; -. DR SwissPalm; P49768; -. DR BioMuta; PSEN1; -. DR DMDM; 1709856; -. DR jPOST; P49768; -. DR MassIVE; P49768; -. DR PaxDb; 9606-ENSP00000326366; -. DR PeptideAtlas; P49768; -. DR ProteomicsDB; 56106; -. [P49768-1] DR ProteomicsDB; 56107; -. [P49768-2] DR ProteomicsDB; 56108; -. [P49768-3] DR ProteomicsDB; 56109; -. [P49768-4] DR ProteomicsDB; 56110; -. [P49768-5] DR ProteomicsDB; 56111; -. [P49768-6] DR ProteomicsDB; 56112; -. [P49768-7] DR Pumba; P49768; -. DR Antibodypedia; 3480; 972 antibodies from 47 providers. DR DNASU; 5663; -. DR Ensembl; ENST00000324501.10; ENSP00000326366.5; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000357710.8; ENSP00000350342.4; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000394157.7; ENSP00000377712.3; ENSG00000080815.21. [P49768-4] DR Ensembl; ENST00000394164.5; ENSP00000377719.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553599.6; ENSP00000452477.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553855.5; ENSP00000452242.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000554131.6; ENSP00000451915.2; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000555386.6; ENSP00000450845.1; ENSG00000080815.21. [P49768-3] DR Ensembl; ENST00000556951.6; ENSP00000450551.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000557511.5; ENSP00000451429.1; ENSG00000080815.21. [P49768-6] DR Ensembl; ENST00000700265.1; ENSP00000514901.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700267.1; ENSP00000514903.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700268.1; ENSP00000514904.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700269.1; ENSP00000514905.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700273.1; ENSP00000514908.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700306.1; ENSP00000514933.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700313.1; ENSP00000514940.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700317.1; ENSP00000514944.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700321.1; ENSP00000514948.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700322.1; ENSP00000514949.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700323.1; ENSP00000514950.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700324.1; ENSP00000514951.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700375.1; ENSP00000514966.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700378.1; ENSP00000514968.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700389.1; ENSP00000514970.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700436.1; ENSP00000514987.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000700469.1; ENSP00000515002.1; ENSG00000080815.21. [P49768-2] DR GeneID; 5663; -. DR KEGG; hsa:5663; -. DR MANE-Select; ENST00000324501.10; ENSP00000326366.5; NM_000021.4; NP_000012.1. DR UCSC; uc001xnq.5; human. [P49768-1] DR AGR; HGNC:9508; -. DR ClinPGx; PA33855; -. DR CTD; 5663; -. DR DisGeNET; 5663; -. DR GeneCards; PSEN1; -. DR GeneReviews; PSEN1; -. DR HGNC; HGNC:9508; PSEN1. DR HPA; ENSG00000080815; Low tissue specificity. DR MalaCards; PSEN1; -. DR MIM; 104311; gene. DR MIM; 172700; phenotype. DR MIM; 600274; phenotype. DR MIM; 607822; phenotype. DR MIM; 613694; phenotype. DR MIM; 613737; phenotype. DR OpenTargets; ENSG00000080815; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000080815; -. DR eggNOG; KOG2736; Eukaryota. DR GeneTree; ENSGT00940000158751; -. DR HOGENOM; CLU_022975_3_0_1; -. DR InParanoid; P49768; -. DR OMA; NATCNQQ; -. DR OrthoDB; 20287at2759; -. DR PAN-GO; P49768; 26 GO annotations based on evolutionary models. DR PhylomeDB; P49768; -. DR PathwayCommons; P49768; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3. DR Reactome; R-HSA-9839383; TGFBR3 PTM regulation. DR SignaLink; P49768; -. DR SIGNOR; P49768; -. DR Agora; ENSG00000080815; -. DR BioGRID-ORCS; 5663; 16 hits in 1162 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PSEN1; human. DR EvolutionaryTrace; P49768; -. DR GeneWiki; PSEN1; -. DR GenomeRNAi; 5663; -. DR Pharos; P49768; Tchem. DR PRO; PR:P49768; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P49768; protein. DR Bgee; ENSG00000080815; Expressed in middle frontal gyrus and 202 other cell types or tissues. DR ExpressionAtlas; P49768; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:UniProtKB. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0005938; C:cell cortex; IEA:Ensembl. DR GO; GO:0030054; C:cell junction; IDA:HPA. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0035253; C:ciliary rootlet; IEA:Ensembl. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0043198; C:dendritic shaft; IEA:Ensembl. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl. DR GO; GO:0043005; C:neuron projection; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB. DR GO; GO:0005640; C:nuclear outer membrane; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IMP:CAFA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA. DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; NAS:ARUK-UCL. DR GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IPI:UniProtKB. DR GO; GO:0045296; F:cadherin binding; IEA:Ensembl. DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB. DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI. DR GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL. DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL. DR GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL. DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl. DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl. DR GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl. DR GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central. DR GO; GO:0001708; P:cell fate specification; IEA:Ensembl. DR GO; GO:0098609; P:cell-cell adhesion; IMP:MGI. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl. DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl. DR GO; GO:0015871; P:choline transport; IEA:Ensembl. DR GO; GO:0006974; P:DNA damage response; IDA:ARUK-UCL. DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl. DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl. DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IDA:MGI. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0098712; P:L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL. DR GO; GO:0040011; P:locomotion; IEA:Ensembl. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:0007613; P:memory; IGI:ARUK-UCL. DR GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl. DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0003407; P:neural retina development; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0001764; P:neuron migration; IEA:Ensembl. DR GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL. DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; IGI:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:CACAO. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:CACAO. DR GO; GO:0010628; P:positive regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL. DR GO; GO:0002038; P:positive regulation of L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL. DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl. DR GO; GO:0140249; P:protein catabolic process at postsynapse; IEA:Ensembl. DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL. DR GO; GO:0015031; P:protein transport; IEA:Ensembl. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0010975; P:regulation of neuron projection development; IMP:UniProtKB. DR GO; GO:0099175; P:regulation of postsynapse organization; IEA:Ensembl. DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl. DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0098693; P:regulation of synaptic vesicle cycle; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0051208; P:sequestering of calcium ion; IEA:Ensembl. DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl. DR GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl. DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl. DR GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL. DR GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl. DR GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl. DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR DisProt; DP01292; -. DR FunFam; 1.10.472.100:FF:000001; Presenilin; 1. DR Gene3D; 1.10.472.100; Presenilin; 1. DR InterPro; IPR002031; Pept_A22A_PS1. DR InterPro; IPR001108; Peptidase_A22A. DR InterPro; IPR006639; Preselin/SPP. DR InterPro; IPR042524; Presenilin_C. DR PANTHER; PTHR10202; PRESENILIN; 1. DR PANTHER; PTHR10202:SF18; PRESENILIN-1; 1. DR Pfam; PF01080; Presenilin; 1. DR PRINTS; PR01072; PRESENILIN. DR PRINTS; PR01073; PRESENILIN1. DR SMART; SM00730; PSN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Apoptosis; Cardiomyopathy; Cell adhesion; Cell membrane; Cell projection; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Endosome; Golgi apparatus; Hydrolase; Membrane; Neurodegeneration; KW Notch signaling pathway; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; Synapse; Transmembrane; KW Transmembrane helix. FT CHAIN 1..298 FT /note="Presenilin-1 NTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025591" FT CHAIN 299..467 FT /note="Presenilin-1 CTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025592" FT CHAIN 346..467 FT /note="Presenilin-1 CTF12" FT /evidence="ECO:0000269|PubMed:9485372" FT /id="PRO_0000236055" FT TOPO_DOM 1..82 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 83..103 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 104..132 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 133..153 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 154..166 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 167..189 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 190..194 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 195..216 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 217..220 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 221..241 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 242..248 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 249..272 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 273..380 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 381..401 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 402..407 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 408..428 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 429..432 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 433..453 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 454..467 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT REGION 13..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 288..290 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 305..333 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 322..450 FT /note="Required for interaction with CTNNB1" FT /evidence="ECO:0000269|PubMed:9738936" FT REGION 372..399 FT /note="Required for interaction with CTNND2" FT /evidence="ECO:0000269|PubMed:10037471" FT REGION 377..381 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 432..434 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 464..467 FT /note="Interaction with MTCH1" FT /evidence="ECO:0000269|PubMed:10551805" FT MOTIF 433..435 FT /note="PAL" FT /evidence="ECO:0000305|PubMed:16305624" FT COMPBIAS 13..29 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 30..45 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 257 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515" FT ACT_SITE 385 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515, FT ECO:0000305|PubMed:30598546, ECO:0000305|PubMed:30630874" FT SITE 291..292 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 292..293 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 298..299 FT /note="Cleavage" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 345..346 FT /note="Cleavage; by caspase" FT /evidence="ECO:0000269|PubMed:9485372" FT MOD_RES 43 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 51 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97887" FT MOD_RES 310 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 346 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 367 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 26..29 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:7596406, ECO:0000303|PubMed:8641442" FT /id="VSP_005191" FT VAR_SEQ 162..184 FT /note="IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFLWLGILVTVT FT (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007986" FT VAR_SEQ 185..467 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007987" FT VAR_SEQ 257..289 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000305" FT /id="VSP_041440" FT VAR_SEQ 319..467 FT /note="STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILA FT GEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFK FT KALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPM FT APRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI (in isoform 3 FT and isoform 5)" FT /evidence="ECO:0000303|PubMed:8641442, ECO:0000303|Ref.5" FT /id="VSP_005192" FT VAR_SEQ 319..376 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_012288" FT VARIANT 35 FT /note="R -> Q (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750592)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075260" FT VARIANT 79 FT /note="A -> V (in AD3; also found in late-onset Alzheimer FT disease; impaired protease activity with APP; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; no effect on interaction with FT GFAP; dbSNP:rs63749824)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:12058025, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:17366635, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9384602" FT /id="VAR_006413" FT VARIANT 82 FT /note="V -> L (in AD3; decreased protease activity with FT APP; no effect on interaction with GFAP; dbSNP:rs63749967)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006414" FT VARIANT 83 FT /note="I -> T (in AD3)" FT /evidence="ECO:0000269|PubMed:26145164" FT /id="VAR_075261" FT VARIANT 85 FT /note="L -> P (in AD3; the patient also manifest spastic FT paraparesis and apraxia; loss of protease activity with APP FT in vitro; altered amyloid-beta production in cells FT transfected with the mutant and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs63750599)" FT /evidence="ECO:0000269|PubMed:15534188, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081228" FT VARIANT 89 FT /note="V -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750815)" FT /evidence="ECO:0000269|PubMed:11796781" FT /id="VAR_081229" FT VARIANT 92 FT /note="C -> S (in AD3; loss of protease activity with APP; FT dbSNP:rs63751141)" FT /evidence="ECO:0000269|PubMed:11027672, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016214" FT VARIANT 94 FT /note="V -> M (in AD3; uncertain significance; reduced FT protease activity with APP; no relevant change in amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750831)" FT /evidence="ECO:0000269|PubMed:11568920" FT /id="VAR_081230" FT VARIANT 96 FT /note="V -> F (in AD3; loss of protease activity with APP; FT dbSNP:rs63750601)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006415" FT VARIANT 97 FT /note="V -> L (in AD3; uncertain significance; slightly FT reduced protease activity with APP; dbSNP:rs63750852)" FT /evidence="ECO:0000269|PubMed:15851849, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081231" FT VARIANT 105 FT /note="F -> L (in AD3; dbSNP:rs63750321)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_009208" FT VARIANT 113 FT /note="L -> P (in FTD1; dbSNP:rs63751399)" FT /evidence="ECO:0000269|PubMed:11094121" FT /id="VAR_016215" FT VARIANT 115 FT /note="Y -> C (in AD3; dbSNP:rs63750450)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:9384602" FT /id="VAR_006416" FT VARIANT 115 FT /note="Y -> H (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:8634712" FT /id="VAR_006417" FT VARIANT 116 FT /note="T -> I (in AD3; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:30200536" FT /id="VAR_081232" FT VARIANT 116 FT /note="T -> N (in AD3; unusual amyloid cotton wool plaques FT detected in one patient's brain; severe decrease of FT protease activity with APP; results in increased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:10439444, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29404783" FT /id="VAR_010120" FT VARIANT 117 FT /note="P -> L (in AD3; impaired ability to cleave Ephb2/ FT CTF1; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; impaired FT regulation of neurite outgrowth; dbSNP:rs63749805)" FT /evidence="ECO:0000269|PubMed:15004326, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:9507958" FT /id="VAR_009209" FT VARIANT 117 FT /note="P -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; impaired regulation of neurite outgrowth; FT dbSNP:rs63750550)" FT /evidence="ECO:0000269|PubMed:15004326" FT /id="VAR_081233" FT VARIANT 120 FT /note="E -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751272)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9521423" FT /id="VAR_006418" FT VARIANT 120 FT /note="E -> K (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750800)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006419" FT VARIANT 134 FT /note="L -> R (in AD3; uncertain significance; loss of FT protease activity with APP; dbSNP:rs1595002439)" FT /evidence="ECO:0000269|PubMed:22503161, FT ECO:0000269|PubMed:27930341" FT /id="VAR_070023" FT VARIANT 135 FT /note="N -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750353)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9225696" FT /id="VAR_010121" FT VARIANT 139 FT /note="M -> I (in AD3; dbSNP:rs63750522)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_006420" FT VARIANT 139 FT /note="M -> K (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:9719376" FT /id="VAR_010122" FT VARIANT 139 FT /note="M -> T (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006421" FT VARIANT 139 FT /note="M -> V (in AD3; increased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751037)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7550356" FT /id="VAR_006422" FT VARIANT 142 FT /note="V -> F (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:29175279" FT /id="VAR_081234" FT VARIANT 143 FT /note="I -> F (in AD3; dbSNP:rs63750322)" FT /evidence="ECO:0000269|PubMed:10090481" FT /id="VAR_006423" FT VARIANT 143 FT /note="I -> T (in AD3; impaired protease activity with APP; FT results in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750004)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006424" FT VARIANT 146 FT /note="M -> I (in AD3; dbSNP:rs63750391)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037" FT /id="VAR_006425" FT VARIANT 146 FT /note="M -> L (in AD3; disease phenotype shows high FT clinical variability; founder mutation originating from FT Southern Italy and distributed worldwide; alters the FT conformation of the active site; slightly increased FT protease activity with APP; decreased activity for Notch1 FT cleavage; no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006426" FT VARIANT 146 FT /note="M -> V (in AD3; loss of function as calcium-leak FT channel; results in calcium overload in the endoplasmic FT reticulum; dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:7550356" FT /id="VAR_006427" FT VARIANT 147 FT /note="T -> I (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750907)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010123" FT VARIANT 153 FT /note="L -> V (in AD3; abolishes protease activity with APP FT resulting in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63751441)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:27930341" FT /id="VAR_081235" FT VARIANT 154 FT /note="Y -> C (in AD3; uncertain significance; FT dbSNP:rs63751292)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081236" FT VARIANT 154 FT /note="Y -> N (in AD3; disease phenotype includes spastic FT paraparesis; abolishes protease activity with APP resulting FT in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63750588)" FT /evidence="ECO:0000269|PubMed:15364419, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081237" FT VARIANT 156 FT /note="Y -> FTY (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075262" FT VARIANT 159 FT /note="Y -> F (in AD3; uncertain significance; FT dbSNP:rs778630379)" FT /evidence="ECO:0000269|PubMed:23123781" FT /id="VAR_081238" FT VARIANT 163 FT /note="H -> R (in AD3; abolishes protease activity with FT APP; decreased activity for Notch cleavage; FT dbSNP:rs63750590)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8634712, FT ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9521423" FT /id="VAR_006428" FT VARIANT 163 FT /note="H -> Y (in AD3; slightly increased protease activity FT with APP and slightly increased amyloid-beta 42 production; FT dbSNP:rs63749885)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006429" FT VARIANT 165 FT /note="W -> C (in AD3; dbSNP:rs63751484)" FT /evidence="ECO:0000269|PubMed:10441572" FT /id="VAR_010124" FT VARIANT 166 FT /note="L -> P (in AD3; onset in adolescence; severe FT decrease of protease activity with APP; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; results in reduced Notch FT proteolysis; dbSNP:rs63750265)" FT /evidence="ECO:0000269|PubMed:12048239, FT ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23843529, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016216" FT VARIANT 168 FT /note="Missing (in AD3; uncertain significance; abolishes FT protease activity with APP resulting in decreased amyloid- FT beta 42 and amyloid-beta 40 production)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081239" FT VARIANT 169 FT /note="S -> L (in AD3; dbSNP:rs63751210)" FT /evidence="ECO:0000269|PubMed:9831473" FT /id="VAR_006430" FT VARIANT 169 FT /note="S -> P (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750418)" FT /evidence="ECO:0000269|PubMed:10025789, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006431" FT VARIANT 170 FT /note="S -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750577)" FT /evidence="ECO:0000269|PubMed:16344340, FT ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29466804" FT /id="VAR_081240" FT VARIANT 171 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750963)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9833068" FT /id="VAR_006432" FT VARIANT 173 FT /note="L -> W (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750299)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010125" FT VARIANT 174 FT /note="L -> M (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751144)" FT /evidence="ECO:0000269|PubMed:12484344, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016217" FT VARIANT 177 FT /note="F -> L (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749911)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075263" FT VARIANT 177 FT /note="F -> S (in AD3; uncertain significance; FT dbSNP:rs63749806)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075264" FT VARIANT 178 FT /note="S -> P (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750155)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075265" FT VARIANT 183 FT /note="G -> V (in PIDB and AD3; uncertain significance; FT neuropathologic examination of brain sections from a FT patient shows the presence of Pick bodies and absence of FT beta-amyloid plaques; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro; dbSNP:rs63751068)" FT /evidence="ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081241" FT VARIANT 184 FT /note="E -> D (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750311)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081242" FT VARIANT 205 FT /note="F -> L (in dbSNP:rs1042864)" FT /id="VAR_011876" FT VARIANT 206 FT /note="G -> A (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:27073747, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016218" FT VARIANT 206 FT /note="G -> D (in AD3; affects APP processing resulting in FT increased amyloid-beta 42/amyloid-beta 40 ratio; does not FT affect NOTCH processing; does not affect endoproteolysis; FT reduced interaction with PEN2; results in decreased protein FT levels in the endoplasmic reticulum but increased levels in FT early endosome; reduced ability to maintain ER calcium FT homeostasis; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:21335660, FT ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:29175279" FT /id="VAR_081243" FT VARIANT 206 FT /note="G -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750569)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075266" FT VARIANT 209 FT /note="G -> E (in AD3; uncertain significance; FT dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075267" FT VARIANT 209 FT /note="G -> R (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749880)" FT /evidence="ECO:0000269|PubMed:10447269, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009210" FT VARIANT 209 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006433" FT VARIANT 213 FT /note="I -> L (in AD3; increases protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750861)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075268" FT VARIANT 213 FT /note="I -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751309)" FT /evidence="ECO:0000269|PubMed:18430735, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006434" FT VARIANT 214 FT /note="H -> Y (found in a patient with dementia; uncertain FT significance; dbSNP:rs63751003)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070024" FT VARIANT 217 FT /note="G -> R (in AD3; with unusual amyloid cotton wool FT plaques; decreased protease activity with APP resulting in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs267606983)" FT /evidence="ECO:0000269|PubMed:19667325, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081244" FT VARIANT 219 FT /note="L -> P (in AD3; dbSNP:rs63750761)" FT /evidence="ECO:0000269|PubMed:10208579" FT /id="VAR_010126" FT VARIANT 222 FT /note="Q -> R (in AD3; uncertain significance; slightly FT increased protease activity with APP and slightly increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750009)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075269" FT VARIANT 229 FT /note="I -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749970)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081245" FT VARIANT 231 FT /note="A -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749836)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006435" FT VARIANT 231 FT /note="A -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750799)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:9384602" FT /id="VAR_006436" FT VARIANT 233 FT /note="M -> L (in AD3; slightly decreased protease activity FT with APP resulting in altered amyloid-beta production and FT mildly increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751287)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_009211" FT VARIANT 233 FT /note="M -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751024)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9172170" FT /id="VAR_006437" FT VARIANT 235 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63749835)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_006438" FT VARIANT 235 FT /note="L -> R (in AD3; abolishes protease activity with FT APP)" FT /evidence="ECO:0000269|PubMed:21501661, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081246" FT VARIANT 235 FT /note="L -> V (in AD3; reduced APP cleavage resulting in FT decreased amyloid-beta 42 and amyloid-beta 40 production; FT no relevant change in amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751130)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081247" FT VARIANT 237 FT /note="F -> I (in AD3; uncertain significance; disease FT phenotype includes spastic paraparesis; severe decrease of FT protease activity with APP; results in decreased amyloid- FT beta 42 and amyloid-beta 40 production; dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:11561050, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_081248" FT VARIANT 237 FT /note="F -> L (in AD3; uncertain significance; FT dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081249" FT VARIANT 246 FT /note="A -> E (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750526)" FT /evidence="ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006439" FT VARIANT 250 FT /note="L -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751163)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006440" FT VARIANT 260 FT /note="A -> V (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63751420)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9521423" FT /id="VAR_006441" FT VARIANT 261 FT /note="V -> F (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750964)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075270" FT VARIANT 262 FT /note="L -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750248)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006442" FT VARIANT 262 FT /note="L -> V (in AD3)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070025" FT VARIANT 263 FT /note="C -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751102)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:16752394" FT /id="VAR_081250" FT VARIANT 263 FT /note="C -> R (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750543)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006443" FT VARIANT 264 FT /note="P -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63750301)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006444" FT VARIANT 266 FT /note="G -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs121917807)" FT /evidence="ECO:0000269|PubMed:11920851, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016219" FT VARIANT 267 FT /note="P -> S (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751229)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006445" FT VARIANT 269 FT /note="R -> G (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751019)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006447" FT VARIANT 269 FT /note="R -> H (in AD3; dbSNP:rs63750900)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_006448" FT VARIANT 271 FT /note="L -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750886)" FT /evidence="ECO:0000269|PubMed:12493737, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016220" FT VARIANT 274 FT /note="T -> R (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750284)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075271" FT VARIANT 275 FT /note="A -> V (in AD3; uncertain significance; reduced FT protease activity with APP resulting in reduced amyloid- FT beta 40 levels but no relevant changes in amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs1555355869)" FT /evidence="ECO:0000269|PubMed:24582897, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081251" FT VARIANT 278 FT /note="R -> I (in AD3; atypical phenotype presenting as FT language impairment, impaired frontal executive function FT and relative preservation of memory; severe decrease of APP FT and Notch proteolysis; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:15534260, FT ECO:0000269|PubMed:23843529" FT /id="VAR_081252" FT VARIANT 278 FT /note="R -> T (in AD3; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:9172170" FT /id="VAR_006449" FT VARIANT 280 FT /note="E -> A (in AD3; strong deposition of amyloid-beta 42 FT is observed in brain regions of AD3 patients; decreased FT protease activity with APP resulting in altered amyloid- FT beta production and increased amyloid-beta 42/amyloid-beta FT 40 ratio; decreased activity for Notch1 cleavage; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:28269784, ECO:0000269|PubMed:7550356, FT ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9298817" FT /id="VAR_006450" FT VARIANT 280 FT /note="E -> G (in AD3; some AD3 patients manifest spastic FT paraparesis and unusual amyloid plaques with prominent FT amyloid angiopathy on brain biopsy; decreased protease FT activity with APP; increased amyloid-beta 42/amyloid-beta FT 40 ratio; impaired ability to cleave Ephb2/CTF1; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:12370477, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006451" FT VARIANT 282 FT /note="L -> R (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750050)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009212" FT VARIANT 282 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749937)" FT /evidence="ECO:0000269|PubMed:11701593, FT ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:16752394" FT /id="VAR_081253" FT VARIANT 285 FT /note="A -> V (in AD3; slightly decreased protease activity FT with APP and slightly decreased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751139)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536" FT /id="VAR_006452" FT VARIANT 286 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751235)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406" FT /id="VAR_006453" FT VARIANT 289 FT /note="S -> C (in AD3)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_010127" FT VARIANT 311 FT /note="K -> R (found in patients with late-onset Alzheimer FT disease; uncertain significance; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs115865530)" FT /evidence="ECO:0000269|PubMed:28269784" FT /id="VAR_081254" FT VARIANT 315 FT /note="Y -> C (found in a renal cell carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:21248752" FT /id="VAR_064747" FT VARIANT 318 FT /note="E -> G (in dbSNP:rs17125721)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:18485326, FT ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9851443, FT ECO:0000269|PubMed:9851450, ECO:0000269|PubMed:9915968" FT /id="VAR_006454" FT VARIANT 333 FT /note="D -> G (in CMD1U; results in slightly decreased FT protease activity with APP and slightly decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs121917809)" FT /evidence="ECO:0000269|PubMed:17186461, FT ECO:0000269|PubMed:27930341" FT /id="VAR_064902" FT VARIANT 352 FT /note="R -> RR (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075272" FT VARIANT 354 FT /note="T -> I (in AD3; uncertain significance; results in FT decreased protease activity with APP and decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63751164)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075273" FT VARIANT 358 FT /note="R -> Q (in AD3; uncertain significance; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs63751174)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075274" FT VARIANT 365 FT /note="S -> Y (in AD3; uncertain significance; FT dbSNP:rs63750941)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075275" FT VARIANT 377 FT /note="R -> M (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081255" FT VARIANT 378 FT /note="G -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10200054, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006455" FT VARIANT 378 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750323)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341" FT /id="VAR_081256" FT VARIANT 381 FT /note="L -> F (in AD3; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:24121961" FT /id="VAR_081257" FT VARIANT 381 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:19797784, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081258" FT VARIANT 384 FT /note="G -> A (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750646)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006456" FT VARIANT 390 FT /note="S -> I (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750883)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010128" FT VARIANT 392 FT /note="L -> V (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751416)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634712" FT /id="VAR_006457" FT VARIANT 394 FT /note="G -> V (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750929)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075276" FT VARIANT 396 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_070026" FT VARIANT 405 FT /note="N -> S (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63751254)" FT /evidence="ECO:0000269|PubMed:10644793, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010129" FT VARIANT 408 FT /note="I -> T (in AD3; dbSNP:rs906454643)" FT /evidence="ECO:0000269|PubMed:26549787" FT /id="VAR_075277" FT VARIANT 409 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750227)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009213" FT VARIANT 410 FT /note="C -> Y (in AD3; results in reduced APP and Notch FT proteolysis; dbSNP:rs661)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006458" FT VARIANT 417 FT /note="G -> A (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:30180983" FT /id="VAR_081259" FT VARIANT 418 FT /note="L -> F (in AD3; uncertain significance; nearly FT abolishes protease activity with APP; dbSNP:rs63751316)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075278" FT VARIANT 426 FT /note="A -> P (in AD3; uncertain significance; slightly FT decreased protease activity with APP; dbSNP:rs63751223)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006459" FT VARIANT 431 FT /note="A -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750083)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16897084, FT ECO:0000269|PubMed:27930341, ECO:0000269|Ref.95" FT /id="VAR_025605" FT VARIANT 435 FT /note="L -> F (in AD3; with unusual amyloid cotton wool FT plaques; almost abolishes gamma-secretase activity; no FT endoproteolytic cleavage; no APP nor NOTCH1 processing; no FT detectable amyloid-beta; dbSNP:rs63750001)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341" FT /id="VAR_075280" FT VARIANT 436 FT /note="P -> Q (in AD3; severe decrease of protease activity FT with APP; dbSNP:rs121917808)" FT /evidence="ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:9831473" FT /id="VAR_006460" FT VARIANT 436 FT /note="P -> S (in AD3; partially abolishes gamma-secretase FT activity; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63749925)" FT /evidence="ECO:0000269|PubMed:10090481, FT ECO:0000269|PubMed:21248752, ECO:0000269|PubMed:27930341" FT /id="VAR_008141" FT VARIANT 439 FT /note="I -> V (in AD3; uncertain significance; no FT significant change of protease activity with APP; FT dbSNP:rs63750249)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075282" FT MUTAGEN 66..72 FT /note="Missing: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 76..77 FT /note="KY->AA: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82..83 FT /note="VI->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82 FT /note="V->K,E: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 84..85 FT /note="ML->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 99 FT /note="T->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 105 FT /note="F->I: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 108 FT /note="R->Q: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 112 FT /note="Q->C: Formation of an artifactual disulfide bond FT with a substrate protein." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 113 FT /note="L->Q: Severe decrease of protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 117 FT /note="P->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 123 FT /note="E->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 131 FT /note="H->R: Severe decrease of protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 136 FT /note="A->G: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 143 FT /note="I->V: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 150 FT /note="L->P: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 165 FT /note="W->G: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 168 FT /note="I->T: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 176 FT /note="F->L: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 184 FT /note="E->G: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 202 FT /note="I->F: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 212 FT /note="S->Y: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 214 FT /note="H->D: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 219 FT /note="L->F: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 223 FT /note="Q->R: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 226 FT /note="L->F: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 230 FT /note="S->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 238 FT /note="I->M: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 239 FT /note="K->N: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 245 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 248 FT /note="L->R: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 256 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 256 FT /note="Y->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 257 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Reduces production of NICD in NOTCH1 FT processing. Impaired ability to cleave Ephb2/CTF1." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:22529981" FT MUTAGEN 257 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515" FT MUTAGEN 272 FT /note="V->A: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 273 FT /note="E->A: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 278 FT /note="R->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 284 FT /note="P->S: No significant change of protease activity FT with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 286 FT /note="L->A,E,P,Q,R,W: Increases production of amyloid-beta FT in APP processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 286 FT /note="L->E,R: Reduces production of NICD in NOTCH1 FT processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 288..290 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 291 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 292 FT /note="M->D: Loss of endoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10545183" FT MUTAGEN 310 FT /note="S->A: Abolishes PKA-mediated phosphorylation; no FT effect on caspase-mediated cleavage." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 345 FT /note="D->N: Abolishes caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 346 FT /note="S->A: Abolishes PKC-mediated phosphorylation; no FT effect on PKA-mediated phosphorylation." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 346 FT /note="S->E: Inhibits caspase-mediated cleavage. Modulates FT progression of apoptosis." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 352 FT /note="R->C: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 365 FT /note="S->A: Slightly increased protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 373 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 377..381 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 377 FT /note="R->W: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 385 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of FT the N-cadherin/PS1 complex at the cell surface. Impairs FT CDH2 processing." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 386 FT /note="F->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 389 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 391 FT /note="V->F: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 412 FT /note="V->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 420 FT /note="L->R: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 424 FT /note="L->V: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 432..434 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 432 FT /note="L->P: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 433 FT /note="P->A: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Slightly increased FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 433 FT /note="P->D,F,L,N,V: No endoproteolytic cleavage; no APP, FT nor NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:20460383" FT MUTAGEN 433 FT /note="P->G: Very little endoproteolysis. Little APP FT processing. No NOTCH1 processing. Very low levels amyloid- FT beta protein 40 and no detectable amyloid-beta protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->C: Some loss of endoproteolytic cleavage. Some FT loss of APP and NOTCH1 processing. 6 to 13-fold increase in FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 434 FT /note="A->D,I,L,V: No endoproteolytic cleavage. No APP nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->G: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Reduced amyloid-beta FT protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->A: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. FT Greatly reduced amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->G: Greatly reduced endoproteolytic cleavage. Very FT little APP and NOTCH1 processing. Very low levels of FT amyloid-beta protein 40 and no detectable amyloid-beta FT protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->I: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->R: No endoproteolytic cleavage; no APP, nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:20460383" FT MUTAGEN 435 FT /note="L->V: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. Some FT increase in amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 437 FT /note="I->V: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT CONFLICT 128 FT /note="R -> G (in Ref. 7; AAL16811)" FT /evidence="ECO:0000305" FT STRAND 77..80 FT /evidence="ECO:0007829|PDB:6LR4" FT HELIX 83..102 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:8X52" FT STRAND 120..123 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 125..155 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 159..175 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 177..188 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 195..214 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 219..240 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 243..262 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 263..266 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 267..277 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:6IDF" FT TURN 284..286 FT /evidence="ECO:0007829|PDB:8KCU" FT STRAND 287..289 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 293..299 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 341..345 FT /evidence="ECO:0007829|PDB:2KR6" FT HELIX 356..368 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 380..382 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 383..398 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 400..402 FT /evidence="ECO:0007829|PDB:8OQY" FT HELIX 403..428 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 435..451 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 454..463 FT /evidence="ECO:0007829|PDB:8KCS" SQ SEQUENCE 467 AA; 52668 MW; 5E0F451EF82BCF20 CRC64; MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI // ID REST_HUMAN Reviewed; 1097 AA. AC Q13127; A2RUE0; B9EGJ0; Q12956; Q12957; Q13134; Q59ER1; Q8IWI3; DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 28-JAN-2026, entry version 209. DE RecName: Full=RE1-silencing transcription factor; DE AltName: Full=Neural-restrictive silencer factor; DE AltName: Full=X2 box repressor; GN Name=REST; Synonyms=NRSF, XBR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=7697725; DOI=10.1016/0092-8674(95)90298-8; RA Chong J.A., Tapia-Ramirez J., Kim S., Toledo-Aral J.J., Zheng Y., RA Boutros M.C., Altshuller Y.M., Frohman M.A., Kraner S.D., Mandel G.; RT "REST: a mammalian silencer protein that restricts sodium channel gene RT expression to neurons."; RL Cell 80:949-957(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF 1-599 RP (ISOFORM 1), AND FUNCTION. RX PubMed=7871435; DOI=10.1126/science.7871435; RA Schoenherr C.J., Anderson D.J.; RT "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of RT multiple neuron-specific genes."; RL Science 267:1360-1363(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND RP VARIANT LEU-797. RX PubMed=8568247; RA Scholl T., Stevens M.B., Mahanta S., Strominger J.L.; RT "A zinc finger protein that represses transcription of the human MHC class RT II gene, DPA."; RL J. Immunol. 156:1448-1457(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ILE-626. RC TISSUE=Testis, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 3 AND 4). RX PubMed=10521596; DOI=10.1016/s0169-328x(99)00196-5; RA Palm K., Metsis M., Timmusk T.; RT "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR RT is frequent in neuroblastomas and conserved in human, mouse and rat."; RL Brain Res. Mol. Brain Res. 72:30-39(1999). RN [9] RP FUNCTION, AND INTERACTION WITH RCOR1. RX PubMed=10449787; DOI=10.1073/pnas.96.17.9873; RA Andres M.E., Burger C., Peral-Rubio M.J., Battaglioli E., Anderson M.E., RA Grimes J., Dallman J., Ballas N., Mandel G.; RT "CoREST: a functional corepressor required for regulation of neural- RT specific gene expression."; RL Proc. Natl. Acad. Sci. U.S.A. 96:9873-9878(1999). RN [10] RP FUNCTION, AND INTERACTION WITH RCOR1 AND SIN3A. RX PubMed=10734093; DOI=10.1074/jbc.275.13.9461; RA Grimes J.A., Nielsen S.J., Battaglioli E., Miska E.A., Speh J.C., RA Berry D.L., Atouf F., Holdener B.C., Mandel G., Kouzarides T.; RT "The co-repressor mSin3A is a functional component of the REST-CoREST RT repressor complex."; RL J. Biol. Chem. 275:9461-9467(2000). RN [11] RP FUNCTION. RX PubMed=11779185; DOI=10.1006/bbrc.2001.6194; RA Tabuchi A., Yamada T., Sasagawa S., Naruse Y., Mori N., Tsuda M.; RT "REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene RT promoter activation."; RL Biochem. Biophys. Res. Commun. 290:415-420(2002). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION (ISOFORM 3). RX PubMed=11741002; DOI=10.1016/s0197-0186(01)00091-2; RA Magin A., Lietz M., Cibelli G., Thiel G.; RT "RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional RT repressor nor a de-repressor."; RL Neurochem. Int. 40:195-202(2002). RN [13] RP FUNCTION. RX PubMed=12399542; DOI=10.1126/science.1076469; RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RT "Corepressor-dependent silencing of chromosomal regions encoding neuronal RT genes."; RL Science 298:1747-1752(2002). RN [14] RP ERRATUM OF PUBMED:12399542. RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RL Science 299:1663-1663(2003). RN [15] RP INTERACTION WITH PRICKLE1. RC TISSUE=Brain; RX PubMed=14645515; DOI=10.1128/mcb.23.24.9025-9031.2003; RA Shimojo M., Hersh L.B.; RT "REST/NRSF-interacting LIM domain protein, a putative nuclear translocation RT receptor."; RL Mol. Cell. Biol. 23:9025-9031(2003). RN [16] RP INTERACTION WITH PRICKLE1, SUBCELLULAR LOCATION (ISOFORMS 1; 2; 3 AND 4), RP AND MUTAGENESIS OF 512-LYS--LYS-522. RX PubMed=16442230; DOI=10.1016/j.neulet.2005.12.080; RA Shimojo M.; RT "Characterization of the nuclear targeting signal of REST/NRSF."; RL Neurosci. Lett. 398:161-166(2006). RN [17] RP FUNCTION, INTERACTION WITH CDYL; EHMT1 AND EHMT2, AND IDENTIFICATION IN A RP COMPLEX WITH CDYL; SETB1; EHMT1; EHMT2 AND WIZ. RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025; RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B., Macia E., RA Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J., Shi Y.; RT "CDYL bridges REST and histone methyltransferases for gene repression and RT suppression of cellular transformation."; RL Mol. Cell 32:718-726(2008). RN [18] RP INTERACTION WITH FBXW11 AND BTRC, DEVELOPMENTAL STAGE, PHOSPHORYLATION, RP UBIQUITINATION BY BTRC, AND MUTAGENESIS OF 1009-GLU--SER-1013. RX PubMed=18354482; DOI=10.1038/nature06641; RA Guardavaccaro D., Frescas D., Dorrello N.V., Peschiaroli A., Multani A.S., RA Cardozo T., Lasorella A., Iavarone A., Chang S., Hernando E., Pagano M.; RT "Control of chromosome stability by the beta-TrCP-REST-Mad2 axis."; RL Nature 452:365-369(2008). RN [19] 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 [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP INTERACTION WITH ZFP90. RX PubMed=21284946; DOI=10.1016/j.yjmcc.2011.01.017; RA Hata L., Murakami M., Kuwahara K., Nakagawa Y., Kinoshita H., Usami S., RA Yasuno S., Fujiwara M., Kuwabara Y., Minami T., Yamada Y., Yamada C., RA Nakao K., Ueshima K., Nishikimi T., Nakao K.; RT "Zinc-finger protein 90 negatively regulates neuron-restrictive silencer RT factor-mediated transcriptional repression of fetal cardiac genes."; RL J. Mol. Cell. Cardiol. 50:972-981(2011). RN [22] RP FUNCTION, INTERACTION WITH USP7, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP INDUCTION, UBIQUITINATION BY BTRC, DEUBIQUITINATION BY USP7, AND RP MUTAGENESIS OF SER-313 AND SER-1042. RX PubMed=21258371; DOI=10.1038/ncb2153; RA Huang Z., Wu Q., Guryanova O.A., Cheng L., Shou W., Rich J.N., Bao S.; RT "Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural RT progenitor cells."; RL Nat. Cell Biol. 13:142-152(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, 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 [24] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, RP AND INDUCTION BY WNT SIGNALING; AGING AND OXIDATIVE STRESS. RX PubMed=24670762; DOI=10.1038/nature13163; RA Lu T., Aron L., Zullo J., Pan Y., Kim H., Chen Y., Yang T.H., Kim H.M., RA Drake D., Liu X.S., Bennett D.A., Colaiacovo M.P., Yankner B.A.; RT "REST and stress resistance in ageing and Alzheimer's disease."; RL Nature 507:448-454(2014). RN [25] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=26053433; DOI=10.1038/srep11207; RA Lee N.S., Evgrafov O.V., Souaiaia T., Bonyad A., Herstein J., Lee J.Y., RA Kim J., Ning Y., Sixto M., Weitz A.C., Lenz H.J., Wang K., Knowles J.A., RA Press M.F., Salvaterra P.M., Shung K.K., Chow R.H.; RT "Non-coding RNAs derived from an alternatively spliced REST transcript RT (REST-003) regulate breast cancer invasiveness."; RL Sci. Rep. 5:11207-11207(2015). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27531581; DOI=10.1038/srep31355; RA Cavadas M.A., Mesnieres M., Crifo B., Manresa M.C., Selfridge A.C., RA Keogh C.E., Fabian Z., Scholz C.C., Nolan K.A., Rocha L.M., Tambuwala M.M., RA Brown S., Wdowicz A., Corbett D., Murphy K.J., Godson C., Cummins E.P., RA Taylor C.T., Cheong A.; RT "REST is a hypoxia-responsive transcriptional repressor."; RL Sci. Rep. 6:31355-31355(2016). RN [27] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30684677; DOI=10.1016/j.neulet.2019.01.042; RA Kawamura M., Sato S., Matsumoto G., Fukuda T., Shiba-Fukushima K., Noda S., RA Takanashi M., Mori N., Hattori N.; RT "Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's RT disease patients."; RL Neurosci. Lett. 699:59-63(2019). RN [28] RP STRUCTURE BY NMR OF 43-57 IN COMPLEX WITH SIN3B, AND INTERACTION WITH RP SIN3B. RX PubMed=16288918; DOI=10.1016/j.jmb.2005.10.008; RA Nomura M., Uda-Tochio H., Murai K., Mori N., Nishimura Y.; RT "The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 RT corepressor by using its distinct short hydrophobic helix."; RL J. Mol. Biol. 354:903-915(2005). RN [29] RP INVOLVEMENT IN WT6, VARIANTS WT6 PRO-160; TYR-290; ARG-322 AND GLN-412, RP CHARACTERIZATION OF VARIANT PRO-160; TYR-290 AND ARG-322, FUNCTION, AND RP MUTAGENESIS OF GLU-91; MET-420; SER-593; ALA-642 AND HIS-918. RX PubMed=26551668; DOI=10.1038/ng.3440; RA Mahamdallie S.S., Hanks S., Karlin K.L., Zachariou A., Perdeaux E.R., RA Ruark E., Shaw C.A., Renwick A., Ramsay E., Yost S., Elliott A., Birch J., RA Capra M., Gray J., Hale J., Kingston J., Levitt G., McLean T., Sheridan E., RA Renwick A., Seal S., Stiller C., Sebire N., Westbrook T.F., Rahman N.; RT "Mutations in the transcriptional repressor REST predispose to Wilms RT tumor."; RL Nat. Genet. 47:1471-1474(2015). RN [30] RP INVOLVEMENT IN GINGF5, AND VARIANT GINGF5 437-LEU--GLU-1097 DEL. RX PubMed=28686854; DOI=10.1016/j.ajhg.2017.06.006; RG Baylor-Hopkins Center for Mendelian Genomics; RA Bayram Y., White J.J., Elcioglu N., Cho M.T., Zadeh N., Gedikbasi A., RA Palanduz S., Ozturk S., Cefle K., Kasapcopur O., Coban Akdemir Z., RA Pehlivan D., Begtrup A., Carvalho C.M.B., Paine I.S., Mentes A., RA Bektas-Kayhan K., Karaca E., Jhangiani S.N., Muzny D.M., Gibbs R.A., RA Lupski J.R.; RT "REST final-exon-truncating mutations cause hereditary gingival RT fibromatosis."; RL Am. J. Hum. Genet. 101:149-156(2017). RN [31] RP INVOLVEMENT IN DFNA27, AND ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=29961578; DOI=10.1016/j.cell.2018.06.004; RA Nakano Y., Kelly M.C., Rehman A.U., Boger E.T., Morell R.J., Kelley M.W., RA Friedman T.B., Banfi B.; RT "Defects in the Alternative Splicing-Dependent Regulation of REST Cause RT Deafness."; RL Cell 174:536-548.E21(2018). CC -!- FUNCTION: Transcriptional repressor which binds neuron-restrictive CC silencer element (NRSE) and represses neuronal gene transcription in CC non-neuronal cells (PubMed:11741002, PubMed:11779185, PubMed:12399542, CC PubMed:26551668, PubMed:7697725, PubMed:7871435, PubMed:8568247). CC Restricts the expression of neuronal genes by associating with two CC distinct corepressors, SIN3A and RCOR1, which in turn recruit histone CC deacetylase to the promoters of REST-regulated genes (PubMed:10449787, CC PubMed:10734093). Mediates repression by recruiting the BHC complex at CC RE1/NRSE sites which acts by deacetylating and demethylating specific CC sites on histones, thereby acting as a chromatin modifier (By CC similarity). Transcriptional repression by REST-CDYL via the CC recruitment of histone methyltransferase EHMT2 may be important in CC transformation suppression (PubMed:19061646). Represses the expression CC of SRRM4 in non-neural cells to prevent the activation of neural- CC specific splicing events and to prevent production of REST isoform 3 CC (By similarity). Repressor activity may be inhibited by forming CC heterodimers with isoform 3, thereby preventing binding to NRSE or CC binding to corepressors and leading to derepression of target genes CC (PubMed:11779185). Also maintains repression of neuronal genes in CC neural stem cells, and allows transcription and differentiation into CC neurons by dissociation from RE1/NRSE sites of target genes (By CC similarity). Thereby is involved in maintaining the quiescent state of CC adult neural stem cells and preventing premature differentiation into CC mature neurons (PubMed:21258371). Plays a role in the developmental CC switch in synaptic NMDA receptor composition during postnatal CC development, by repressing GRIN2B expression and thereby altering NMDA CC receptor properties from containing primarily GRIN2B to primarily CC GRIN2A subunits (By similarity). Acts as a regulator of osteoblast CC differentiation (By similarity). Key repressor of gene expression in CC hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE CC site on their promoter regions (PubMed:27531581). May also function in CC stress resistance in the brain during aging; possibly by regulating CC expression of genes involved in cell death and in the stress response CC (PubMed:24670762). Repressor of gene expression in the hippocampus CC after ischemia by directly binding to RE1/NRSE sites and recruiting CC SIN3A and RCOR1 to promoters of target genes, thereby promoting changes CC in chromatin modifications and ischemia-induced cell death (By CC similarity). After ischemia, might play a role in repression of miR-132 CC expression in hippocampal neurons, thereby leading to neuronal cell CC death (By similarity). Negatively regulates the expression of SRRM3 in CC breast cancer cell lines (PubMed:26053433). CC {ECO:0000250|UniProtKB:O54963, ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:11779185, CC ECO:0000269|PubMed:12399542, ECO:0000269|PubMed:19061646, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:26053433, ECO:0000269|PubMed:26551668, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:7697725, CC ECO:0000269|PubMed:7871435, ECO:0000269|PubMed:8568247}. CC -!- FUNCTION: [Isoform 3]: Binds to the 3' region of the neuron-restrictive CC silencer element (NRSE), with lower affinity than full-length REST CC isoform 1 (By similarity). Exhibits weaker repressor activity compared CC to isoform 1 (PubMed:11779185). May negatively regulate the repressor CC activity of isoform 1 by binding to isoform 1, thereby preventing its CC binding to NRSE and leading to derepression of target genes CC (PubMed:11779185). However, in another study, does not appear to be CC implicated in repressor activity of a NRSE motif-containing reporter CC construct nor in inhibitory activity on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). Post-transcriptional inactivation CC of REST by SRRM4-dependent alternative splicing into isoform 3 is CC required in mechanosensory hair cells in the inner ear for derepression CC of neuronal genes and hearing (By similarity). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SUBUNIT: Isoform 1 and isoform 3 form heterodimers (By similarity). CC Isoform 3: Forms homodimers and homooligomers; binds to the neuron- CC restrictive silencer element (NRSE) as monomer (By similarity). CC Interacts with SIN3A, SIN3B and RCOR1 (PubMed:10449787, CC PubMed:10734093, PubMed:16288918). Interacts with CDYL CC (PubMed:19061646). Interacts with EHMT1 and EHMT2 only in the presence CC of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, CC REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts (via CC zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the CC interaction inhibits REST repressor activity (PubMed:21284946). CC Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (PubMed:14645515, CC PubMed:16442230). Interacts with FBXW11 and BTRC (PubMed:18354482). CC Interacts with USP7 (PubMed:21258371). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:14645515, ECO:0000269|PubMed:16288918, CC ECO:0000269|PubMed:16442230, ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:19061646, ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:21284946}. CC -!- INTERACTION: CC Q13127; Q9Y297: BTRC; NbExp=10; IntAct=EBI-926706, EBI-307461; CC Q13127; Q9UKB1: FBXW11; NbExp=3; IntAct=EBI-926706, EBI-355189; CC Q13127; P07900: HSP90AA1; NbExp=4; IntAct=EBI-926706, EBI-296047; CC Q13127; P41229: KDM5C; NbExp=3; IntAct=EBI-926706, EBI-1246541; CC Q13127; P51532: SMARCA4; NbExp=2; IntAct=EBI-926706, EBI-302489; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16442230, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:30684677}. Cytoplasm CC {ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. Note=Colocalizes with ZFP90 in the CC nucleus (By similarity). In response to hypoxia, there is a more CC pronounced increase in levels in the nucleus as compared to the CC cytoplasm (PubMed:27531581). In aging neurons, increased levels in the CC nucleus as compared to the cytoplasm (PubMed:24670762, CC PubMed:30684677). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Nucleus CC {ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=REST1 {ECO:0000303|PubMed:16442230}; CC IsoId=Q13127-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13127-2; Sequence=VSP_022064, VSP_022065; CC Name=3; Synonyms=N4, REST4 {ECO:0000303|PubMed:11779185}; CC IsoId=Q13127-3; Sequence=VSP_022066, VSP_022068; CC Name=4; CC IsoId=Q13127-4; Sequence=VSP_022067; CC -!- TISSUE SPECIFICITY: Expressed in neurons of the prefrontal cortex, in CC hippocampal pyramidal neurons, dentate gyrus granule neurons and CC cerebellar Purkinje and granule neurons (at protein level) CC (PubMed:24670762). Expressed in dopaminergic neurons of the substantia CC nigra (at protein level) (PubMed:30684677). Expressed in neural CC progenitor cells (at protein level) (PubMed:21258371). In patients CC suffering from Alzheimer disease, frontotemporal dementia or dementia CC with Lewy bodies, decreased nuclear levels have been observed in CC neurons of the prefrontal cortex and the hippocampus, but not in CC neurons of the dentate gyrus and cerebellum (at protein level) CC (PubMed:24670762). In patients with Parkinson disease or dementia with CC Lewy bodies, decreased nuclear levels have been observed in CC dopaminergic neurons and in cortical neurons and localization to Lewy CC bodies and pale bodies was detected (at protein level) CC (PubMed:30684677). Expressed at higher levels in weakly invasive breast CC cancer cell lines and at lower levels in highly invasive breast cancer CC lines (at protein level) (PubMed:26053433). Ubiquitous CC (PubMed:8568247). Expressed at higher levels in the tissues of the CC lymphocytic compartment, including spleen, thymus, peripheral blood CC lymphocytes and ovary (PubMed:8568247). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:26053433, CC ECO:0000269|PubMed:30684677, ECO:0000269|PubMed:8568247}. CC -!- DEVELOPMENTAL STAGE: Expression is cell cycle-dependent with decreased CC levels in G2 phase; mediated by proteasomal degradation (at protein CC level) (PubMed:18354482). In aged individuals, increased expression in CC hippocampal CA1, CA3 and CA4 pyramidal neurons and in dentate granule CC cell neurons, but not in the cerebellum (PubMed:24670762). CC {ECO:0000269|PubMed:18354482, ECO:0000269|PubMed:24670762}. CC -!- INDUCTION: Up-regulated by Wnt signaling (PubMed:24670762). Up- CC regulated in the brain of aging individuals but not in Alzheimer CC disease patients (PubMed:24670762). Up-regulated by oxidative stress CC (PubMed:24670762). Down-regulated during neural progenitor cell CC differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762}. CC -!- DOMAIN: The C2H2-type zinc finger 5 is required for nuclear CC localization. {ECO:0000269|PubMed:16442230}. CC -!- PTM: O-glycosylated. {ECO:0000250|UniProtKB:Q8VIG1}. CC -!- PTM: Phosphorylated; phosphorylation is required for ubiquitination. CC {ECO:0000269|PubMed:18354482}. CC -!- PTM: Ubiquitinated; ubiquitination is mediated by BTRC and leads to CC proteasomal degradation in G2 phase (PubMed:18354482, PubMed:21258371). CC Ubiquitination increases during neuronal differentiation CC (PubMed:21258371). Deubiquitinated by USP7; leading to its CC stabilization and promoting the maintenance of neural progenitor cells CC (PubMed:21258371). {ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:21258371}. CC -!- DISEASE: Wilms tumor 6 (WT6) [MIM:616806]: A pediatric malignancy of CC kidney, and the most common childhood abdominal malignancy. It is CC caused by the uncontrolled multiplication of renal stem, stromal, and CC epithelial cells. {ECO:0000269|PubMed:26551668}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Fibromatosis, gingival, 5 (GINGF5) [MIM:617626]: An autosomal CC dominant form of hereditary gingival fibromatosis, a rare condition CC characterized by a slow, progressive overgrowth of the gingiva. The CC excess gingival tissue can cover part of or the entire crown, and can CC result in diastemas, teeth displacement, or retention of primary or CC impacted teeth. {ECO:0000269|PubMed:28686854}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=An intronic variant that affects alternative splicing of CC REST into isoform 3 and inactivation of REST repressor activity is CC associated with progressive hearing loss and deafness. CC {ECO:0000269|PubMed:29961578}. CC -!- DISEASE: Deafness, autosomal dominant, 27 (DFNA27) [MIM:612431]: A form CC of non-syndromic deafness characterized by postlingual, progressive, CC moderate to profound sensorineural hearing loss. CC {ECO:0000269|PubMed:29961578}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. An intronic CC variant that affects alternative splicing of REST and inactivation of CC REST repressor activity fully segregates with deafness in a 3- CC generation family. {ECO:0000269|PubMed:29961578}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by SRRM4-dependent alternative CC splicing in neurons and inner ear hair cells (By similarity). Lacks the CC four C-terminal zinc fingers and the RCOR1 corepressor interaction site CC found in full length REST isoform 1, which are required for full DNA- CC binding and repressive activity (PubMed:11741002). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002}. CC -!- CAUTION: [Isoform 3]: Controversial data exists concerning the CC repressor activity of isoform 3. A study showed that isoform 3 exhibits CC weak repressor activity of a NRSE motif-containing reporter construct CC (PubMed:11779185). Another report, however, does not observe any CC isoform 3 transcriptional repressor activity of a NRSE motif-containing CC reporter construct (PubMed:11741002). Controversial data also exists CC regarding the function of isoform 3 on the negative regulation of CC isoform 1. It was shown that isoform 3 negatively regulates the CC repressor activity of isoform 1 by binding to isoform 1, thereby CC preventing its binding to NRSE and leading to derepression of target CC genes (PubMed:11779185). Another study, however, did not observe any CC inhibitory activity of isoform 3 on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). {ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA98503.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAC50114.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC50115.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH38985.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=BAD92987.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44266/REST"; 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; U22314; AAB17211.1; -; mRNA. DR EMBL; U13877; AAC50114.1; ALT_INIT; mRNA. DR EMBL; U13879; AAC50115.1; ALT_INIT; mRNA. DR EMBL; U22680; AAA98503.1; ALT_FRAME; mRNA. DR EMBL; AB209750; BAD92987.1; ALT_INIT; mRNA. DR EMBL; AC069307; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471057; EAX05517.1; -; Genomic_DNA. DR EMBL; BC038985; AAH38985.1; ALT_SEQ; mRNA. DR EMBL; BC132859; AAI32860.1; -; mRNA. DR EMBL; BC136491; AAI36492.1; -; mRNA. DR CCDS; CCDS3509.1; -. [Q13127-1] DR PIR; A56138; A56138. DR PIR; I38754; I38754. DR PIR; I38755; I38755. DR RefSeq; NP_001180437.1; NM_001193508.2. [Q13127-1] DR RefSeq; NP_001350382.1; NM_001363453.3. [Q13127-1] DR RefSeq; NP_005603.3; NM_005612.4. [Q13127-1] DR PDB; 2CZY; NMR; -; B=43-57. DR PDB; 6DU2; X-ray; 2.50 A; C/D=858-869. DR PDB; 6DU3; X-ray; 2.58 A; C/D=858-869. DR PDBsum; 2CZY; -. DR PDBsum; 6DU2; -. DR PDBsum; 6DU3; -. DR AlphaFoldDB; Q13127; -. DR BMRB; Q13127; -. DR SMR; Q13127; -. DR BioGRID; 111910; 267. DR CORUM; Q13127; -. DR DIP; DIP-35264N; -. DR FunCoup; Q13127; 4087. DR IntAct; Q13127; 20. DR MINT; Q13127; -. DR STRING; 9606.ENSP00000311816; -. DR GlyGen; Q13127; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13127; -. DR PhosphoSitePlus; Q13127; -. DR BioMuta; REST; -. DR DMDM; 296452989; -. DR jPOST; Q13127; -. DR MassIVE; Q13127; -. DR PaxDb; 9606-ENSP00000311816; -. DR PeptideAtlas; Q13127; -. DR ProteomicsDB; 59175; -. [Q13127-1] DR ProteomicsDB; 59176; -. [Q13127-2] DR ProteomicsDB; 59177; -. [Q13127-3] DR ProteomicsDB; 59178; -. [Q13127-4] DR Pumba; Q13127; -. DR Antibodypedia; 1755; 291 antibodies from 38 providers. DR DNASU; 5978; -. DR Ensembl; ENST00000309042.12; ENSP00000311816.7; ENSG00000084093.20. [Q13127-1] DR Ensembl; ENST00000675105.1; ENSP00000502313.1; ENSG00000084093.20. [Q13127-1] DR GeneID; 5978; -. DR KEGG; hsa:5978; -. DR MANE-Select; ENST00000309042.12; ENSP00000311816.7; NM_005612.5; NP_005603.3. DR UCSC; uc003hch.4; human. [Q13127-1] DR AGR; HGNC:9966; -. DR ClinPGx; PA34334; -. DR CTD; 5978; -. DR DisGeNET; 5978; -. DR GeneCards; REST; -. DR HGNC; HGNC:9966; REST. DR HPA; ENSG00000084093; Low tissue specificity. DR MalaCards; REST; -. DR MIM; 600571; gene. DR MIM; 612431; phenotype. DR MIM; 616806; phenotype. DR MIM; 617626; phenotype. DR OpenTargets; ENSG00000084093; -. DR Orphanet; 2024; Hereditary gingival fibromatosis. DR Orphanet; 654; Nephroblastoma. DR VEuPathDB; HostDB:ENSG00000084093; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000155341; -. DR HOGENOM; CLU_009801_2_0_1; -. DR InParanoid; Q13127; -. DR OrthoDB; 427030at2759; -. DR PAN-GO; Q13127; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13127; -. DR PathwayCommons; Q13127; -. DR Reactome; R-HSA-3214815; HDACs deacetylate histones. DR Reactome; R-HSA-8943724; Regulation of PTEN gene transcription. DR Reactome; R-HSA-9031628; NGF-stimulated transcription. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription. DR SignaLink; Q13127; -. DR SIGNOR; Q13127; -. DR Agora; ENSG00000084093; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5978; 49 hits in 1187 CRISPR screens. DR ChiTaRS; REST; human. DR GeneWiki; RE1-silencing_transcription_factor; -. DR GenomeRNAi; 5978; -. DR Pharos; Q13127; Tbio. DR PRO; PR:Q13127; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q13127; protein. DR Bgee; ENSG00000084093; Expressed in primordial germ cell in gonad and 209 other cell types or tissues. DR ExpressionAtlas; Q13127; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0060088; P:auditory receptor cell stereocilium organization; ISS:UniProtKB. DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; ISS:UniProtKB. DR GO; GO:0071257; P:cellular response to electrical stimulus; IMP:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IDA:UniProtKB. DR GO; GO:0033554; P:cellular response to stress; IEA:Ensembl. DR GO; GO:0006338; P:chromatin remodeling; ISS:UniProtKB. DR GO; GO:0050910; P:detection of mechanical stimulus involved in sensory perception of sound; ISS:UniProtKB. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0043922; P:host-mediated suppression of viral transcription; IDA:UniProtKB. DR GO; GO:0099563; P:modification of synaptic structure; ISS:UniProtKB. DR GO; GO:0032348; P:negative regulation of aldosterone biosynthetic process; IMP:UniProtKB. DR GO; GO:2000798; P:negative regulation of amniotic stem cell differentiation; IMP:UniProtKB. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; ISS:UniProtKB. DR GO; GO:2000065; P:negative regulation of cortisol biosynthetic process; IMP:UniProtKB. DR GO; GO:2000706; P:negative regulation of dense core granule biogenesis; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:UniProtKB. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0050877; P:nervous system process; IMP:UniProtKB. DR GO; GO:0050885; P:neuromuscular process controlling balance; ISS:UniProtKB. DR GO; GO:0097150; P:neuronal stem cell population maintenance; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISS:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; ISS:UniProtKB. DR GO; GO:1902459; P:positive regulation of stem cell population maintenance; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0002931; P:response to ischemia; ISS:UniProtKB. DR GO; GO:0035019; P:somatic stem cell population maintenance; ISS:UniProtKB. DR FunFam; 3.30.160.60:FF:002187; RE1-silencing transcription factor; 1. DR FunFam; 3.30.160.60:FF:000448; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000662; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000805; RE1-silencing transcription factor B; 1. DR FunFam; 3.30.160.60:FF:000952; RE1-silencing transcription factor B; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 5. DR IDEAL; IID00169; -. DR InterPro; IPR057281; Zfn-C2H2_REST. DR InterPro; IPR050688; Zinc_finger/UBP_domain. DR InterPro; IPR036236; Znf_C2H2_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR24403:SF102; RE1-SILENCING TRANSCRIPTION FACTOR; 1. DR PANTHER; PTHR24403; ZINC FINGER PROTEIN; 1. DR Pfam; PF00096; zf-C2H2; 1. DR Pfam; PF24540; zf-C2H2_REST; 1. DR SMART; SM00355; ZnF_C2H2; 9. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 6. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; Disease variant; KW Metal-binding; Non-syndromic deafness; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation; Ubl conjugation; Zinc; KW Zinc-finger. FT CHAIN 1..1097 FT /note="RE1-silencing transcription factor" FT /id="PRO_0000269547" FT ZN_FING 159..181 FT /note="C2H2-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 216..238 FT /note="C2H2-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 248..270 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 276..298 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 304..326 FT /note="C2H2-type 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 332..355 FT /note="C2H2-type 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 361..383 FT /note="C2H2-type 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 389..412 FT /note="C2H2-type 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 1060..1082 FT /note="C2H2-type 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 32..122 FT /note="Interaction with SIN3A" FT /evidence="ECO:0000269|PubMed:10734093" FT REGION 43..57 FT /note="Interaction with SIN3B" FT /evidence="ECO:0000269|PubMed:16288918" FT REGION 83..103 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 127..159 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..418 FT /note="Interaction with ZFP90" FT /evidence="ECO:0000269|PubMed:21284946" FT REGION 201..212 FT /note="Required for binding to the neuron-restrictive FT silencer element" FT /evidence="ECO:0000250|UniProtKB:Q8VIG1" FT REGION 452..642 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 774..837 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 853..938 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 961..1049 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1009..1087 FT /note="Interaction with RCOR1" FT /evidence="ECO:0000269|PubMed:10449787" FT COMPBIAS 86..96 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 452..479 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 480..490 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 495..504 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 559..570 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 577..593 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 803..836 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 913..930 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 864 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 971 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O54963" FT VAR_SEQ 301..313 FT /note="ERPYKCELCPYSS -> KRSFLVHKFSSLF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022064" FT VAR_SEQ 304..326 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_022067" FT VAR_SEQ 314..1097 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022065" FT VAR_SEQ 329 FT /note="E -> W (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022066" FT VAR_SEQ 330..1097 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022068" FT VARIANT 160 FT /note="R -> P (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076333" FT VARIANT 290 FT /note="N -> Y (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076334" FT VARIANT 322 FT /note="H -> R (in WT6; inhibits transcriptional repression FT activity; dbSNP:rs869025312)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076335" FT VARIANT 412 FT /note="H -> Q (in WT6)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076336" FT VARIANT 437..1097 FT /note="Missing (in GINGF5)" FT /evidence="ECO:0000269|PubMed:28686854" FT /id="VAR_079529" FT VARIANT 626 FT /note="V -> I (in dbSNP:rs2228991)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_029795" FT VARIANT 692 FT /note="E -> D (in dbSNP:rs2227902)" FT /id="VAR_029796" FT VARIANT 762 FT /note="K -> Q (in dbSNP:rs2227903)" FT /id="VAR_029797" FT VARIANT 797 FT /note="P -> L (in dbSNP:rs3796529)" FT /evidence="ECO:0000269|PubMed:8568247" FT /id="VAR_029798" FT MUTAGEN 91 FT /note="E->G: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 313 FT /note="S->A: Lack of deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT MUTAGEN 420 FT /note="M->T: Inhibits transcriptional repression activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->AFSKTADSMDA: No effect on nuclear FT localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->GS: Reduced nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="Missing: No effect on nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 593 FT /note="S->N: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 642 FT /note="A->T: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 918 FT /note="H->Y: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 1009..1013 FT /note="EGIHS->AGIHA: Loss of interaction with BTRC. Reduced FT ubiquitination. Decreased proteasomal degradation in G2. FT Decreased average time from nuclear envelope breakdown to FT anaphase onset. Increased number of lagging chromosomes and FT chromosome bridges in anaphase and prematurely separated FT sister chromatids. Reduced MAD2 levels." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1009 FT /note="E->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1013 FT /note="S->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1042 FT /note="S->A: No impact on deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT CONFLICT 295 FT /note="V -> L (in Ref. 2; AAC50114)" FT /evidence="ECO:0000305" FT CONFLICT 596..599 FT /note="PQKE -> SRNS (in Ref. 2; AAC50115)" FT /evidence="ECO:0000305" FT CONFLICT 630 FT /note="P -> L (in Ref. 1; AAB17211)" FT /evidence="ECO:0000305" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:2CZY" SQ SEQUENCE 1097 AA; 121872 MW; EBC652EED19CA161 CRC64; MATQVMGQSS GGGGLFTSSG NIGMALPNDM YDLHDLSKAE LAAPQLIMLA NVALTGEVNG SCCDYLVGEE RQMAELMPVG DNNFSDSEEG EGLEESADIK GEPHGLENME LRSLELSVVE PQPVFEASGA PDIYSSNKDL PPETPGAEDK GKSSKTKPFR CKPCQYEAES EEQFVHHIRV HSAKKFFVEE SAEKQAKARE SGSSTAEEGD FSKGPIRCDR CGYNTNRYDH YTAHLKHHTR AGDNERVYKC IICTYTTVSE YHWRKHLRNH FPRKVYTCGK CNYFSDRKNN YVQHVRTHTG ERPYKCELCP YSSSQKTHLT RHMRTHSGEK PFKCDQCSYV ASNQHEVTRH ARQVHNGPKP LNCPHCDYKT ADRSNFKKHV ELHVNPRQFN CPVCDYAASK KCNLQYHFKS KHPTCPNKTM DVSKVKLKKT KKREADLPDN ITNEKTEIEQ TKIKGDVAGK KNEKSVKAEK RDVSKEKKPS NNVSVIQVTT RTRKSVTEVK EMDVHTGSNS EKFSKTKKSK RKLEVDSHSL HGPVNDEESS TKKKKKVESK SKNNSQEVPK GDSKVEENKK QNTCMKKSTK KKTLKNKSSK KSSKPPQKEP VEKGSAQMDP PQMGPAPTEA VQKGPVQVEP PPPMEHAQME GAQIRPAPDE PVQMEVVQEG PAQKELLPPV EPAQMVGAQI VLAHMELPPP METAQTEVAQ MGPAPMEPAQ MEVAQVESAP MQVVQKEPVQ MELSPPMEVV QKEPVQIELS PPMEVVQKEP VKIELSPPIE VVQKEPVQME LSPPMGVVQK EPAQREPPPP REPPLHMEPI SKKPPLRKDK KEKSNMQSER ARKEQVLIEV GLVPVKDSWL LKESVSTEDL SPPSPPLPKE NLREEASGDQ KLLNTGEGNK EAPLQKVGAE EADESLPGLA ANINESTHIS SSGQNLNTPE GETLNGKHQT DSIVCEMKMD TDQNTRENLT GINSTVEEPV SPMLPPSAVE EREAVSKTAL ASPPATMAAN ESQEIDEDEG IHSHEGSDLS DNMSEGSDDS GLHGARPVPQ ESSRKNAKEA LAVKAAKGDF VCIFCDRSFR KGKDYSKHLN RHLVNVYYLE EAAQGQE // ID SQSTM_HUMAN Reviewed; 440 AA. AC Q13501; A6NFN7; B2R661; B3KUW5; Q13446; Q9BUV7; Q9BVS6; Q9UEU1; DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 28-JAN-2026, entry version 237. DE RecName: Full=Sequestosome-1 {ECO:0000305}; DE AltName: Full=EBI3-associated protein of 60 kDa {ECO:0000303|PubMed:8551575}; DE Short=EBIAP; DE Short=p60 {ECO:0000303|PubMed:8551575}; DE AltName: Full=Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa {ECO:0000303|PubMed:8650207}; DE AltName: Full=Ubiquitin-binding protein p62 {ECO:0000303|PubMed:8650207}; DE Short=p62 {ECO:0000303|PubMed:30266909}; GN Name=SQSTM1 {ECO:0000303|PubMed:16286508, ECO:0000312|HGNC:HGNC:11280}; GN Synonyms=ORCA, OSIL; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|Proteomes:UP000005640}; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 345-361 AND RP 394-411, AND INTERACTION WITH EBI3. RC TISSUE=B-cell; RX PubMed=8551575; DOI=10.1128/jvi.70.2.1143-1153.1996; RA Devergne O., Hummel M., Koeppen H., Le Beau M.M., Nathanson E.C., Kieff E., RA Birkenbach M.; RT "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr RT virus infection in B lymphocytes."; RL J. Virol. 70:1143-1153(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 51-96; 184-187; RP 213-217; 239-264 AND 268-281, TISSUE SPECIFICITY, INTERACTION WITH LCK, AND RP MUTAGENESIS OF TYR-9. RC TISSUE=Cervix carcinoma; RX PubMed=8650207; DOI=10.1073/pnas.93.12.5991; RA Joung I., Strominger J.L., Shin J.; RT "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck RT SH2 domain."; RL Proc. Natl. Acad. Sci. U.S.A. 93:5991-5995(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Caudate nucleus, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Pancreas, Placenta, Skin, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, AND INDUCTION. RX PubMed=9762895; DOI=10.1016/s0014-5793(98)01021-7; RA Vadlamudi R.K., Shin J.; RT "Genomic structure and promoter analysis of the p62 gene encoding a non- RT proteasomal multiubiquitin chain binding protein."; RL FEBS Lett. 435:138-142(1998). RN [7] RP PROTEIN SEQUENCE OF 51-60; 166-174 AND 379-388. RX PubMed=10362795; DOI=10.1016/s0002-9440(10)65426-0; RA Stumptner C., Heid H., Fuchsbichler A., Hauser H., Mischinger H.-J., RA Zatloukal K., Denk H.; RT "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. RT Demonstration of p62 as major constituent."; RL Am. J. Pathol. 154:1701-1710(1999). RN [8] RP INTERACTION WITH LCK AND RASA1. RX PubMed=8618896; DOI=10.1073/pnas.92.26.12338; RA Park I., Chung J., Walsh C.T., Yun Y., Strominger J.L., Shin J.; RT "Phosphotyrosine-independent binding of a 62-kDa protein to the src RT homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of RT Ser-59 in the lck unique N-terminal region."; RL Proc. Natl. Acad. Sci. U.S.A. 92:12338-12342(1995). RN [9] RP INTERACTION WITH UBIQUITIN. RX PubMed=8702753; DOI=10.1074/jbc.271.34.20235; RA Vadlamudi R.K., Joung I., Strominger J.L., Shin J.; RT "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, RT belongs to a new class of ubiquitin-binding proteins."; RL J. Biol. Chem. 271:20235-20237(1996). RN [10] RP INTERACTION WITH NR2F2. RX PubMed=8910285; DOI=10.1074/jbc.271.44.27197; RA Marcus S.L., Winrow C.J., Capone J.P., Rachubinski R.A.; RT "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone RT receptor."; RL J. Biol. Chem. 271:27197-27200(1996). RN [11] RP INTERACTION WITH PRKCI AND PRKCZ, AND SUBCELLULAR LOCATION. RX PubMed=9566925; DOI=10.1128/mcb.18.5.3069; RA Sanchez P., De Carcer G., Sandoval I.V., Moscat J., Diaz-Meco M.T.; RT "Localization of atypical protein kinase C isoforms into lysosome-targeted RT endosomes through interaction with p62."; RL Mol. Cell. Biol. 18:3069-3080(1998). RN [12] RP INTERACTION WITH RIPK1; PRKCZ; PRKCI; IKBKB; TRADD AND TNFRSF1A, AND RP FUNCTION. RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044; RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.; RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB RT activation."; RL EMBO J. 18:3044-3053(1999). RN [13] RP INTERACTION WITH MAPKAPK5, AND SUBCELLULAR LOCATION. RX PubMed=10708586; DOI=10.1006/bbrc.2000.2333; RA Sudo T., Maruyama M., Osada H.; RT "p62 functions as a p38 MAP kinase regulator."; RL Biochem. Biophys. Res. Commun. 269:521-525(2000). RN [14] RP INTERACTION WITH TRAF6 AND RIPK1, DOMAIN, AND FUNCTION. RX PubMed=10747026; DOI=10.1093/emboj/19.7.1576; RA Sanz L., Diaz-Meco M.T., Nakano H., Moscat J.; RT "The atypical PKC-interacting protein p62 channels NF-kappaB activation by RT the IL-1-TRAF6 pathway."; RL EMBO J. 19:1576-1586(2000). RN [15] RP INTERACTION WITH NTRK1; TRAF6; NGFR AND PRKCZ, AND FUNCTION. RX PubMed=11244088; DOI=10.1074/jbc.c000869200; RA Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A., RA Moscat J.; RT "The atypical protein kinase C-interacting protein p62 is a scaffold for RT NF-kappaB activation by nerve growth factor."; RL J. Biol. Chem. 276:7709-7712(2001). RN [16] RP SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=11786419; DOI=10.1016/s0002-9440(10)64369-6; RA Zatloukal K., Stumptner C., Fuchsbichler A., Heid H., Schnoelzer M., RA Kenner L., Kleinert R., Prinz M., Aguzzi A., Denk H.; RT "p62 Is a common component of cytoplasmic inclusions in protein aggregation RT diseases."; RL Am. J. Pathol. 160:255-263(2002). RN [17] RP INTERACTION WITH PAWR AND PRKCZ. RX PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0; RA Chang S., Kim J.H., Shin J.; RT "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4- RT induced PKCzeta inhibition."; RL FEBS Lett. 510:57-61(2002). RN [18] RP SUBCELLULAR LOCATION. RX PubMed=11981755; DOI=10.1053/jhep.2002.32674; RA Stumptner C., Fuchsbichler A., Heid H., Zatloukal K., Denk H.; RT "Mallory body -- a disease-associated type of sequestosome."; RL Hepatology 35:1053-1062(2002). RN [19] RP INTERACTION WITH NTRK1; NTRK2 AND NTRK3, SUBCELLULAR LOCATION, AND RP FUNCTION. RX PubMed=12471037; DOI=10.1074/jbc.m208468200; RA Geetha T., Wooten M.W.; RT "Association of the atypical protein kinase C-interacting protein p62/ZIP RT with nerve growth factor receptor TrkA regulates receptor trafficking and RT Erk5 signaling."; RL J. Biol. Chem. 278:4730-4739(2003). RN [20] RP INTERACTION WITH PRKCI; PRKCZ; MAP2K5 AND NBR1, DOMAIN, MUTAGENESIS OF RP LYS-7; LYS-13; 21-ARG-ARG-22; TYR-67; ASP-69; ASP-71; ASP-73; ASP-80 AND RP GLU-82, AND DIMERIZATION. RX PubMed=12813044; DOI=10.1074/jbc.m303221200; RA Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A., RA Michaelsen E., Bjoerkoey G., Johansen T.; RT "Interaction codes within the family of mammalian Phox and Bem1p domain- RT containing proteins."; RL J. Biol. Chem. 278:34568-34581(2003). RN [21] RP INTERACTION WITH PRKCZ, DOMAIN, OLIGOMERIZATION, AND MUTAGENESIS OF LYS-7; RP ASP-69 AND ASP-73. RX PubMed=12887891; DOI=10.1016/s1097-2765(03)00246-6; RA Wilson M.I., Gill D.J., Perisic O., Quinn M.T., Williams R.L.; RT "PB1 domain-mediated heterodimerization in NADPH oxidase and signaling RT complexes of atypical protein kinase C with Par6 and p62."; RL Mol. Cell 12:39-50(2003). RN [22] RP INDUCTION. RX PubMed=12700667; DOI=10.1038/sj.onc.1206325; RA Thompson H.G.R., Harris J.W., Wold B.J., Lin F., Brody J.P.; RT "p62 overexpression in breast tumors and regulation by prostate-derived Ets RT factor in breast cancer cells."; RL Oncogene 22:2322-2333(2003). RN [23] RP SUBCELLULAR LOCATION. RX PubMed=15158159; DOI=10.1016/j.brainres.2004.03.029; RA Nakaso K., Yoshimoto Y., Nakano T., Takeshima T., Fukuhara Y., Yasui K., RA Araga S., Yanagawa T., Ishii T., Nakashima K.; RT "Transcriptional activation of p62/A170/ZIP during the formation of the RT aggregates: possible mechanisms and the role in Lewy body formation in RT Parkinson's disease."; RL Brain Res. 1012:42-51(2004). RN [24] RP INTERACTION WITH TRAF6; PSMC2 AND PSMD4, DOMAIN, MUTAGENESIS OF LEU-398; RP PHE-406; LEU-413; LEU-417 AND ILE-431, AND FUNCTION. RX PubMed=15340068; DOI=10.1128/mcb.24.18.8055-8068.2004; RA Seibenhener M.L., Babu J.R., Geetha T., Wong H.C., Krishna N.R., RA Wooten M.W.; RT "Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in RT ubiquitin proteasome degradation."; RL Mol. Cell. Biol. 24:8055-8068(2004). RN [25] RP FUNCTION. RX PubMed=16079148; DOI=10.1074/jbc.c500237200; RA Wooten M.W., Geetha T., Seibenhener M.L., Babu J.R., Diaz-Meco M.T., RA Moscat J.; RT "The p62 scaffold regulates nerve growth factor-induced NF-kappaB RT activation by influencing TRAF6 polyubiquitination."; RL J. Biol. Chem. 280:35625-35629(2005). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, INTERACTION WITH RP MAP1LC3B, POSSIBLE PROTECTIVE ROLE IN HD, AND MUTAGENESIS OF ASP-69 AND RP ILE-431. RX PubMed=16286508; DOI=10.1083/jcb.200507002; RA Bjorkoy G., Lamark T., Brech A., Outzen H., Perander M., Overvatn A., RA Stenmark H., Johansen T.; RT "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a RT protective effect on huntingtin-induced cell death."; RL J. Cell Biol. 171:603-614(2005). RN [27] RP INTERACTION WITH MAPT, DOMAIN, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x; RA Babu J.R., Geetha T., Wooten M.W.; RT "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal RT degradation."; RL J. Neurochem. 94:192-203(2005). RN [28] RP INTERACTION WITH AJUBA AND LIMD1. RX PubMed=15870274; DOI=10.1128/mcb.25.10.4010-4022.2005; RA Feng Y., Longmore G.D.; RT "The LIM protein Ajuba influences interleukin-1-induced NF-kappaB RT activation by affecting the assembly and activity of the protein kinase RT Czeta/p62/TRAF6 signaling complex."; RL Mol. Cell. Biol. 25:4010-4022(2005). RN [29] RP INDUCTION, AND FUNCTION. RX PubMed=15911346; DOI=10.1016/j.mcn.2005.02.011; RA Wang Z., Figueiredo-Pereira M.E.; RT "Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of RT ubiquitinated proteins induced by prostaglandin J2 without reducing its RT neurotoxicity."; RL Mol. Cell. Neurosci. 29:222-231(2005). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-148, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [31] RP INTERACTION WITH NBR1 AND TRIM55, PHOSPHORYLATION, DOMAIN, AND FUNCTION. RX PubMed=15802564; DOI=10.1126/science.1110463; RA Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E., RA Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G., RA Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L., Ehler E., RA Udd B., Gautel M.; RT "The kinase domain of titin controls muscle gene expression and protein RT turnover."; RL Science 308:1599-1603(2005). RN [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-332, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [34] RP FUNCTION, INTERACTION WITH GABARAP; GABARAPL1; GABARAPL2; MAP1LC3A AND RP MAP1LC3B, AND MUTAGENESIS OF 323-GLU-GLU-324; SER-332; 335-ASP--ASP-337; RP TRP-338 AND SER-342. RX PubMed=17580304; DOI=10.1074/jbc.m702824200; RA Pankiv S., Clausen T.H., Lamark T., Brech A., Bruun J.A., Outzen H., RA Overvatn A., Bjorkoy G., Johansen T.; RT "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of RT ubiquitinated protein aggregates by autophagy."; RL J. Biol. Chem. 282:24131-24145(2007). RN [35] RP PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION). RX PubMed=24331465; DOI=10.1016/j.chom.2013.11.003; RA Barnett T.C., Liebl D., Seymour L.M., Gillen C.M., Lim J.Y., Larock C.N., RA Davies M.R., Schulz B.L., Nizet V., Teasdale R.D., Walker M.J.; RT "The globally disseminated M1T1 clone of group A Streptococcus evades RT autophagy for intracellular replication."; RL Cell Host Microbe 14:675-682(2013). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-328; SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [38] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [39] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [40] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-355 AND SER-361, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [41] RP FUNCTION, INTERACTION WITH WDFY3, AND SUBCELLULAR LOCATION. RX PubMed=20168092; DOI=10.4161/auto.6.3.11226; RA Clausen T.H., Lamark T., Isakson P., Finley K., Larsen K.B., Brech A., RA Overvatn A., Stenmark H., Bjorkoy G., Simonsen A., Johansen T.; RT "p62/SQSTM1 and ALFY interact to facilitate the formation of p62 RT bodies/ALIS and their degradation by autophagy."; RL Autophagy 6:330-344(2010). RN [42] RP INTERACTION WITH KEAP1. RX PubMed=20495340; DOI=10.4161/auto.6.5.12189; RA Fan W., Tang Z., Chen D., Moughon D., Ding X., Chen S., Zhu M., Zhong Q.; RT "Keap1 facilitates p62-mediated ubiquitin aggregate clearance via RT autophagy."; RL Autophagy 6:614-621(2010). RN [43] RP FUNCTION, INTERACTION WITH KEAP1, INDUCTION, AND MUTAGENESIS OF ASP-347; RP THR-350; GLY-351 AND GLU-352. RX PubMed=20452972; DOI=10.1074/jbc.m110.118976; RA Jain A., Lamark T., Sjoettem E., Larsen K.B., Awuh J.A., Oevervatn A., RA McMahon M., Hayes J.D., Johansen T.; RT "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a RT positive feedback loop by inducing antioxidant response element-driven gene RT transcription."; RL J. Biol. Chem. 285:22576-22591(2010). RN [44] RP INTERACTION WITH FHOD3. RX PubMed=21149568; DOI=10.1083/jcb.201005060; RA Iskratsch T., Lange S., Dwyer J., Kho A.L., dos Remedios C., Ehler E.; RT "Formin follows function: a muscle-specific isoform of FHOD3 is regulated RT by CK2 phosphorylation and promotes myofibril maintenance."; RL J. Cell Biol. 191:1159-1172(2010). RN [45] RP INTERACTION WITH TRIM5, AND SUBCELLULAR LOCATION. RX PubMed=20357094; DOI=10.1128/jvi.02412-09; RA O'Connor C., Pertel T., Gray S., Robia S.L., Bakowska J.C., Luban J., RA Campbell E.M.; RT "p62/sequestosome-1 associates with and sustains the expression of RT retroviral restriction factor TRIM5alpha."; RL J. Virol. 84:5997-6006(2010). RN [46] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; SER-207; SER-249; RP SER-266; SER-272 AND SER-332, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [47] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228; RP LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425. RX PubMed=22084127; DOI=10.1001/archneurol.2011.250; RA Fecto F., Yan J., Vemula S.P., Liu E., Yang Y., Chen W., Zheng J.G., RA Shi Y., Siddique N., Arrat H., Donkervoort S., Ajroud-Driss S., Sufit R.L., RA Heller S.L., Deng H.X., Siddique T.; RT "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."; RL Arch. Neurol. 68:1440-1446(2011). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [49] RP IDENTIFICATION IN A COMPLEX WITH ZFAND5 AND UBIQUITIN, AND SUBCELLULAR RP LOCATION. RX PubMed=21923101; DOI=10.1021/bi201137e; RA Garner T.P., Strachan J., Shedden E.C., Long J.E., Cavey J.R., Shaw B., RA Layfield R., Searle M.S.; RT "Independent interactions of ubiquitin-binding domains in a ubiquitin- RT mediated ternary complex."; RL Biochemistry 50:9076-9087(2011). RN [50] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-24; SER-207; RP THR-269; SER-272; SER-282; SER-332; SER-366 AND SER-403, AND MUTAGENESIS OF RP SER-403. RX PubMed=22017874; DOI=10.1016/j.molcel.2011.07.039; RA Matsumoto G., Wada K., Okuno M., Kurosawa M., Nukina N.; RT "Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic RT clearance of ubiquitinated proteins."; RL Mol. Cell 44:279-289(2011). RN [51] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-272, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [52] RP FUNCTION. RX PubMed=22622177; DOI=10.4161/auto.19381; RA Taillebourg E., Gregoire I., Viargues P., Jacomin A.C., Thevenon D., RA Faure M., Fauvarque M.O.; RT "The deubiquitinating enzyme USP36 controls selective autophagy activation RT by ubiquitinated proteins."; RL Autophagy 8:767-779(2012). RN [53] RP INTERACTION WITH TRIM13, AND SUBCELLULAR LOCATION. RX PubMed=22178386; DOI=10.1016/j.bbamcr.2011.11.015; RA Tomar D., Singh R., Singh A.K., Pandya C.D., Singh R.; RT "TRIM13 regulates ER stress induced autophagy and clonogenic ability of the RT cells."; RL Biochim. Biophys. Acta 1823:316-326(2012). RN [54] RP INTERACTION WITH MAP1LC3A. RX PubMed=22421968; DOI=10.1038/cdd.2012.30; RA Seillier M., Peuget S., Gayet O., Gauthier C., N'guessan P., Monte M., RA Carrier A., Iovanna J.L., Dusetti N.J.; RT "TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins RT through the LC3-interacting region (LIR) and promotes autophagy-dependent RT cell death."; RL Cell Death Differ. 19:1525-1535(2012). RN [55] RP INTERACTION WITH TRIM50, AND SUBCELLULAR LOCATION. RX PubMed=22792322; DOI=10.1371/journal.pone.0040440; RA Fusco C., Micale L., Egorov M., Monti M., D'Addetta E.V., Augello B., RA Cozzolino F., Calcagni A., Fontana A., Polishchuk R.S., Didelot G., RA Reymond A., Pucci P., Merla G.; RT "The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes RT the sequestration and clearance of ubiquitinated proteins into the RT aggresome."; RL PLoS ONE 7:E40440-E40440(2012). RN [56] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, ACETYLATION [LARGE SCALE RP ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS] RP (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [57] RP FUNCTION. RX PubMed=24128730; DOI=10.4161/auto.26085; RA Isakson P., Lystad A.H., Breen K., Koster G., Stenmark H., Simonsen A.; RT "TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody RT ring degradation by selective autophagy."; RL Autophagy 9:1955-1964(2013). RN [58] RP INTERACTION WITH SESN1 AND SESN2. RX PubMed=23274085; DOI=10.1016/j.cmet.2012.12.002; RA Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E., RA Kang D., Rhee S.G.; RT "Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation RT of Keap1 and prevent oxidative liver damage."; RL Cell Metab. 17:73-84(2013). RN [59] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [60] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; VAL-381; LEU-387 AND RP LEU-392. RX PubMed=24042580; DOI=10.1001/jamaneurol.2013.3849; RG French Clinical and Genetic Research Network on FTD/FTD-ALS; RA Le Ber I., Camuzat A., Guerreiro R., Bouya-Ahmed K., Bras J., Nicolas G., RA Gabelle A., Didic M., De Septenville A., Millecamps S., Lenglet T., RA Latouche M., Kabashi E., Campion D., Hannequin D., Hardy J., Brice A.; RT "SQSTM1 mutations in French patients with frontotemporal dementia or RT frontotemporal dementia with amyotrophic lateral sclerosis."; RL JAMA Neurol. 70:1403-1410(2013). RN [61] RP LIR MOTIF. RX PubMed=23908376; DOI=10.1242/jcs.126128; RA Birgisdottir A.B., Lamark T., Johansen T.; RT "The LIR motif - crucial for selective autophagy."; RL J. Cell Sci. 126:3237-3247(2013). RN [62] RP INTERACTION WITH MAP1LC3B. RX PubMed=24089205; DOI=10.1038/nature12606; RA Tang Z., Lin M.G., Stowe T.R., Chen S., Zhu M., Stearns T., Franco B., RA Zhong Q.; RT "Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar RT satellites."; RL Nature 502:254-257(2013). RN [63] RP FUNCTION, INTERACTION WITH TNS2 AND IRS1, AND DEVELOPMENTAL STAGE. RX PubMed=25101860; DOI=10.1016/j.cellsig.2014.07.033; RA Koh A., Park D., Jeong H., Lee J., Lee M.N., Suh P.G., Ryu S.H.; RT "Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated RT sequestration and degradation."; RL Cell. Signal. 26:2470-2480(2014). RN [64] RP INTERACTION WITH TRIM5. RX PubMed=25127057; DOI=10.1016/j.devcel.2014.06.013; RA Mandell M.A., Jain A., Arko-Mensah J., Chauhan S., Kimura T., Dinkins C., RA Silvestri G., Munch J., Kirchhoff F., Simonsen A., Wei Y., Levine B., RA Johansen T., Deretic V.; RT "TRIM proteins regulate autophagy and can target autophagic substrates by RT direct recognition."; RL Dev. Cell 30:394-409(2014). RN [65] RP INTERACTION WITH SESN2 AND ULK1, AND PHOSPHORYLATION AT SER-403 BY ULK1. RX PubMed=25040165; DOI=10.1111/febs.12905; RA Ro S.H., Semple I.A., Park H., Park H., Park H.W., Kim M., Kim J.S., RA Lee J.H.; RT "Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of RT p62/sequestosome-1."; RL FEBS J. 281:3816-3827(2014). RN [66] RP INTERACTION WITH GABARAP, AND MUTAGENESIS OF TRP-338. RX PubMed=24668264; DOI=10.1002/embr.201338003; RA Lystad A.H., Ichimura Y., Takagi K., Yang Y., Pankiv S., Kanegae Y., RA Kageyama S., Suzuki M., Saito I., Mizushima T., Komatsu M., Simonsen A.; RT "Structural determinants in GABARAP required for the selective binding and RT recruitment of ALFY to LC3B-positive structures."; RL EMBO Rep. 15:557-565(2014). RN [67] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-176; SER-233; SER-306 RP AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [68] RP INTERACTION WITH UBD. RX PubMed=25422469; DOI=10.1073/pnas.1403383111; RA Theng S.S., Wang W., Mah W.C., Chan C., Zhuo J., Gao Y., Qin H., Lim L., RA Chong S.S., Song J., Lee C.G.; RT "Disruption of FAT10-MAD2 binding inhibits tumor progression."; RL Proc. Natl. Acad. Sci. U.S.A. 111:E5282-E5291(2014). RN [69] RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH NU214. RX PubMed=20851865; DOI=10.3324/haematol.2010.029769; RA Gorello P., La Starza R., Di Giacomo D., Messina M., Puzzolo M.C., RA Crescenzi B., Santoro A., Chiaretti S., Mecucci C.; RT "SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic RT leukemia."; RL Haematologica 95:2161-2163(2010). RN [70] RP INVOLVEMENT IN FTDALS3, AND VARIANT FTDALS3 LYS-238 DEL. RX PubMed=25114083; DOI=10.3233/jad-141512; RA Boutoleau-Bretonniere C., Camuzat A., Le Ber I., Bouya-Ahmed K., RA Guerreiro R., Deruet A.L., Evrard C., Bras J., Lamy E., Auffray-Calvier E., RA Pallardy A., Hardy J., Brice A., Derkinderen P., Vercelletto M.; RT "A phenotype of atypical apraxia of speech in a family carrying SQSTM1 RT mutation."; RL J. Alzheimers Dis. 43:625-630(2015). RN [71] RP FUNCTION, AND INTERACTION WITH PEX5. RX PubMed=26344566; DOI=10.1038/ncb3230; RA Zhang J., Tripathi D.N., Jing J., Alexander A., Kim J., Powell R.T., RA Dere R., Tait-Mulder J., Lee J.H., Paull T.T., Pandita R.K., Charaka V.K., RA Pandita T.K., Kastan M.B., Walker C.L.; RT "ATM functions at the peroxisome to induce pexophagy in response to ROS."; RL Nat. Cell Biol. 17:1259-1269(2015). RN [72] RP INVOLVEMENT IN DMRV. RX PubMed=26208961; DOI=10.1212/wnl.0000000000001864; RA Bucelli R.C., Arhzaouy K., Pestronk A., Pittman S.K., Rojas L., Sue C.M., RA Evilae A., Hackman P., Udd B., Harms M.B., Weihl C.C.; RT "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."; RL Neurology 85:665-674(2015). RN [73] RP INVOLVEMENT IN NADGP. RX PubMed=27545679; DOI=10.1016/j.ajhg.2016.06.026; RA Haack T.B., Ignatius E., Calvo-Garrido J., Iuso A., Isohanni P., RA Maffezzini C., Loennqvist T., Suomalainen A., Gorza M., Kremer L.S., RA Graf E., Hartig M., Berutti R., Paucar M., Svenningsson P., Stranneheim H., RA Brandberg G., Wedell A., Kurian M.A., Hayflick S.A., Venco P., Tiranti V., RA Strom T.M., Dichgans M., Horvath R., Holinski-Feder E., Freyer C., RA Meitinger T., Prokisch H., Senderek J., Wredenberg A., Carroll C.J., RA Klopstock T.; RT "Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset RT neurodegeneration with ataxia, dystonia, and gaze palsy."; RL Am. J. Hum. Genet. 99:735-743(2016). RN [74] RP FUNCTION, AND UBIQUITINATION. RX PubMed=27368102; DOI=10.1016/j.cell.2016.05.078; RA Jongsma M.L., Berlin I., Wijdeven R.H., Janssen L., Janssen G.M., RA Garstka M.A., Janssen H., Mensink M., van Veelen P.A., Spaapen R.M., RA Neefjes J.; RT "An ER-associated pathway defines endosomal architecture for controlled RT cargo transport."; RL Cell 166:152-166(2016). RN [75] RP INTERACTION WITH TRIM11. RX PubMed=27498865; DOI=10.1016/j.celrep.2016.07.019; RA Liu T., Tang Q., Liu K., Xie W., Liu X., Wang H., Wang R.F., Cui J.; RT "TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent RT selective autophagy."; RL Cell Rep. 16:1988-2002(2016). RN [76] RP UBIQUITINATION, AND FUNCTION. RX PubMed=27880896; DOI=10.1016/j.celrep.2016.11.005; RA Heath R.J., Goel G., Baxt L.A., Rush J.S., Mohanan V., Paulus G.L.C., RA Jani V., Lassen K.G., Xavier R.J.; RT "RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial RT Autophagy."; RL Cell Rep. 17:2183-2194(2016). RN [77] RP FUNCTION, UBIQUITINATION AT LYS-420, AND MUTAGENESIS OF LYS-420. RX PubMed=28380357; DOI=10.1016/j.celrep.2017.03.030; RA Lee Y., Chou T.F., Pittman S.K., Keith A.L., Razani B., Weihl C.C.; RT "Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain RT ubiquitination."; RL Cell Rep. 19:188-202(2017). RN [78] RP DOMAIN, AND UBIQUITINATION. RX PubMed=28322253; DOI=10.1038/cr.2017.40; RA Peng H., Yang J., Li G., You Q., Han W., Li T., Gao D., Xie X., Lee B.H., RA Du J., Hou J., Zhang T., Rao H., Huang Y., Li Q., Zeng R., Hui L., Wang H., RA Xia Q., Zhang X., He Y., Komatsu M., Dikic I., Finley D., Hu R.; RT "Ubiquitylation of p62/sequestosome1 activates its autophagy receptor RT function and controls selective autophagy upon ubiquitin stress."; RL Cell Res. 27:657-674(2017). RN [79] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-435, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [80] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-403, MUTAGENESIS OF RP SER-403, AND CHARACTERIZATION OF VARIANTS PDB3 THR-404 AND SER-411. RX PubMed=29507397; DOI=10.1038/s41422-018-0017-7; RA Sun D., Wu R., Zheng J., Li P., Yu L.; RT "Polyubiquitin chain-induced p62 phase separation drives autophagic cargo RT segregation."; RL Cell Res. 28:405-415(2018). RN [81] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=29343546; DOI=10.15252/embj.201798308; RA Zaffagnini G., Savova A., Danieli A., Romanov J., Tremel S., Ebner M., RA Peterbauer T., Sztacho M., Trapannone R., Tarafder A.K., Sachse C., RA Martens S.; RT "p62 filaments capture and present ubiquitinated cargos for autophagy."; RL EMBO J. 37:0-0(2018). RN [82] RP INTERACTION WITH TRIM16. RX PubMed=30143514; DOI=10.15252/embj.201798358; RA Jena K.K., Kolapalli S.P., Mehto S., Nath P., Das B., Sahoo P.K., Ahad A., RA Syed G.H., Raghav S.K., Senapati S., Chauhan S., Chauhan S.; RT "TRIM16 controls assembly and degradation of protein aggregates by RT modulating the p62-NRF2 axis and autophagy."; RL EMBO J. 37:0-0(2018). RN [83] RP INTERACTION WITH LRRC25. RX PubMed=29288164; DOI=10.15252/embj.201796781; RA Du Y., Duan T., Feng Y., Liu Q., Lin M., Cui J., Wang R.F.; RT "LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I RT for autophagic degradation."; RL EMBO J. 37:351-366(2018). RN [84] RP FUNCTION, INTERACTION WITH WDR81, AND DOMAIN. RX PubMed=28404643; DOI=10.1083/jcb.201608039; RA Liu X., Li Y., Wang X., Xing R., Liu K., Gan Q., Tang C., Gao Z., Jian Y., RA Luo S., Guo W., Yang C.; RT "The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote RT aggrephagy."; RL J. Cell Biol. 216:1301-1320(2017). RN [85] RP INTERACTION WITH TRIM23. RX PubMed=28871090; DOI=10.1038/s41564-017-0017-2; RA Sparrer K.M.J., Gableske S., Zurenski M.A., Parker Z.M., Full F., RA Baumgart G.J., Kato J., Pacheco-Rodriguez G., Liang C., Pornillos O., RA Moss J., Vaughan M., Gack M.U.; RT "TRIM23 mediates virus-induced autophagy via activation of TBK1."; RL Nat. Microbiol. 2:1543-1557(2017). RN [86] RP FUNCTION, PHOSPHORYLATION AT SER-403, AND MUTAGENESIS OF SER-403. RX PubMed=29496741; DOI=10.15252/embj.201797858; RA Prabakaran T., Bodda C., Krapp C., Zhang B.C., Christensen M.H., Sun C., RA Reinert L., Cai Y., Jensen S.B., Skouboe M.K., Nyengaard J.R., RA Thompson C.B., Lebbink R.J., Sen G.C., van Loo G., Nielsen R., Komatsu M., RA Nejsum L.N., Jakobsen M.R., Gyrd-Hansen M., Paludan S.R.; RT "Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent RT autophagy pathway activated by TBK1."; RL EMBO J. 37:0-0(2018). RN [87] RP INTERACTION WITH USP12. RX PubMed=30266909; DOI=10.1038/s41467-018-05653-z; RA Aron R., Pellegrini P., Green E.W., Maddison D.C., Opoku-Nsiah K., RA Oliveira A.O., Wong J.S., Daub A.C., Giorgini F., Muchowski P., RA Finkbeiner S.; RT "Deubiquitinase Usp12 functions noncatalytically to induce autophagy and RT confer neuroprotection in models of Huntington's disease."; RL Nat. Commun. 9:3191-3191(2018). RN [88] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, ACETYLATION AT LYS-420 AND LYS-435, RP AND MUTAGENESIS OF LYS-420 AND LYS-435. RX PubMed=31857589; DOI=10.1038/s41467-019-13718-w; RA You Z., Jiang W.X., Qin L.Y., Gong Z., Wan W., Li J., Wang Y., Zhang H., RA Peng C., Zhou T., Tang C., Liu W.; RT "Requirement for p62 acetylation in the aggregation of ubiquitylated RT proteins under nutrient stress."; RL Nat. Commun. 10:5792-5792(2019). RN [89] RP INTERACTION WITH ECSIT. RX PubMed=31281713; DOI=10.4110/in.2019.19.e16; RA Kim M.J., Min Y., Kwon J., Son J., Im J.S., Shin J., Lee K.Y.; RT "p62 Negatively Regulates TLR4 Signaling via Functional Regulation of the RT TRAF6-ECSIT Complex."; RL Immune Netw. 19:e16-e16(2019). RN [90] RP INTERACTION WITH CYLD. RX PubMed=32185393; DOI=10.1093/brain/awaa039; RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G., RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T., RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K., RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A., RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M., RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N., RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P., RA Kwok J.B.; RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral RT sclerosis."; RL Brain 143:783-799(2020). RN [91] RP FUNCTION, AND INTERACTION WITH MOAP1. RX PubMed=33393215; DOI=10.15252/embr.202050854; RA Tan C.T., Chang H.C., Zhou Q., Yu C., Fu N.Y., Sabapathy K., Yu V.C.; RT "MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and RT suppresses Nrf2 signaling."; RL EMBO Rep. 22:e50854-e50854(2021). RN [92] RP FUNCTION, AND UBIQUITINATION AT LYS-435. RX PubMed=33472082; DOI=10.1016/j.celrep.2020.108659; RA Cremer T., Jongsma M.L.M., Trulsson F., Vertegaal A.C.O., Neefjes J., RA Berlin I.; RT "The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal RT control over the endolysosomal pathway."; RL Cell Rep. 34:108659-108659(2021). RN [93] RP FUNCTION, AND DEUBIQUITINATION BY EPSTEIN-BARR VIRUS PROTEIN BPLF1 RP (MICROBIAL INFECTION). RX PubMed=33509017; DOI=10.1080/15548627.2021.1874660; RA Ylae-Anttila P., Gupta S., Masucci M.G.; RT "The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit RT selective autophagy."; RL Autophagy 17:3461-3474(2021). RN [94] RP SUBCELLULAR LOCATION, INTERACTION WITH TAX1BP1, AND FUNCTION. RX PubMed=34471133; DOI=10.1038/s41467-021-25572-w; RA Turco E., Savova A., Gere F., Ferrari L., Romanov J., Schuschnig M., RA Martens S.; RT "Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin RT condensate formation and autophagy initiation."; RL Nat. Commun. 12:5212-5212(2021). RN [95] RP INTERACTION WITH ASB6. RX PubMed=34164402; DOI=10.3389/fcell.2021.684885; RA Gong L., Wang K., Wang M., Hu R., Li H., Gao D., Lin M.; RT "CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to RT Regulate Cell Proliferation and Autophagy."; RL Front. Cell Dev. Biol. 9:684885-684885(2021). RN [96] RP FUNCTION. RX PubMed=34893540; DOI=10.1073/pnas.2107993118; RA Heo A.J., Kim S.B., Ji C.H., Han D., Lee S.J., Lee S.H., Lee M.J., RA Lee J.S., Ciechanover A., Kim B.Y., Kwon Y.T.; RT "The N-terminal cysteine is a dual sensor of oxygen and oxidative stress."; RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021). RN [97] RP FUNCTION, AND INTERACTION WITH GRB2. RX PubMed=35831301; DOI=10.1038/s41420-022-01106-1; RA Hou B., Huang H., Li Y., Liang J., Xi Z., Jiang X., Liu L., Li E.; RT "Grb2 interacts with necrosome components and is involved in rasfonin- RT induced necroptosis."; RL Cell. Death. Discov. 8:319-319(2022). RN [98] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-349; SER-403 AND RP SER-407, AND MUTAGENESIS OF SER-349; THR-350 AND 403-SER--SER-407. RX PubMed=37306101; DOI=10.15252/embj.2022113349; RA Ikeda R., Noshiro D., Morishita H., Takada S., Kageyama S., Fujioka Y., RA Funakoshi T., Komatsu-Hirota S., Arai R., Ryzhii E., Abe M., Koga T., RA Motohashi H., Nakao M., Sakimura K., Horii A., Waguri S., Ichimura Y., RA Noda N.N., Komatsu M.; RT "Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox- RT independent stress response."; RL EMBO J. 42:e113349-e113349(2023). RN [99] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-289 AND CYS-290, AND RP MUTAGENESIS OF 289-CYS-CYS-290. RX PubMed=37802024; DOI=10.1016/j.molcel.2023.09.004; RA Huang X., Yao J., Liu L., Chen J., Mei L., Huangfu J., Luo D., Wang X., RA Lin C., Chen X., Yang Y., Ouyang S., Wei F., Wang Z., Zhang S., Xiang T., RA Neculai D., Sun Q., Kong E., Tate E.W., Yang A.; RT "S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in RT mammalian autophagy."; RL Mol. Cell 83:3485-3501(2023). RN [100] RP INTERACTION WITH WDR83. RX PubMed=38103557; DOI=10.1016/j.molcel.2023.11.023; RA Abudu Y.P., Kournoutis A., Brenne H.B., Lamark T., Johansen T.; RT "MORG1 limits mTORC1 signaling by inhibiting Rag GTPases."; RL Mol. Cell 0:0-0(2023). RN [101] RP STRUCTURE BY NMR OF 387-436, CHARACTERIZATION OF VARIANT LEU-392, AND RP DOMAIN. RX PubMed=12857745; DOI=10.1074/jbc.m307416200; RA Ciani B., Layfield R., Cavey J.R., Sheppard P.W., Searle M.S.; RT "Structure of the ubiquitin-associated domain of p62 (SQSTM1) and RT implications for mutations that cause Paget's disease of bone."; RL J. Biol. Chem. 278:37409-37412(2003). RN [102] RP STRUCTURE BY NMR OF 387-436, AND INTERACTION WITH UBIQUITIN. RX PubMed=18083707; DOI=10.1074/jbc.m704973200; RA Long J., Gallagher T.R., Cavey J.R., Sheppard P.W., Ralston S.H., RA Layfield R., Searle M.S.; RT "Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a RT novel conformational switch."; RL J. Biol. Chem. 283:5427-5440(2008). RN [103] RP STRUCTURE BY NMR OF 387-436. RX PubMed=17932931; DOI=10.1002/prot.21692; RA Evans C.L., Long J.E., Gallagher T.R., Hirst J.D., Searle M.S.; RT "Conformation and dynamics of the three-helix bundle UBA domain of p62 from RT experiment and simulation."; RL Proteins 71:227-240(2008). RN [104] RP STRUCTURE BY NMR OF 387-436, SUBUNIT, FUNCTION, MUTAGENESIS OF GLU-409 AND RP GLY-410, AND CHARACTERIZATION OF VARIANT PDB3 ARG-425. RX PubMed=19931284; DOI=10.1016/j.jmb.2009.11.032; RA Long J., Garner T.P., Pandya M.J., Craven C.J., Chen P., Shaw B., RA Williamson M.P., Layfield R., Searle M.S.; RT "Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and RT regulates NF-kappaB signalling."; RL J. Mol. Biol. 396:178-194(2010). RN [105] RP VARIANT PDB3 LEU-392, AND VARIANTS VAL-117 AND GLN-274. RX PubMed=11992264; DOI=10.1086/340731; RA Laurin N., Brown J.P., Morissette J., Raymond V.; RT "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in RT Paget disease of bone."; RL Am. J. Hum. Genet. 70:1582-1588(2002). RN [106] RP VARIANT PDB3 LEU-392. RX PubMed=12374763; DOI=10.1093/hmg/11.22.2735; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Mangion J., Olavesen M., RA Cundy T., Nicholson G.C., Ward L., Bennett S.T., Wuyts W., Van Hul W., RA Ralston S.H.; RT "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and RT sporadic Paget's disease."; RL Hum. Mol. Genet. 11:2735-2739(2002). RN [107] RP VARIANT PDB3 LEU-387. RX PubMed=14584883; DOI=10.1359/jbmr.2003.18.10.1748; RA Johnson-Pais T.L., Wisdom J.H., Weldon K.S., Cody J.D., Hansen M.F., RA Singer F.R., Leach R.J.; RT "Three novel mutations in SQSTM1 identified in familial Paget's disease of RT bone."; RL J. Bone Miner. Res. 18:1748-1753(2003). RN [108] RP VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425. RX PubMed=15146436; DOI=10.1002/art.20224; RA Eekhoff E.W.M., Karperien M., Houtsma D., Zwinderman A.H., Dragoiescu C., RA Kneppers A.L.J., Papapoulos S.E.; RT "Familial Paget's disease in The Netherlands: occurrence, identification of RT new mutations in the sequestosome 1 gene, and their clinical RT associations."; RL Arthritis Rheum. 50:1650-1654(2004). RN [109] RP VARIANT PDB3 LEU-392. RX PubMed=15207768; DOI=10.1016/j.bone.2004.01.010; RA Good D.A., Busfield F., Fletcher B.H., Lovelock P.K., Duffy D.L., RA Kesting J.B., Andersen J., Shaw J.T.E.; RT "Identification of SQSTM1 mutations in familial Paget's disease in RT Australian pedigrees."; RL Bone 35:277-282(2004). RN [110] RP VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425. RX PubMed=15125799; DOI=10.1359/jbmr.040203; RA Falchetti A., Di Stefano M., Marini F., Del Monte F., Mavilia C., RA Strigoli D., De Feo M.L., Isaia G., Masi L., Amedei A., Cioppi F., RA Ghinoi V., Maddali Bongi S., Di Fede G., Sferrazza C., Rini G.B., RA Melchiorre D., Matucci-Cerinic M., Brandi M.L.; RT "Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an RT Italian series of patients affected by Paget's disease of bone (PDB)."; RL J. Bone Miner. Res. 19:1013-1017(2004). RN [111] RP VARIANTS PDB3 VAL-404; SER-411 AND ARG-425, AND CHARACTERIZATION OF RP VARIANTS VAL-404; SER-411 AND ARG-425. RX PubMed=15176995; DOI=10.1359/jbmr.0403015; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Cundy T., Nicholson G.C., RA Donath J., Walsh J.P., Finlayson C., Cavey J.R., Ciani B., Sheppard P.W., RA Searle M.S., Layfield R., Ralston S.H.; RT "Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype RT phenotype correlation, functional analysis, and structural consequences."; RL J. Bone Miner. Res. 19:1122-1127(2004). RN [112] RP VARIANT GLU-238, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17488105; DOI=10.1021/pr0700908; RA Bunger M.K., Cargile B.J., Sevinsky J.R., Deyanova E., Yates N.A., RA Hendrickson R.C., Stephenson J.L. Jr.; RT "Detection and validation of non-synonymous coding SNPs from orthogonal RT analysis of shotgun proteomics data."; RL J. Proteome Res. 6:2331-2340(2007). RN [113] RP INVOLVEMENT IN FTDALS3, VARIANTS FTDALS3 VAL-16; VAL-33; GLU-80; MET-90; RP TRP-107; ASN-129; CYS-212; VAL-219; PRO-226; LEU-228; THR-232; LYS-238 DEL; RP ASN-258; CYS-321; GLY-329; LEU-348; LEU-387; LEU-392 AND PRO-430, AND RP VARIANTS VAL-17; ARG-103; GLN-107; TYR-108; HIS-110; VAL-117; SER-118; RP GLY-119; SER-125; CYS-139; ILE-153; LEU-180; HIS-217; GLU-238; RP 265-SER-ARG-266 DELINS SER-ARG; ASP-274; ILE-278; VAL-308; LYS-319; GLY-334 RP DEL; THR-349 AND LEU-439. RX PubMed=24899140; DOI=10.1007/s00401-014-1298-7; RA van der Zee J., Van Langenhove T., Kovacs G.G., Dillen L., Deschamps W., RA Engelborghs S., Matej R., Vandenbulcke M., Sieben A., Dermaut B., Smets K., RA Van Damme P., Merlin C., Laureys A., Van Den Broeck M., Mattheijssens M., RA Peeters K., Benussi L., Binetti G., Ghidoni R., Borroni B., Padovani A., RA Archetti S., Pastor P., Razquin C., Ortega-Cubero S., Hernandez I., RA Boada M., Ruiz A., de Mendonca A., Miltenberger-Miltenyi G., do Couto F.S., RA Sorbi S., Nacmias B., Bagnoli S., Graff C., Chiang H.H., Thonberg H., RA Perneczky R., Diehl-Schmid J., Alexopoulos P., Frisoni G.B., Bonvicini C., RA Synofzik M., Maetzler W., vom Hagen J.M., Schoels L., Haack T.B., RA Strom T.M., Prokisch H., Dols-Icardo O., Clarimon J., Lleo A., Santana I., RA Almeida M.R., Santiago B., Heneka M.T., Jessen F., Ramirez A., RA Sanchez-Valle R., Llado A., Gelpi E., Sarafov S., Tournev I., Jordanova A., RA Parobkova E., Fabrizi G.M., Testi S., Salmon E., Stroebel T., Santens P., RA Robberecht W., De Jonghe P., Martin J.J., Cras P., Vandenberghe R., RA De Deyn P.P., Cruts M., Sleegers K., Van Broeckhoven C.; RT "Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar RT degeneration."; RL Acta Neuropathol. 128:397-410(2014). CC -!- FUNCTION: Molecular adapter required for selective macroautophagy CC (aggrephagy) by acting as a bridge between polyubiquitinated proteins CC and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, CC PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, CC PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the CC recruitment of ubiquitinated cargo proteins to autophagosomes via CC multiple domains that bridge proteins and organelles in different steps CC (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, CC PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, CC PubMed:37802024). SQSTM1 first mediates the assembly and removal of CC ubiquitinated proteins by undergoing liquid-liquid phase separation CC upon binding to ubiquitinated proteins via its UBA domain, leading to CC the formation of insoluble cytoplasmic inclusions, known as p62 bodies CC (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, CC PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). CC SQSTM1 then interacts with ATG8 family proteins on autophagosomes via CC its LIR motif, leading to p62 body recruitment to autophagosomes, CC followed by autophagic clearance of ubiquitinated proteins CC (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself CC degraded along with its ubiquitinated cargos (PubMed:16286508, CC PubMed:17580304, PubMed:37802024). Also required to recruit CC ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). CC Also involved in autophagy of peroxisomes (pexophagy) in response to CC reactive oxygen species (ROS) by acting as a bridge between CC ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts CC as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: CC interaction inactivates the BCR(KEAP1) complex by sequestering the CC complex in inclusion bodies, promoting nuclear accumulation of CC NFE2L2/NRF2 and subsequent expression of cytoprotective genes CC (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). CC Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to CC autophagosomes (PubMed:29496741). Involved in endosome organization by CC retaining vesicles in the perinuclear cloud: following ubiquitination CC by RNF26, attracts specific vesicle-associated adapters, forming a CC molecular bridge that restrains cognate vesicles in the perinuclear CC region and organizes the endosomal pathway for efficient cargo CC transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 CC into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal CC degradation (PubMed:25101860). May regulate the activation of NFKB1 by CC TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, CC PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, CC PubMed:19931284). May play a role in titin/TTN downstream signaling in CC muscle cells (PubMed:15802564). Adapter that mediates the interaction CC between TRAF6 and CYLD (By similarity). {ECO:0000250|UniProtKB:Q64337, CC ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037, CC ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362, CC ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22622177, CC ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27368102, CC ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:28404643, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:33472082, CC ECO:0000269|PubMed:33509017, ECO:0000269|PubMed:34471133, CC ECO:0000269|PubMed:34893540, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. CC -!- SUBUNIT: Homooligomer or heterooligomer; may form homotypic arrays CC (PubMed:12887891, PubMed:19931284). Dimerization interferes with CC ubiquitin binding (PubMed:19931284). Component of a ternary complex CC with PAWR and PRKCZ (PubMed:11755531). Forms a complex with JUB/Ajuba, CC PRKCZ and TRAF6 (PubMed:15870274). Identified in a complex with TRAF6 CC and CYLD (By similarity). Identified in a heterotrimeric complex with CC ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the CC same ubiquitin molecule (PubMed:21923101). Interacts (via LIR motif) CC with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members, CC including GABARAP, GABARAPL1 and GABARAPL2; these interactions are CC necessary for the recruitment MAP1 LC3 family members to inclusion CC bodies containing polyubiquitinated protein aggregates and for their CC degradation by autophagy (PubMed:16286508, PubMed:17580304, CC PubMed:22421968, PubMed:24089205, PubMed:24668264). Interacts directly CC with PRKCI and PRKCZ (PubMed:10356400, PubMed:12813044, CC PubMed:12887891, PubMed:9566925). Interacts with EBI3, LCK, RASA1, CC NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5 (PubMed:10708586, CC PubMed:11244088, PubMed:12471037, PubMed:8551575, PubMed:8618896, CC PubMed:8650207, PubMed:8910285). Upon TNF stimulation, interacts with CC RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF- CC R1/TNFRSF1A, TRADD and RIPK1 (PubMed:10747026). Interacts with the CC proteasome subunits PSMD4 and PSMC2 (PubMed:15340068). Interacts with CC TRAF6 (PubMed:10747026). Interacts with 'Lys-63'-linked CC polyubiquitinated MAPT/TAU (PubMed:15953362). Interacts with FHOD3 CC (PubMed:21149568). Interacts with CYLD (PubMed:32185393). Interacts CC with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085, CC PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with CC UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct CC and regulates the interaction of SQSTM1 with ubiquitinated proteins CC (PubMed:28404643). Interacts with WDFY3; this interaction is required CC to recruit WDFY3 to cytoplasmic bodies and to PML bodies CC (PubMed:20168092). Interacts with LRRC25 (PubMed:29288164). Interacts CC with STING1; leading to relocalization of STING1 to autophagosomes CC (PubMed:29496741). Interacts (when phosphorylated at Ser-349) with CC KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex CC by sequestering KEAP1 in inclusion bodies, promoting its degradation CC (PubMed:20452972, PubMed:20495340, PubMed:37306101). Interacts with CC MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester CC KEAP1 (PubMed:33393215). Interacts with GBP1 (By similarity). Interacts CC with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5; CC specifically binds PEX5 ubiquitinated at 'Lys-209' in response to CC reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1 CC domain) with TNS2; the interaction leads to sequestration of TNS2 in CC cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and CC proteasomal degradation (PubMed:25101860). Interacts with IRS1; the CC interaction is disrupted by the presence of tensin TNS2 CC (PubMed:25101860). Interacts with TRIM5 (PubMed:20357094, CC PubMed:25127057). Interacts with TRIM11 (when ubiquitinated); promoting CC AIM2 recruitment to autophagosomes and autophagy-dependent degradation CC of AIM2 (PubMed:27498865). Interacts with TRIM13 (PubMed:22178386). CC Interacts with TRIM16 (PubMed:30143514). Interacts with TRIM23 CC (PubMed:28871090). Interacts with TRIM50 (PubMed:22792322). Interacts CC with TRIM55 (PubMed:15802564). Interacts with ECSIT; this interaction CC inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT CC complex (PubMed:31281713). Interacts with GABRR1, GABRR2 and GABRR3 (By CC similarity). Interacts with WDR83 (PubMed:38103557). Interacts with CC GRB2 (PubMed:35831301). Interacts with USP12; the interaction is CC independent of USP12 deubiquitinase activity and may be involved in CC regulation of autophagic flux (PubMed:30266909). Interacts with ASB6 CC (PubMed:34164402). {ECO:0000250|UniProtKB:O08623, CC ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400, CC ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:11755531, CC ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:12813044, CC ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15870274, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:20495340, CC ECO:0000269|PubMed:21149568, ECO:0000269|PubMed:21923101, CC ECO:0000269|PubMed:22178386, ECO:0000269|PubMed:22421968, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:23274085, CC ECO:0000269|PubMed:24089205, ECO:0000269|PubMed:24668264, CC ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:25127057, ECO:0000269|PubMed:25422469, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27498865, CC ECO:0000269|PubMed:28404643, ECO:0000269|PubMed:28871090, CC ECO:0000269|PubMed:29288164, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:30143514, ECO:0000269|PubMed:30266909, CC ECO:0000269|PubMed:31281713, ECO:0000269|PubMed:32185393, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:34164402, CC ECO:0000269|PubMed:34471133, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:38103557, CC ECO:0000269|PubMed:8551575, ECO:0000269|PubMed:8618896, CC ECO:0000269|PubMed:8650207, ECO:0000269|PubMed:8910285, CC ECO:0000269|PubMed:9566925}. CC -!- INTERACTION: CC Q13501; P05067: APP; NbExp=6; IntAct=EBI-307104, EBI-77613; CC Q13501; P54253: ATXN1; NbExp=4; IntAct=EBI-307104, EBI-930964; CC Q13501; O95817: BAG3; NbExp=3; IntAct=EBI-307104, EBI-747185; CC Q13501; Q16543: CDC37; NbExp=8; IntAct=EBI-307104, EBI-295634; CC Q13501; P57739: CLDN2; NbExp=4; IntAct=EBI-307104, EBI-751440; CC Q13501; P34972: CNR2; NbExp=5; IntAct=EBI-307104, EBI-2835940; CC Q13501; Q15038: DAZAP2; NbExp=4; IntAct=EBI-307104, EBI-724310; CC Q13501; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-307104, EBI-25840445; CC Q13501; O14682: ENC1; NbExp=7; IntAct=EBI-307104, EBI-6425462; CC Q13501; Q2V2M9: FHOD3; NbExp=6; IntAct=EBI-307104, EBI-6395541; CC Q13501; Q2V2M9-4: FHOD3; NbExp=4; IntAct=EBI-307104, EBI-6395505; CC Q13501; O95166: GABARAP; NbExp=17; IntAct=EBI-307104, EBI-712001; CC Q13501; Q9H0R8: GABARAPL1; NbExp=18; IntAct=EBI-307104, EBI-746969; CC Q13501; P60520: GABARAPL2; NbExp=25; IntAct=EBI-307104, EBI-720116; CC Q13501; P0DMV8: HSPA1A; NbExp=3; IntAct=EBI-307104, EBI-11052499; CC Q13501; P42858: HTT; NbExp=11; IntAct=EBI-307104, EBI-466029; CC Q13501; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-307104, EBI-81279; CC Q13501; Q14145: KEAP1; NbExp=21; IntAct=EBI-307104, EBI-751001; CC Q13501; Q5S007: LRRK2; NbExp=18; IntAct=EBI-307104, EBI-5323863; CC Q13501; Q9UDY8: MALT1; NbExp=2; IntAct=EBI-307104, EBI-1047372; CC Q13501; Q9H492: MAP1LC3A; NbExp=16; IntAct=EBI-307104, EBI-720768; CC Q13501; Q9GZQ8: MAP1LC3B; NbExp=31; IntAct=EBI-307104, EBI-373144; CC Q13501; Q9BXW4: MAP1LC3C; NbExp=8; IntAct=EBI-307104, EBI-2603996; CC Q13501; Q13163: MAP2K5; NbExp=5; IntAct=EBI-307104, EBI-307294; CC Q13501; Q14596: NBR1; NbExp=7; IntAct=EBI-307104, EBI-742698; CC Q13501; Q9BPW8: NIPSNAP1; NbExp=3; IntAct=EBI-307104, EBI-307125; CC Q13501; P04629: NTRK1; NbExp=2; IntAct=EBI-307104, EBI-1028226; CC Q13501; Q96CV9: OPTN; NbExp=7; IntAct=EBI-307104, EBI-748974; CC Q13501; P50542-3: PEX5; NbExp=2; IntAct=EBI-307104, EBI-12181987; CC Q13501; Q9UGJ0: PRKAG2; NbExp=3; IntAct=EBI-307104, EBI-2959705; CC Q13501; P41743: PRKCI; NbExp=11; IntAct=EBI-307104, EBI-286199; CC Q13501; Q12923: PTPN13; NbExp=2; IntAct=EBI-307104, EBI-355227; CC Q13501; P54725: RAD23A; NbExp=3; IntAct=EBI-307104, EBI-746453; CC Q13501; P58004: SESN2; NbExp=9; IntAct=EBI-307104, EBI-3939642; CC Q13501; Q96B97: SH3KBP1; NbExp=4; IntAct=EBI-307104, EBI-346595; CC Q13501; P84022: SMAD3; NbExp=3; IntAct=EBI-307104, EBI-347161; CC Q13501; P37840: SNCA; NbExp=3; IntAct=EBI-307104, EBI-985879; CC Q13501; Q13501: SQSTM1; NbExp=10; IntAct=EBI-307104, EBI-307104; CC Q13501; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-307104, EBI-357085; CC Q13501; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-307104, EBI-359276; CC Q13501; P07437: TUBB; NbExp=4; IntAct=EBI-307104, EBI-350864; CC Q13501; P0CG48: UBC; NbExp=5; IntAct=EBI-307104, EBI-3390054; CC Q13501; P11473: VDR; NbExp=4; IntAct=EBI-307104, EBI-286357; CC Q13501; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-307104, EBI-11141397; CC Q13501; Q8IZQ1: WDFY3; NbExp=7; IntAct=EBI-307104, EBI-1569256; CC Q13501; P19544-6: WT1; NbExp=3; IntAct=EBI-307104, EBI-11745701; CC Q13501; P17028: ZNF24; NbExp=3; IntAct=EBI-307104, EBI-707773; CC Q13501; A8K2U6; NbExp=3; IntAct=EBI-307104, EBI-25877771; CC Q13501; P38182: ATG8; Xeno; NbExp=3; IntAct=EBI-307104, EBI-2684; CC Q13501; Q9Z2X8: Keap1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-647110; CC Q13501; P12709: PGI1; Xeno; NbExp=3; IntAct=EBI-307104, EBI-7238; CC Q13501; P28700: Rxra; Xeno; NbExp=3; IntAct=EBI-307104, EBI-346715; CC Q13501; O70405: Ulk1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-8390771; CC Q13501; P12504: vif; Xeno; NbExp=2; IntAct=EBI-307104, EBI-779991; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, autophagosome CC {ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:20168092, CC ECO:0000269|PubMed:37802024}. Preautophagosomal structure CC {ECO:0000269|PubMed:34471133}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:11786419, ECO:0000269|PubMed:11981755, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:21923101, ECO:0000269|PubMed:22017874, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:29343546, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. Nucleus, PML CC body {ECO:0000269|PubMed:20168092}. Late endosome CC {ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:9566925}. Lysosome CC {ECO:0000269|PubMed:9566925}. Nucleus {ECO:0000269|PubMed:10708586}. CC Endoplasmic reticulum {ECO:0000269|PubMed:22178386}. Cytoplasm, CC myofibril, sarcomere {ECO:0000250|UniProtKB:O08623}. Note=In cardiac CC muscle, localizes to the sarcomeric band (By similarity). Localizes to CC cytoplasmic membraneless inclusion bodies, known as p62 bodies, CC containing polyubiquitinated protein aggregates (PubMed:11786419, CC PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:37306101, PubMed:37802024). In CC neurodegenerative diseases, detected in Lewy bodies in Parkinson CC disease, neurofibrillary tangles in Alzheimer disease, and HTT CC aggregates in Huntington disease (PubMed:15158159). In protein CC aggregate diseases of the liver, found in large amounts in Mallory CC bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in CC hepatocellular carcinoma, and in SERPINA1 aggregates (PubMed:11981755). CC Enriched in Rosenthal fibers of pilocytic astrocytoma CC (PubMed:11786419). In the cytoplasm, observed in both membrane-free CC ubiquitin-containing protein aggregates (sequestosomes) and membrane- CC surrounded autophagosomes (PubMed:15953362, PubMed:17580304). CC Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum CC (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies CC (PubMed:20357094). When nuclear export is blocked by treatment with CC leptomycin B, accumulates in PML bodies (PubMed:20168092). CC {ECO:0000250|UniProtKB:O08623, ECO:0000269|PubMed:11786419, CC ECO:0000269|PubMed:11981755, ECO:0000269|PubMed:15158159, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:17580304, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22178386, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29507397, CC ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:37306101, CC ECO:0000269|PubMed:37802024}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13501-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13501-2; Sequence=VSP_015841; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {ECO:0000269|PubMed:8650207}. CC -!- DEVELOPMENTAL STAGE: During myogenesis, there is a marked increase in CC levels in fully differentiated myotubes compared to undifferentiated CC myoblasts. {ECO:0000269|PubMed:25101860}. CC -!- INDUCTION: By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at CC protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is CC directly activated by NFE2L2/NRF2; creating a positive feedback loop CC (PubMed:20452972). {ECO:0000269|PubMed:12700667, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:9762895}. CC -!- DOMAIN: The UBA domain binds specifically 'Lys-63'-linked polyubiquitin CC chains of polyubiquitinated substrates (PubMed:12857745, CC PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the CC interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains CC are necessary and sufficient for the localization into the ubiquitin- CC containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12857745, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28322253, CC ECO:0000269|PubMed:31857589}. CC -!- DOMAIN: The PB1 domain mediates homooligomerization and interactions CC with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044, CC PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and CC UBA domains are necessary and sufficient for the localization into the CC ubiquitin-containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12813044, ECO:0000269|PubMed:12887891, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28404643}. CC -!- DOMAIN: The ZZ-type zinc finger mediates the interaction with RIPK1. CC {ECO:0000269|PubMed:10747026}. CC -!- DOMAIN: The LIR (LC3-interacting region) motif mediates the interaction CC with ATG8 family proteins. {ECO:0000269|PubMed:23908376}. CC -!- PTM: Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer CC interface and increases binding affinity to ubiquitinated proteins (By CC similarity). Phosphorylation at Ser-407 also primes for subsequent CC phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 CC by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing CC the affinity between the UBA domain and polyubiquitin chains CC (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1 CC is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by CC TBK1, leading to promote relocalization of 'Lys-63'-linked CC ubiquitinated STING1 to autophagosomes (PubMed:29496741). CC Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and CC inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear CC accumulation and expression of phase II detoxifying enzymes CC (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564). CC {ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:25040165, CC ECO:0000269|PubMed:29496741, ECO:0000269|PubMed:37306101}. CC -!- PTM: Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 CC attracts specific vesicle-associated adapters, forming a molecular CC bridge that restrains cognate vesicles in the perinuclear region and CC organizes the endosomal pathway for efficient cargo transport CC (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 CC increases its ability to bind polyubiquitin chains by destabilizing the CC UBA dimer interface (PubMed:28322253). Deubiquitination by USP15 CC releases target vesicles for fast transport into the cell periphery CC (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, CC increasing SQSTM1 sequestering activity and promoting its degradation CC (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked CC polyubiquitination leading to xenophagic targeting of bacteria and CC inhibition of their replication (PubMed:27880896). CC {ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:27880896, CC ECO:0000269|PubMed:28322253, ECO:0000269|PubMed:28380357, CC ECO:0000269|PubMed:33472082}. CC -!- PTM: Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity CC by destabilizing the UBA dimer interface and increases binding affinity CC to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 CC (PubMed:31857589). {ECO:0000269|PubMed:31857589}. CC -!- PTM: Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for CC efficient autophagic degradation of SQSTM1-cargo complexes by promoting CC affinity for ATG8 proteins and recruitment of p62 bodies to CC autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 CC by LYPLA1 (PubMed:37802024). {ECO:0000269|PubMed:37802024}. CC -!- PTM: (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading CC to its degradation (PubMed:24331465). Degradation by SpeB prevents CC autophagy, promoting to S.pyogenes intracellular replication CC (PubMed:24331465). {ECO:0000269|PubMed:24331465}. CC -!- PTM: (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; CC leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1- CC positive structures. {ECO:0000269|PubMed:33509017}. CC -!- DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of CC bone remodeling characterized by increased bone turnover affecting one CC or more sites throughout the skeleton, primarily the axial skeleton. CC Osteoclastic overactivity followed by compensatory osteoblastic CC activity leads to a structurally disorganized mosaic of bone (woven CC bone), which is mechanically weaker, larger, less compact, more CC vascular, and more susceptible to fracture than normal adult lamellar CC bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, CC ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, CC ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, CC ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:29507397}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=In a cell model for Huntington disease (HD), appears to CC form a shell surrounding aggregates of mutant HTT that may protect CC cells from apoptosis, possibly by recruiting autophagosomal components CC to the polyubiquitinated protein aggregates. CC {ECO:0000269|PubMed:16286508}. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 CC (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by CC frontotemporal dementia and/or amyotrophic lateral sclerosis in CC affected individuals. There is high intrafamilial variation. CC Frontotemporal dementia is characterized by frontal and temporal lobe CC atrophy associated with neuronal loss, gliosis, and dementia. Patients CC exhibit progressive changes in social, behavioral, and/or language CC function. Amyotrophic lateral sclerosis is characterized by the death CC of motor neurons in the brain, brainstem, and spinal cord, resulting in CC fatal paralysis. Some FTDALS3 patients may also develop Paget disease CC of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, CC ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy, CC childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder CC characterized by gait abnormalities, ataxia, dysarthria, dystonia, CC vertical gaze palsy, and cognitive decline. Disease onset is in CC childhood or adolescence. NADGP transmission pattern is consistent with CC autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An CC autosomal dominant myopathy with adult onset, characterized by muscle CC weakness of the distal upper and lower limbs, walking difficulties, and CC proximal weakness of the shoulder girdle muscles. Muscle biopsy shows CC rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=A chromosomal aberration involving SQSTM1 is found in a CC form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) CC with NUP214. {ECO:0000269|PubMed:20851865}. 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; U41806; AAA93299.1; -; mRNA. DR EMBL; U46751; AAC52070.1; -; mRNA. DR EMBL; AK098077; BAG53577.1; -; mRNA. DR EMBL; AK312451; BAG35358.1; -; mRNA. DR EMBL; AC008393; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000951; AAH00951.1; -; mRNA. DR EMBL; BC001874; AAH01874.1; -; mRNA. DR EMBL; BC003139; AAH03139.1; -; mRNA. DR EMBL; BC017222; AAH17222.1; -; mRNA. DR EMBL; BC019111; AAH19111.1; -; mRNA. DR EMBL; AF060494; AAC64516.1; -; Genomic_DNA. DR CCDS; CCDS34317.1; -. [Q13501-1] DR CCDS; CCDS47355.1; -. [Q13501-2] DR RefSeq; NP_001135770.1; NM_001142298.2. [Q13501-2] DR RefSeq; NP_001135771.1; NM_001142299.2. [Q13501-2] DR RefSeq; NP_003891.1; NM_003900.5. [Q13501-1] DR PDB; 1Q02; NMR; -; A=387-436. DR PDB; 2JY7; NMR; -; A=387-436. DR PDB; 2JY8; NMR; -; A=387-436. DR PDB; 2K0B; NMR; -; X=387-436. DR PDB; 2KNV; NMR; -; A/B=387-436. DR PDB; 4MJS; X-ray; 2.50 A; B/D/F/H/J/L/N/P/R/T/V/X=3-102. DR PDB; 4UF8; EM; 10.90 A; A/B/C/I=3-102. DR PDB; 4UF9; EM; 10.30 A; A/B/D=1-122. DR PDB; 5YP7; X-ray; 1.42 A; A/D=126-180. DR PDB; 5YP8; X-ray; 1.45 A; A/B=126-180. DR PDB; 5YPA; X-ray; 2.50 A; A/B=126-180. DR PDB; 5YPB; X-ray; 2.90 A; A/B/C/D=126-180. DR PDB; 5YPC; X-ray; 1.96 A; A/B/C/D=126-180. DR PDB; 5YPE; X-ray; 2.85 A; A/B/C/D=126-180. DR PDB; 5YPF; X-ray; 2.95 A; A/B/C/D=126-180. DR PDB; 5YPG; X-ray; 2.20 A; A/B=126-180. DR PDB; 5YPH; X-ray; 1.63 A; A/B=126-180. DR PDB; 6JM4; X-ray; 3.20 A; A/B/C/D=1-102. DR PDB; 6KHZ; X-ray; 2.80 A; A/B/C/D=125-169. DR PDB; 6MIU; X-ray; 1.90 A; A/B=120-171. DR PDB; 6MJ7; X-ray; 1.41 A; A=120-171. DR PDB; 6TGY; EM; 3.50 A; A=1-122. DR PDB; 6TH3; EM; 4.00 A; A/B/C=1-122. DR PDB; 7R1O; X-ray; 2.20 A; AAA/BBB/CCC/DDD=120-172. DR PDBsum; 1Q02; -. DR PDBsum; 2JY7; -. DR PDBsum; 2JY8; -. DR PDBsum; 2K0B; -. DR PDBsum; 2KNV; -. DR PDBsum; 4MJS; -. DR PDBsum; 4UF8; -. DR PDBsum; 4UF9; -. DR PDBsum; 5YP7; -. DR PDBsum; 5YP8; -. DR PDBsum; 5YPA; -. DR PDBsum; 5YPB; -. DR PDBsum; 5YPC; -. DR PDBsum; 5YPE; -. DR PDBsum; 5YPF; -. DR PDBsum; 5YPG; -. DR PDBsum; 5YPH; -. DR PDBsum; 6JM4; -. DR PDBsum; 6KHZ; -. DR PDBsum; 6MIU; -. DR PDBsum; 6MJ7; -. DR PDBsum; 6TGY; -. DR PDBsum; 6TH3; -. DR PDBsum; 7R1O; -. DR AlphaFoldDB; Q13501; -. DR BMRB; Q13501; -. DR EMDB; EMD-10501; -. DR EMDB; EMD-10502; -. DR EMDB; EMD-2936; -. DR EMDB; EMD-2937; -. DR SMR; Q13501; -. DR BioGRID; 114397; 1356. DR CORUM; Q13501; -. DR DIP; DIP-34443N; -. DR ELM; Q13501; -. DR FunCoup; Q13501; 2230. DR IntAct; Q13501; 311. DR MINT; Q13501; -. DR STRING; 9606.ENSP00000374455; -. DR BindingDB; Q13501; -. DR ChEMBL; CHEMBL4295816; -. DR GuidetoPHARMACOLOGY; 3213; -. DR MoonDB; Q13501; Predicted. DR GlyGen; Q13501; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13501; -. DR PhosphoSitePlus; Q13501; -. DR SwissPalm; Q13501; -. DR BioMuta; SQSTM1; -. DR DMDM; 74735628; -. DR jPOST; Q13501; -. DR MassIVE; Q13501; -. DR PaxDb; 9606-ENSP00000374455; -. DR PeptideAtlas; Q13501; -. DR ProteomicsDB; 59496; -. [Q13501-1] DR ProteomicsDB; 59497; -. [Q13501-2] DR Pumba; Q13501; -. DR Antibodypedia; 761; 1362 antibodies from 49 providers. DR DNASU; 8878; -. DR YCharOS; Q13501; Tested 18 antibodies from 6 manufacturers. DR Ensembl; ENST00000360718.5; ENSP00000353944.5; ENSG00000161011.21. [Q13501-2] DR Ensembl; ENST00000389805.9; ENSP00000374455.4; ENSG00000161011.21. [Q13501-1] DR Ensembl; ENST00000640444.2; ENSP00000491834.2; ENSG00000284099.3. [Q13501-1] DR Ensembl; ENST00000643389.2; ENSP00000495843.2; ENSG00000284099.3. [Q13501-1] DR GeneID; 8878; -. DR KEGG; hsa:8878; -. DR MANE-Select; ENST00000389805.9; ENSP00000374455.4; NM_003900.5; NP_003891.1. DR UCSC; uc003mkw.5; human. [Q13501-1] DR AGR; HGNC:11280; -. DR ClinPGx; PA36109; -. DR CTD; 8878; -. DR DisGeNET; 8878; -. DR GeneCards; SQSTM1; -. DR HGNC; HGNC:11280; SQSTM1. DR HPA; ENSG00000161011; Tissue enhanced (skeletal). DR MalaCards; SQSTM1; -. DR MIM; 167250; phenotype. DR MIM; 601530; gene. DR MIM; 616437; phenotype. DR MIM; 617145; phenotype. DR MIM; 617158; phenotype. DR OpenTargets; ENSG00000161011; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 603; Distal myopathy, Welander type. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR VEuPathDB; HostDB:ENSG00000161011; -. DR eggNOG; KOG4582; Eukaryota. DR GeneTree; ENSGT00390000002781; -. DR HOGENOM; CLU_038011_1_0_1; -. DR InParanoid; Q13501; -. DR OMA; NCNGWLT; -. DR OrthoDB; 441278at2759; -. DR PAN-GO; Q13501; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13501; -. DR PathwayCommons; Q13501; -. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes. DR Reactome; R-HSA-209560; NF-kB is activated and signals survival. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-9664873; Pexophagy. DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2. DR SignaLink; Q13501; -. DR SIGNOR; Q13501; -. DR Agora; ENSG00000161011; -. DR BioGRID-ORCS; 8878; 28 hits in 1166 CRISPR screens. DR CD-CODE; 1822EB5E; Synthetic Condensate 000092. DR CD-CODE; 5D6181E1; Synthetic Condensate 000293. DR CD-CODE; 718A9EC3; P62 body. DR CD-CODE; 98C8800A; Synthetic Condensate 000338. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; EF6CBD8C; Synthetic Condensate 000070. DR CD-CODE; F17BA747; P62 cluster. DR CD-CODE; F5639AB0; Synthetic Condensate 000096. DR ChiTaRS; SQSTM1; human. DR EvolutionaryTrace; Q13501; -. DR GeneWiki; Sequestosome_1; -. DR GenomeRNAi; 8878; -. DR Pharos; Q13501; Tbio. DR PRO; PR:Q13501; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q13501; protein. DR Bgee; ENSG00000161011; Expressed in right adrenal gland cortex and 177 other cell types or tissues. DR ExpressionAtlas; Q13501; baseline and differential. DR GO; GO:0016235; C:aggresome; IBA:GO_Central. DR GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL. DR GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0005776; C:autophagosome; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0043232; C:intracellular membraneless organelle; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell. DR GO; GO:0097413; C:Lewy body; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0000932; C:P-body; IDA:UniProtKB. DR GO; GO:0000407; C:phagophore assembly site; IEA:UniProtKB-SubCell. DR GO; GO:0016605; C:PML body; IDA:UniProtKB. DR GO; GO:0030017; C:sarcomere; IEA:UniProtKB-SubCell. DR GO; GO:0097225; C:sperm midpiece; IEA:Ensembl. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0035255; F:ionotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:UniProtKB. DR GO; GO:0140313; F:molecular sequestering activity; IDA:UniProt. DR GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB. DR GO; GO:0005080; F:protein kinase C binding; IPI:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; TAS:ProtInc. DR GO; GO:0042169; F:SH2 domain binding; IDA:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; IDA:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IDA:UniProt. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0035973; P:aggrephagy; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0006914; P:autophagy; IDA:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0070342; P:brown fat cell proliferation; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0033554; P:cellular response to stress; IDA:UniProt. DR GO; GO:0016197; P:endosomal transport; TAS:UniProtKB. DR GO; GO:0007032; P:endosome organization; IDA:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; IEA:Ensembl. DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW. DR GO; GO:0008104; P:intracellular protein localization; TAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IDA:UniProtKB. DR GO; GO:0140694; P:membraneless organelle assembly; IDA:UniProtKB. DR GO; GO:0000423; P:mitophagy; IGI:ParkinsonsUK-UCL. DR GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0000425; P:pexophagy; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt. DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:ARUK-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; TAS:UniProtKB. DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:1905719; P:protein localization to perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0071211; P:protein targeting to vacuole involved in autophagy; IDA:UniProtKB. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0010821; P:regulation of mitochondrion organization; NAS:ParkinsonsUK-UCL. DR GO; GO:0061635; P:regulation of protein complex stability; IDA:UniProtKB. DR GO; GO:0046578; P:regulation of Ras protein signal transduction; NAS:UniProtKB. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0098780; P:response to mitochondrial depolarisation; IGI:ParkinsonsUK-UCL. DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc. DR CDD; cd06402; PB1_p62; 1. DR CDD; cd14320; UBA_SQSTM; 1. DR CDD; cd02340; ZZ_NBR1_like; 1. DR DisProt; DP01111; -. DR FunFam; 1.10.8.10:FF:000034; Sequestosome 1; 1. DR FunFam; 3.10.20.90:FF:000169; Sequestosome 1; 1. DR FunFam; 3.30.60.90:FF:000012; Sequestosome 1; 1. DR Gene3D; 3.30.60.90; -; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00383; -. DR InterPro; IPR052260; Autophagy_Rcpt_SigReg. DR InterPro; IPR053793; PB1-like. DR InterPro; IPR000270; PB1_dom. DR InterPro; IPR034866; PB1_p62. DR InterPro; IPR033741; SQSTM_UBA. DR InterPro; IPR015940; UBA. DR InterPro; IPR009060; UBA-like_sf. DR InterPro; IPR000433; Znf_ZZ. DR InterPro; IPR043145; Znf_ZZ_sf. DR PANTHER; PTHR15090; SEQUESTOSOME 1-RELATED; 1. DR PANTHER; PTHR15090:SF0; SEQUESTOSOME-1; 1. DR Pfam; PF00564; PB1; 1. DR Pfam; PF16577; UBA_5; 1. DR Pfam; PF00569; ZZ; 1. DR SMART; SM00666; PB1; 1. DR SMART; SM00165; UBA; 1. DR SMART; SM00291; ZnF_ZZ; 1. DR SUPFAM; SSF54277; CAD & PB1 domains; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR PROSITE; PS51745; PB1; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS01357; ZF_ZZ_1; 1. DR PROSITE; PS50135; ZF_ZZ_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; KW Amyotrophic lateral sclerosis; Apoptosis; Autophagy; Cytoplasm; KW Cytoplasmic vesicle; Differentiation; Direct protein sequencing; KW Disease variant; Endoplasmic reticulum; Endosome; Immunity; KW Isopeptide bond; Lipoprotein; Lysosome; Metal-binding; Neurodegeneration; KW Nucleus; Palmitate; Phosphoprotein; Proteomics identification; KW Reference proteome; Ubl conjugation; Zinc; Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT CHAIN 2..440 FT /note="Sequestosome-1" FT /id="PRO_0000072176" FT DOMAIN 3..102 FT /note="PB1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01081" FT DOMAIN 389..434 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT ZN_FING 123..173 FT /note="ZZ-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT REGION 2..50 FT /note="Interaction with LCK" FT /evidence="ECO:0000269|PubMed:8650207" FT REGION 43..107 FT /note="Interaction with PRKCZ and dimerization" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 50..80 FT /note="Interaction with PAWR" FT /evidence="ECO:0000269|PubMed:11755531" FT REGION 122..224 FT /note="Interaction with GABRR3" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 170..220 FT /note="LIM protein-binding (LB)" FT REGION 196..235 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 264..390 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 269..440 FT /note="Interaction with NTRK1" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 321..342 FT /note="MAP1LC3B-binding" FT /evidence="ECO:0000269|PubMed:17580304" FT REGION 347..352 FT /note="Interaction with KEAP1" FT /evidence="ECO:0000269|PubMed:20452972" FT MOTIF 228..233 FT /note="TRAF6-binding" FT MOTIF 336..341 FT /note="LIR" FT COMPBIAS 283..296 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 310..324 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 337..347 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 351..373 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 128 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 131 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 142 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 145 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 151 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 154 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 160 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 163 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT SITE 252..253 FT /note="Breakpoint for translocation to form the NUP214- FT SQSTM1 fusion protein" FT /evidence="ECO:0000269|PubMed:20851865" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:24275569" FT MOD_RES 148 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 170 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 176 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 207 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:20068231" FT MOD_RES 233 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 249 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 266 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 269 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163" FT MOD_RES 272 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 282 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874" FT MOD_RES 306 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 328 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 332 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 349 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 355 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 361 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 365 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q64337" FT MOD_RES 366 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 403 FT /note="Phosphoserine; by CK2, ULK1 and TBK1" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:29496741, FT ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:37306101" FT MOD_RES 407 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 420 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT MOD_RES 435 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT LIPID 289 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT LIPID 290 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT CROSSLNK 91 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 189 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 420 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:28380357" FT CROSSLNK 435 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000269|PubMed:33472082, FT ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..84 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015841" FT VARIANT 16 FT /note="A -> V (in FTDALS3; dbSNP:rs1554162295)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073899" FT VARIANT 17 FT /note="A -> V (in dbSNP:rs141502868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073900" FT VARIANT 33 FT /note="A -> V (in FTDALS3; dbSNP:rs200396166)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_073901" FT VARIANT 80 FT /note="D -> E (in FTDALS3; dbSNP:rs148366738)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073902" FT VARIANT 90 FT /note="V -> M (in FTDALS3; dbSNP:rs181263868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073903" FT VARIANT 103 FT /note="K -> R (in dbSNP:rs748170760)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073904" FT VARIANT 107 FT /note="R -> Q" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073905" FT VARIANT 107 FT /note="R -> W (in FTDALS3; dbSNP:rs771903158)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073906" FT VARIANT 108 FT /note="D -> Y" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073907" FT VARIANT 110 FT /note="R -> H (in dbSNP:rs1267306593)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073908" FT VARIANT 117 FT /note="A -> V (in dbSNP:rs147810437)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:24899140" FT /id="VAR_023590" FT VARIANT 118 FT /note="P -> S (in dbSNP:rs200152247)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073909" FT VARIANT 119 FT /note="R -> G (in dbSNP:rs548787835)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073910" FT VARIANT 125 FT /note="N -> S (in dbSNP:rs769325755)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073911" FT VARIANT 129 FT /note="D -> N (in FTDALS3; dbSNP:rs753212399)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073912" FT VARIANT 139 FT /note="R -> C (in dbSNP:rs750256905)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073913" FT VARIANT 153 FT /note="V -> I (in FTDALS3; dbSNP:rs145056421)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073914" FT VARIANT 180 FT /note="S -> L (in dbSNP:rs1582008478)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073915" FT VARIANT 212 FT /note="R -> C (in FTDALS3; dbSNP:rs201263163)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073916" FT VARIANT 217 FT /note="R -> H (in dbSNP:rs761822261)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073917" FT VARIANT 219 FT /note="G -> V (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073918" FT VARIANT 226 FT /note="S -> P (in FTDALS3; dbSNP:rs765200636)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073919" FT VARIANT 228 FT /note="P -> L (in FTDALS3; dbSNP:rs151191977)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073920" FT VARIANT 232 FT /note="P -> T (in FTDALS3; dbSNP:rs1225746517)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073921" FT VARIANT 238 FT /note="K -> E (confirmed at protein level; FT dbSNP:rs11548633)" FT /evidence="ECO:0000269|PubMed:17488105, FT ECO:0000269|PubMed:24899140" FT /id="VAR_068915" FT VARIANT 238 FT /note="Missing (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083" FT /id="VAR_073922" FT VARIANT 258 FT /note="D -> N (in FTDALS3; dbSNP:rs774986849)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073923" FT VARIANT 265..266 FT /note="RS -> SR" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073924" FT VARIANT 274 FT /note="E -> D (in dbSNP:rs55793208)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_061707" FT VARIANT 274 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:11992264" FT /id="VAR_023591" FT VARIANT 278 FT /note="T -> I (in dbSNP:rs200445838)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073925" FT VARIANT 308 FT /note="A -> V (in dbSNP:rs541356917)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073926" FT VARIANT 318 FT /note="S -> P (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073927" FT VARIANT 319 FT /note="E -> K (in dbSNP:rs61748794)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073928" FT VARIANT 321 FT /note="R -> C (in FTDALS3; likely benign; FT dbSNP:rs140226523)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073929" FT VARIANT 329 FT /note="D -> G (in FTDALS3; dbSNP:rs148294622)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073930" FT VARIANT 334 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073931" FT VARIANT 348 FT /note="P -> L (in FTDALS3; dbSNP:rs772889843)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073932" FT VARIANT 349 FT /note="S -> T (in dbSNP:rs774512680)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073933" FT VARIANT 370 FT /note="S -> P (in FTDALS3; dbSNP:rs143956614)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073934" FT VARIANT 381 FT /note="A -> V (in FTDALS3; dbSNP:rs772122047)" FT /evidence="ECO:0000269|PubMed:24042580" FT /id="VAR_073935" FT VARIANT 387 FT /note="P -> L (in PDB3 and FTDALS3; dbSNP:rs776749939)" FT /evidence="ECO:0000269|PubMed:14584883, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023592" FT VARIANT 392 FT /note="P -> L (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; dbSNP:rs104893941)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:12857745, FT ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023593" FT VARIANT 399 FT /note="S -> P (in PDB3; dbSNP:rs1561609625)" FT /evidence="ECO:0000269|PubMed:15146436" FT /id="VAR_023594" FT VARIANT 404 FT /note="M -> T (in PDB3; decreased ability to undergo FT liquid-liquid phase separation and formation of p62 body; FT dbSNP:rs1247551175)" FT /evidence="ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:29507397" FT /id="VAR_023595" FT VARIANT 404 FT /note="M -> V (in PDB3; loss of polyubiquitin-binding; FT dbSNP:rs771966860)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15176995" FT /id="VAR_023596" FT VARIANT 411 FT /note="G -> S (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; decreased ability to undergo liquid- FT liquid phase separation and formation of p62 body; FT dbSNP:rs143511494)" FT /evidence="ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:29507397" FT /id="VAR_023597" FT VARIANT 425 FT /note="G -> R (in PDB3 and FTDALS3; loss of polyubiquitin- FT binding and increased activation of NF-kappa-B; FT dbSNP:rs757212984)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:22084127" FT /id="VAR_023598" FT VARIANT 430 FT /note="T -> P (in FTDALS3; dbSNP:rs770118706)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073936" FT VARIANT 439 FT /note="P -> L (in dbSNP:rs199854262)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073937" FT MUTAGEN 7 FT /note="K->A: Loss of interactions with PRKCZ, PRCKI and FT NBR1. Loss of dimerization; when associated with A-69." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 9 FT /note="Y->F: No effect on interaction with LCK." FT /evidence="ECO:0000269|PubMed:8650207" FT MUTAGEN 13 FT /note="K->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 21..22 FT /note="RR->AA: Loss of interaction with PRKCI. Alters FT dimerization." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 67 FT /note="Y->A: No effect on interaction with PRKCZ." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 69 FT /note="D->A: No effect on interactions with PRKCZ, PRKCI FT and NBR1. Loss of localization in cytoplasmic inclusion FT bodies. Loss of dimerization; when associated with A-7." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:16286508" FT MUTAGEN 71 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 73 FT /note="D->A: No effect on interactions with PRKCZ and FT PRKCI." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 80 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 82 FT /note="E->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 289..290 FT /note="CC->SS: Abolished palmitoylation." FT /evidence="ECO:0000269|PubMed:37802024" FT MUTAGEN 323..324 FT /note="EE->AA: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 332 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 335..337 FT /note="DDD->ADA: 75% decrease in MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 338 FT /note="W->A: Strong decrease in MAP1LC3B-binding, disrupts FT interaction with GABARAP." FT /evidence="ECO:0000269|PubMed:17580304, FT ECO:0000269|PubMed:24668264" FT MUTAGEN 342 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 347 FT /note="D->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 349 FT /note="S->A: Impaired phosphorylation by ULK1, leading to FT decreased p62 body formation." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 350 FT /note="T->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972, FT ECO:0000269|PubMed:37306101" FT MUTAGEN 351 FT /note="G->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 352 FT /note="E->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 398 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 403..407 FT /note="SMGFS->EMGFE: Mimics phosphorylation; increased FT phosphorylation at S-349." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 403 FT /note="S->A: Abolished phosphorylation by CK2, leading to FT decreased affinity for ubiquitinated proteins. Abolished FT ability to promote relocalization of 'Lys-63'-linked FT ubiquitinated STING1 to autophagosomes." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29496741" FT MUTAGEN 403 FT /note="S->E: Mimmics phosphorylation; increased affinity FT for ubiquitinated proteins, leading to increased p62 body FT formation and autophagic degradation." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29507397" FT MUTAGEN 406 FT /note="F->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 409 FT /note="E->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 410 FT /note="G->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 413 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 417 FT /note="L->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 420 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-435." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 420 FT /note="K->R: Decreased ubiquitination by the BCR(KEAP1) FT complex, leading to decreased sequestering activity. FT Strongly reduced acetylation; when associated with R-435." FT /evidence="ECO:0000269|PubMed:28380357, FT ECO:0000269|PubMed:31857589" FT MUTAGEN 431 FT /note="I->V: Partial loss of polyubiquitin-binding. Loss of FT localization to cytoplasmic inclusion bodies." FT /evidence="ECO:0000269|PubMed:15340068, FT ECO:0000269|PubMed:16286508" FT MUTAGEN 435 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-420." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 435 FT /note="K->R: Strongly reduced acetylation; when associated FT with R-420." FT /evidence="ECO:0000269|PubMed:31857589" FT CONFLICT 321 FT /note="R -> A (in Ref. 1; AAA93299)" FT /evidence="ECO:0000305" FT STRAND 5..10 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 13..15 FT /evidence="ECO:0007829|PDB:6TGY" FT STRAND 19..24 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 36..39 FT /evidence="ECO:0007829|PDB:6TGY" FT HELIX 43..54 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 62..64 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 74..76 FT /evidence="ECO:0007829|PDB:4MJS" FT HELIX 80..88 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 92..101 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 129..131 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:6KHZ" FT STRAND 139..147 FT /evidence="ECO:0007829|PDB:6MJ7" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 157..162 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 165..168 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 392..402 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:2JY7" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 412..419 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 420..422 FT /evidence="ECO:0007829|PDB:1Q02" FT HELIX 424..431 FT /evidence="ECO:0007829|PDB:1Q02" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:2JY8" FT INIT_MET Q13501-2:1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q13501-2:2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" SQ SEQUENCE 440 AA; 47687 MW; 462D94C171F337CD CRC64; MASLTVKAYL LGKEDAAREI RRFSFCCSPE PEAEAEAAAG PGPCERLLSR VAALFPALRP GGFQAHYRDE DGDLVAFSSD EELTMAMSYV KDDIFRIYIK EKKECRRDHR PPCAQEAPRN MVHPNVICDG CNGPVVGTRY KCSVCPDYDL CSVCEGKGLH RGHTKLAFPS PFGHLSEGFS HSRWLRKVKH GHFGWPGWEM GPPGNWSPRP PRAGEARPGP TAESASGPSE DPSVNFLKNV GESVAAALSP LGIEVDIDVE HGGKRSRLTP VSPESSSTEE KSSSQPSSCC SDPSKPGGNV EGATQSLAEQ MRKIALESEG RPEEQMESDN CSGGDDDWTH LSSKEVDPST GELQSLQMPE SEGPSSLDPS QEGPTGLKEA ALYPHLPPEA DPRLIESLSQ MLSMGFSDEG GWLTRLLQTK NYDIGAALDT IQYSKHPPPL // ID SYUA_HUMAN Reviewed; 140 AA. AC P37840; A8K2A4; Q13701; Q4JHI3; Q6IAU6; DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1994, sequence version 1. DT 28-JAN-2026, entry version 259. DE RecName: Full=Alpha-synuclein; DE AltName: Full=Non-A beta component of AD amyloid; DE AltName: Full=Non-A4 component of amyloid precursor; DE Short=NACP; GN Name=SNCA; Synonyms=NACP, PARK1; 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 PROTEIN SEQUENCE OF 61-95. RC TISSUE=Brain; RX PubMed=8248242; DOI=10.1073/pnas.90.23.11282; RA Ueda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M., RA Otero D.A., Kondo J., Ihara Y., Saitoh T.; RT "Molecular cloning of cDNA encoding an unrecognized component of amyloid in RT Alzheimer disease."; RL Proc. Natl. Acad. Sci. U.S.A. 90:11282-11286(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2-4 AND 2-5). RX PubMed=7601450; DOI=10.1016/0888-7543(95)80208-4; RA Campion D., Martin C., Heilig R., Charbonnier F., Moreau V., Flaman J.-M., RA Petit J.-L., Hannequin D., Brice A., Frebourg T.; RT "The NACP/synuclein gene: chromosomal assignment and screening for RT alterations in Alzheimer disease."; RL Genomics 26:254-257(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2-4). RC TISSUE=Brain; RX PubMed=7802671; DOI=10.1006/bbrc.1994.2816; RA Ueda K., Saitoh T., Mori H.; RT "Tissue-dependent alternative splicing of mRNA for NACP, the precursor of RT non-A beta component of Alzheimer's disease amyloid."; RL Biochem. Biophys. Res. Commun. 205:1366-1372(1994). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Xia Y., Silva R.D., Chen X.H., Saitoh T.; RL Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2-4). RX PubMed=11156617; DOI=10.1101/gr.165801; RA Touchman J.W., Dehejia A., Chiba-Falek O., Cabin D.E., Schwartz J.R., RA Orrison B.M., Polymeropoulos M.H., Nussbaum R.L.; RT "Human and mouse alpha-synuclein genes: comparative genomic sequence RT analysis and identification of a novel gene regulatory element."; RL Genome Res. 11:78-86(2001). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Hu X., Xu Y., Peng X., Yuan J., Qiang B.; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP PROTEIN SEQUENCE OF 59-96, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [13] RP TISSUE SPECIFICITY. RX PubMed=8194594; DOI=10.1016/0014-5793(94)00395-5; RA Jakes R., Spillantini M.G., Goedert M.; RT "Identification of two distinct synucleins from human brain."; RL FEBS Lett. 345:27-32(1994). RN [14] RP PHOSPHORYLATION AT SER-87 AND SER-129 BY CK1 AND CK2. RX PubMed=10617630; DOI=10.1074/jbc.275.1.390; RA Okochi M., Walter J., Koyama A., Nakajo S., Baba M., Iwatsubo T., RA Meijer L., Kahle P.J., Haass C.; RT "Constitutive phosphorylation of the Parkinson's disease associated alpha- RT synuclein."; RL J. Biol. Chem. 275:390-397(2000). RN [15] RP PHOSPHORYLATION BY G-PROTEIN COUPLED RECEPTOR KINASE. RX PubMed=10852916; DOI=10.1074/jbc.m003542200; RA Pronin A.N., Morris A.J., Surguchov A., Benovic J.L.; RT "Synucleins are a novel class of substrates for G protein-coupled receptor RT kinases."; RL J. Biol. Chem. 275:26515-26522(2000). RN [16] RP PHOSPHORYLATION AT TYR-125 BY FYN. RX PubMed=11162638; DOI=10.1006/bbrc.2000.4253; RA Nakamura T., Yamashita H., Takahashi T., Nakamura S.; RT "Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125."; RL Biochem. Biophys. Res. Commun. 280:1085-1092(2001). RN [17] RP INTERACTION WITH PHOSPHOLIPASE D. RX PubMed=11821392; DOI=10.1074/jbc.m110414200; RA Ahn B.H., Rhim H., Kim S.Y., Sung Y.M., Lee M.Y., Choi J.Y., Wolozin B., RA Chang J.S., Lee Y.H., Kwon T.K., Chung K.C., Yoon S.H., Hahn S.J., RA Kim M.S., Jo Y.H., Min do S.; RT "Alpha-synuclein interacts with phospholipase D isozymes and inhibits RT pervanadate-induced phospholipase D activation in human embryonic kidney- RT 293 cells."; RL J. Biol. Chem. 277:12334-12342(2002). RN [18] RP PHOSPHORYLATION AT SER-129. RX PubMed=11813001; DOI=10.1038/ncb748; RA Fujiwara H., Hasegawa M., Dohmae N., Kawashima A., Masliah E., RA Goldberg M.S., Shen J., Takio K., Iwatsubo T.; RT "alpha-Synuclein is phosphorylated in synucleinopathy lesions."; RL Nat. Cell Biol. 4:160-164(2002). RN [19] RP INTERACTION WITH HISTONES, AND SUBCELLULAR LOCATION. RX PubMed=12859192; DOI=10.1021/bi0341152; RA Goers J., Manning-Bog A.B., McCormack A.L., Millett I.S., Doniach S., RA Di Monte D.A., Uversky V.N., Fink A.L.; RT "Nuclear localization of alpha-synuclein and its interaction with RT histones."; RL Biochemistry 42:8465-8471(2003). RN [20] RP ROLE OF THE C-TERMINUS IN FIBRILLOGENESIS. RX PubMed=12859200; DOI=10.1021/bi027363r; RA Murray I.V., Giasson B.I., Quinn S.M., Koppaka V., Axelsen P.H., RA Ischiropoulos H., Trojanowski J.Q., Lee V.M.; RT "Role of alpha-synuclein carboxy-terminus on fibril formation in vitro."; RL Biochemistry 42:8530-8540(2003). RN [21] RP REVIEW. RX PubMed=12558071; DOI=10.2174/1566524033361690; RA Alves da Costa C.; RT "Recent advances on alpha-synuclein cell biology: functions and RT dysfunctions."; RL Curr. Mol. Med. 3:17-24(2003). RN [22] RP MUTAGENESIS OF TYR-39; TYR-125; TYR-133 AND TYR-136, CHARACTERIZATION OF RP VARIANT THR-53, AND PHOSPHORYLATION AT TYR-125. RX PubMed=12893833; DOI=10.1074/jbc.m213217200; RA Takahashi T., Yamashita H., Nagano Y., Nakamura T., Ohmori H., Avraham H., RA Avraham S., Yasuda M., Matsumoto M.; RT "Identification and characterization of a novel Pyk2/related adhesion focal RT tyrosine kinase-associated protein that inhibits alpha-synuclein RT phosphorylation."; RL J. Biol. Chem. 278:42225-42233(2003). RN [23] RP INTERACTION WITH RPH3A AND RAB3A. RX PubMed=15207266; DOI=10.1016/j.nbd.2004.01.001; RA Dalfo E., Barrachina M., Rosa J.L., Ambrosio S., Ferrer I.; RT "Abnormal alpha-synuclein interactions with rab3a and rabphilin in diffuse RT Lewy body disease."; RL Neurobiol. Dis. 16:92-97(2004). RN [24] RP SUBCELLULAR LOCATION. RX PubMed=15282274; DOI=10.1523/jneurosci.1594-04.2004; RA Fortin D.L., Troyer M.D., Nakamura K., Kubo S., Anthony M.D., Edwards R.H.; RT "Lipid rafts mediate the synaptic localization of alpha-synuclein."; RL J. Neurosci. 24:6715-6723(2004). RN [25] RP FIBRILS FORMATION, DOMAIN NAC, AND MUTAGENESIS OF 67-GLY--VAL-71; RP 71-VAL--VAL-82; 76-ALA-VAL-77; VAL-77; ALA-78 AND 85-ALA--PHE-94. RX PubMed=19722699; DOI=10.1021/bi900539p; RA Waxman E.A., Mazzulli J.R., Giasson B.I.; RT "Characterization of hydrophobic residue requirements for alpha-synuclein RT fibrillization."; RL Biochemistry 48:9427-9436(2009). RN [26] RP FUNCTION, AND INTERACTION WITH VAMP2 AND SNAP25. RX PubMed=20798282; DOI=10.1126/science.1195227; RA Burre J., Sharma M., Tsetsenis T., Buchman V., Etherton M.R., Suedhof T.C.; RT "Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro."; RL Science 329:1663-1667(2010). RN [27] 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 [28] RP COPPER-BINDING, AND MUTAGENESIS OF ASP-2 AND HIS-50. RX PubMed=21319811; DOI=10.1021/bi101912q; RA Dudzik C.G., Walter E.D., Millhauser G.L.; RT "Coordination features and affinity of the Cu(2)+ site in the alpha- RT synuclein protein of Parkinson's disease."; RL Biochemistry 50:1771-1777(2011). RN [29] RP SUBUNIT. RX PubMed=21841800; DOI=10.1038/nature10324; RA Bartels T., Choi J.G., Selkoe D.J.; RT "alpha-Synuclein occurs physiologically as a helically folded tetramer that RT resists aggregation."; RL Nature 477:107-110(2011). RN [30] RP INTERACTION WITH SERF1A. RX PubMed=22854022; DOI=10.1016/j.celrep.2012.06.012; RA Falsone S.F., Meyer N.H., Schrank E., Leitinger G., Pham C.L., RA Fodero-Tavoletti M.T., Holmberg M., Dulle M., Scicluna B., Gesslbauer B., RA Rueckert H.M., Wagner G.E., Merle D.A., Nollen E.A., Kungl A.J., Hill A.F., RA Cappai R., Zangger K.; RT "SERF protein is a direct modifier of amyloid fiber assembly."; RL Cell Rep. 2:358-371(2012). RN [31] RP ACETYLATION AT MET-1. RX PubMed=22407793; DOI=10.1002/pro.2056; RA Trexler A.J., Rhoades E.; RT "N-Terminal acetylation is critical for forming alpha-helical oligomer of RT alpha-synuclein."; RL Protein Sci. 21:601-605(2012). RN [32] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SLC6A3. RX PubMed=26442590; DOI=10.1074/jbc.m115.691592; RA Butler B., Saha K., Rana T., Becker J.P., Sambo D., Davari P., RA Goodwin J.S., Khoshbouei H.; RT "Dopamine Transporter Activity Is Modulated by alpha-Synuclein."; RL J. Biol. Chem. 290:29542-29554(2015). RN [33] RP INTERACTION WITH STXBP1, AND SUBCELLULAR LOCATION. RX PubMed=27597756; DOI=10.1083/jcb.201512016; RA Chai Y.J., Sierecki E., Tomatis V.M., Gormal R.S., Giles N., Morrow I.C., RA Xia D., Goetz J., Parton R.G., Collins B.M., Gambin Y., Meunier F.A.; RT "Munc18-1 is a molecular chaperone for alpha-synuclein, controlling its RT self-replicating aggregation."; RL J. Cell Biol. 214:705-718(2016). RN [34] RP FUNCTION. RX PubMed=28288128; DOI=10.1038/nn.4529; RA Logan T., Bendor J., Toupin C., Thorn K., Edwards R.H.; RT "alpha-Synuclein promotes dilation of the exocytotic fusion pore."; RL Nat. Neurosci. 20:681-689(2017). RN [35] RP FUNCTION. RX PubMed=30404828; DOI=10.1242/jcs.213017; RA Huang C.C., Chiu T.Y., Lee T.Y., Hsieh H.J., Lin C.C., Kao L.S.; RT "Soluble alpha-synuclein facilitates priming and fusion by releasing Ca2+ RT from the thapsigargin-sensitive Ca2+ pool in PC12 cells."; RL J. Cell Sci. 131:0-0(2018). RN [36] RP INTERACTION WITH DDX10, AND SUBCELLULAR LOCATION. RX PubMed=33657088; DOI=10.1371/journal.pgen.1009407; RA Popova B., Wang D., Paetz C., Akkermann D., Lazaro D.F., Galka D., RA Kolog Gulko M., Bohnsack M.T., Moebius W., Bohnsack K.E., Outeiro T.F., RA Braus G.H.; RT "DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of alpha-synuclein RT toxicity and oligomerization."; RL PLoS Genet. 17:e1009407-e1009407(2021). RN [37] RP INTERACTION WITH SERF1A, AND SUBCELLULAR LOCATION. RX PubMed=31034892; DOI=10.1016/j.jmb.2019.04.031; RA Merle D.A., Witternigg A., Tam-Amersdorfer C., Hartlmueller C., RA Spreitzer E., Schrank E., Wagner-Lichtenegger S., Werzer O., Zangger K., RA Kungl A.J., Madl T., Meyer N.H., Falsone S.F.; RT "Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered RT Protein Complex."; RL J. Mol. Biol. 431:2581-2598(2019). RN [38] RP STRUCTURE BY NMR IN COMPLEX WITH DETERGENT MICELLES. RX PubMed=15615727; DOI=10.1074/jbc.m411805200; RA Ulmer T.S., Bax A., Cole N.B., Nussbaum R.L.; RT "Structure and dynamics of micelle-bound human alpha-synuclein."; RL J. Biol. Chem. 280:9595-9603(2005). RN [39] RP STRUCTURE BY NMR OF 1-12, INTERACTION WITH SNCAIP, AND SUBCELLULAR RP LOCATION. RX PubMed=19762560; DOI=10.1096/fj.09-133082; RA Xie Y.Y., Zhou C.J., Zhou Z.R., Hong J., Che M.X., Fu Q.S., Song A.X., RA Lin D.H., Hu H.Y.; RT "Interaction with synphilin-1 promotes inclusion formation of alpha- RT synuclein: mechanistic insights and pathological implication."; RL FASEB J. 24:196-205(2010). RN [40] RP X-RAY CRYSTALLOGRAPHY (1.30 ANGSTROMS) OF 1-57 AND 58-79. RX PubMed=21462277; DOI=10.1002/pro.630; RA Zhao M., Cascio D., Sawaya M.R., Eisenberg D.; RT "Structures of segments of alpha-synuclein fused to maltose-binding protein RT suggest intermediate states during amyloid formation."; RL Protein Sci. 20:996-1004(2011). RN [41] RP STRUCTURE BY NMR OF 1-19, AND INTERACTION WITH CALM1. RX PubMed=23607618; DOI=10.1021/bi400199p; RA Gruschus J.M., Yap T.L., Pistolesi S., Maltsev A.S., Lee J.C.; RT "NMR structure of calmodulin complexed to an N-terminally acetylated alpha- RT synuclein peptide."; RL Biochemistry 52:3436-3445(2013). RN [42] RP STRUCTURE BY ELECTRON MICROSCOPY (1.41 ANGSTROMS) OF 47-56 AND 68-78. RX PubMed=26352473; DOI=10.1038/nature15368; RA Rodriguez J.A., Ivanova M.I., Sawaya M.R., Cascio D., Reyes F.E., Shi D., RA Sangwan S., Guenther E.L., Johnson L.M., Zhang M., Jiang L., Arbing M.A., RA Nannenga B.L., Hattne J., Whitelegge J., Brewster A.S., Messerschmidt M., RA Boutet S., Sauter N.K., Gonen T., Eisenberg D.S.; RT "Structure of the toxic core of alpha-synuclein from invisible crystals."; RL Nature 525:486-490(2015). RN [43] RP STRUCTURE BY NMR. RX PubMed=27018801; DOI=10.1038/nsmb.3194; RA Tuttle M.D., Comellas G., Nieuwkoop A.J., Covell D.J., Berthold D.A., RA Kloepper K.D., Courtney J.M., Kim J.K., Barclay A.M., Kendall A., Wan W., RA Stubbs G., Schwieters C.D., Lee V.M., George J.M., Rienstra C.M.; RT "Solid-state NMR structure of a pathogenic fibril of full-length human RT alpha-synuclein."; RL Nat. Struct. Mol. Biol. 23:409-415(2016). RN [44] RP STRUCTURE BY ELECTRON MICROSCOPY (3.50 ANGSTROMS). RX PubMed=30190461; DOI=10.1038/s41467-018-05971-2; RA Li B., Ge P., Murray K.A., Sheth P., Zhang M., Nair G., Sawaya M.R., RA Shin W.S., Boyer D.R., Ye S., Eisenberg D.S., Zhou Z.H., Jiang L.; RT "Cryo-EM of full-length alpha-synuclein reveals fibril polymorphs with a RT common structural kernel."; RL Nat. Commun. 9:3609-3609(2018). RN [45] RP VARIANT PARK1 THR-53. RX PubMed=9197268; DOI=10.1126/science.276.5321.2045; RA Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A., Dutra A., RA Pike B., Root H., Rubenstein J., Boyer R., Stenroos E.S., RA Chandrasekharappa S., Athanassiadou A., Papapetropoulos T., Johnson W.G., RA Lazzarini A.M., Duvoisin R.C., di Iorio G., Golbe L.I., Nussbaum R.L.; RT "Mutation in the alpha-synuclein gene identified in families with RT Parkinson's disease."; RL Science 276:2045-2047(1997). RN [46] RP VARIANT PARK1 PRO-30. RX PubMed=9462735; DOI=10.1038/ng0298-106; RA Krueger R., Kuhn W., Mueller T., Woitalla D., Graeber M., Koesel S., RA Przuntek H., Epplen J.T., Schoels L., Riess O.; RT "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's RT disease."; RL Nat. Genet. 18:106-108(1998). RN [47] RP VARIANT PARK1/DLB LYS-46. RX PubMed=14755719; DOI=10.1002/ana.10795; RA Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R., RA Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B., Llorens V., RA Gomez Tortosa E., del Ser T., Munoz D.G., de Yebenes J.G.; RT "The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body RT dementia."; RL Ann. Neurol. 55:164-173(2004). RN [48] RP CHARACTERIZATION OF VARIANT LYS-46. RX PubMed=15498564; DOI=10.1016/j.febslet.2004.09.038; RA Choi W., Zibaee S., Jakes R., Serpell L.C., Davletov B., Crowther R.A., RA Goedert M.; RT "Mutation E46K increases phospholipid binding and assembly into filaments RT of human alpha-synuclein."; RL FEBS Lett. 576:363-368(2004). RN [49] RP VARIANT PARK1 GLN-50. RX PubMed=23457019; DOI=10.1002/mds.25421; RA Appel-Cresswell S., Vilarino-Guell C., Encarnacion M., Sherman H., Yu I., RA Shah B., Weir D., Thompson C., Szu-Tu C., Trinh J., Aasly J.O., Rajput A., RA Rajput A.H., Jon Stoessl A., Farrer M.J.; RT "Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's RT disease."; RL Mov. Disord. 28:811-813(2013). RN [50] RP VARIANT PARK1 GLN-50, AND CHARACTERIZATION OF VARIANT PARK1 GLN-50. RX PubMed=23427326; DOI=10.1212/wnl.0b013e31828727ba; RA Proukakis C., Dudzik C.G., Brier T., MacKay D.S., Cooper J.M., RA Millhauser G.L., Houlden H., Schapira A.H.; RT "A novel alpha-synuclein missense mutation in Parkinson disease."; RL Neurology 80:1062-1064(2013). RN [51] RP CHARACTERIZATION OF VARIANT PARK1 GLN-50, SUBCELLULAR LOCATION, SUBUNIT, RP AND PHOSPHORYLATION AT SER-129. RX PubMed=24936070; DOI=10.1074/jbc.m114.553297; RA Khalaf O., Fauvet B., Oueslati A., Dikiy I., Mahul-Mellier A.L., RA Ruggeri F.S., Mbefo M.K., Vercruysse F., Dietler G., Lee S.J., Eliezer D., RA Lashuel H.A.; RT "The H50Q mutation enhances alpha-synuclein aggregation, secretion, and RT toxicity."; RL J. Biol. Chem. 289:21856-21876(2014). RN [52] RP CHARACTERIZATION OF VARIANTS PARK1 PRO-30; LYS-46; GLN-50 AND THR-53, RP MUTAGENESIS OF GLU-35 AND GLU-57, SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=25561023; DOI=10.1021/cn500332w; RA Tsigelny I.F., Sharikov Y., Kouznetsova V.L., Greenberg J.P., Wrasidlo W., RA Overk C., Gonzalez T., Trejo M., Spencer B., Kosberg K., Masliah E.; RT "Molecular determinants of alpha-synuclein mutants' oligomerization and RT membrane interactions."; RL ACS Chem. Neurosci. 6:403-416(2015). CC -!- FUNCTION: Neuronal protein that plays several roles in synaptic CC activity such as regulation of synaptic vesicle trafficking and CC subsequent neurotransmitter release (PubMed:20798282, PubMed:26442590, CC PubMed:28288128, PubMed:30404828). Participates as a monomer in CC synaptic vesicle exocytosis by enhancing vesicle priming, fusion and CC dilation of exocytotic fusion pores (PubMed:28288128, PubMed:30404828). CC Mechanistically, acts by increasing local Ca(2+) release from CC microdomains which is essential for the enhancement of ATP-induced CC exocytosis (PubMed:30404828). Also acts as a molecular chaperone in its CC multimeric membrane-bound state, assisting in the folding of synaptic CC fusion components called SNAREs (Soluble NSF Attachment Protein CC REceptors) at presynaptic plasma membrane in conjunction with cysteine CC string protein-alpha/DNAJC5 (PubMed:20798282). This chaperone activity CC is important to sustain normal SNARE-complex assembly during aging CC (PubMed:20798282). Also plays a role in the regulation of the dopamine CC neurotransmission by associating with the dopamine transporter (DAT1) CC and thereby modulating its activity (PubMed:26442590). CC {ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:26442590, CC ECO:0000269|PubMed:28288128, ECO:0000269|PubMed:30404828}. CC -!- SUBUNIT: Soluble monomer. Homotetramer (PubMed:21841800). A dynamic CC intracellular population of tetramers and monomers coexists normally CC and the tetramer plays an essential role in maintaining homeostasis CC (PubMed:21841800). Interacts with UCHL1 (By similarity). Interacts with CC phospholipase D and histones. Interacts (via N-terminus) with CC synphilin-1/SNCAIP; this interaction promotes formation of SNCA CC inclusions in the cytoplasm (PubMed:19762560). Interacts with CALM1 CC (PubMed:23607618). Interacts with STXBP1; this interaction controls CC SNCA self-replicating aggregation (PubMed:27597756). Interacts with CC SNARE components VAMP2 and SNAP25; these interactions allows SNARE CC complex assembly and integrity (PubMed:20798282). Interacts with RPH3A CC and RAB3A (PubMed:15207266). Interacts with SERF1A; this interaction CC promotes the aggregation of SNCA (PubMed:22854022, PubMed:31034892). CC Interacts with SEPTIN4 (By similarity). Interacts with DDX10; this CC interaction causes DDX10 mislocalization to the nucleoplasm and CC cytoplasmic inclusions (PubMed:33657088). CC {ECO:0000250|UniProtKB:O55042, ECO:0000250|UniProtKB:P37377, CC ECO:0000269|PubMed:15207266, ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:21841800, CC ECO:0000269|PubMed:22854022, ECO:0000269|PubMed:23607618, CC ECO:0000269|PubMed:27597756, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. CC -!- INTERACTION: CC P37840; Q6PCB6: ABHD17C; NbExp=3; IntAct=EBI-985879, EBI-22011868; CC P37840; P00519: ABL1; NbExp=3; IntAct=EBI-985879, EBI-375543; CC P37840; P00519-1: ABL1; NbExp=6; IntAct=EBI-985879, EBI-5278159; CC P37840; P00519-2: ABL1; NbExp=5; IntAct=EBI-985879, EBI-9254597; CC P37840; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-985879, EBI-25840993; CC P37840; P63010-2: AP2B1; NbExp=3; IntAct=EBI-985879, EBI-11529439; CC P37840; O00203: AP3B1; NbExp=3; IntAct=EBI-985879, EBI-1044383; CC P37840; P02647: APOA1; NbExp=3; IntAct=EBI-985879, EBI-701692; CC P37840; P02649: APOE; NbExp=11; IntAct=EBI-985879, EBI-1222467; CC P37840; P05067: APP; NbExp=6; IntAct=EBI-985879, EBI-77613; CC P37840; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-985879, EBI-10694449; CC P37840; Q9NP61: ARFGAP3; NbExp=3; IntAct=EBI-985879, EBI-2875816; CC P37840; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-985879, EBI-10186132; CC P37840; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-985879, EBI-707573; CC P37840; P18847: ATF3; NbExp=3; IntAct=EBI-985879, EBI-712767; CC P37840; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-985879, EBI-1048913; CC P37840; P46379-2: BAG6; NbExp=3; IntAct=EBI-985879, EBI-10988864; CC P37840; Q07812: BAX; NbExp=4; IntAct=EBI-985879, EBI-516580; CC P37840; Q07817: BCL2L1; NbExp=3; IntAct=EBI-985879, EBI-78035; CC P37840; O15392: BIRC5; NbExp=3; IntAct=EBI-985879, EBI-518823; CC P37840; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-985879, EBI-2837444; CC P37840; Q5SZD1: C6orf141; NbExp=3; IntAct=EBI-985879, EBI-10697767; CC P37840; P62158: CALM3; NbExp=3; IntAct=EBI-985879, EBI-397435; CC P37840; Q8N5S9-2: CAMKK1; NbExp=3; IntAct=EBI-985879, EBI-25850646; CC P37840; P55212: CASP6; NbExp=3; IntAct=EBI-985879, EBI-718729; CC P37840; Q7Z7K6: CENPV; NbExp=4; IntAct=EBI-985879, EBI-1210604; CC P37840; Q9HD42: CHMP1A; NbExp=3; IntAct=EBI-985879, EBI-1057156; CC P37840; Q16740: CLPP; NbExp=3; IntAct=EBI-985879, EBI-1056029; CC P37840; P10909: CLU; NbExp=4; IntAct=EBI-985879, EBI-1104674; CC P37840; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-985879, EBI-350590; CC P37840; Q8IUI8: CRLF3; NbExp=3; IntAct=EBI-985879, EBI-2872414; CC P37840; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-985879, EBI-9087876; CC P37840; P99999: CYCS; NbExp=3; IntAct=EBI-985879, EBI-446479; CC P37840; O75398: DEAF1; NbExp=3; IntAct=EBI-985879, EBI-718185; CC P37840; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-985879, EBI-25842538; CC P37840; O60479: DLX3; NbExp=3; IntAct=EBI-985879, EBI-3908248; CC P37840; A0AVK6: E2F8; NbExp=3; IntAct=EBI-985879, EBI-7779316; CC P37840; O75530-2: EED; NbExp=3; IntAct=EBI-985879, EBI-11132357; CC P37840; O00472: ELL2; NbExp=3; IntAct=EBI-985879, EBI-395274; CC P37840; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-985879, EBI-9246952; CC P37840; O00471: EXOC5; NbExp=3; IntAct=EBI-985879, EBI-949824; CC P37840; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-985879, EBI-396453; CC P37840; Q0VDC6: FKBP1A; NbExp=3; IntAct=EBI-985879, EBI-10226858; CC P37840; Q6PIV2: FOXR1; NbExp=3; IntAct=EBI-985879, EBI-10253815; CC P37840; P02792: FTL; NbExp=3; IntAct=EBI-985879, EBI-713279; CC P37840; P06241: FYN; NbExp=3; IntAct=EBI-985879, EBI-515315; CC P37840; P06241-3: FYN; NbExp=3; IntAct=EBI-985879, EBI-10691738; CC P37840; P62879: GNB2; NbExp=3; IntAct=EBI-985879, EBI-356942; CC P37840; P49841: GSK3B; NbExp=2; IntAct=EBI-985879, EBI-373586; CC P37840; P68431: H3C12; NbExp=3; IntAct=EBI-985879, EBI-79722; CC P37840; Q71DI3: H3C15; NbExp=3; IntAct=EBI-985879, EBI-750650; CC P37840; Q969S8: HDAC10; NbExp=3; IntAct=EBI-985879, EBI-301762; CC P37840; Q9HCC6: HES4; NbExp=3; IntAct=EBI-985879, EBI-2680288; CC P37840; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-985879, EBI-25845242; CC P37840; P09017: HOXC4; NbExp=3; IntAct=EBI-985879, EBI-3923226; CC P37840; P08107: HSPA1B; NbExp=7; IntAct=EBI-985879, EBI-629985; CC P37840; P42858: HTT; NbExp=4; IntAct=EBI-985879, EBI-466029; CC P37840; P80217-2: IFI35; NbExp=3; IntAct=EBI-985879, EBI-12823003; CC P37840; Q16352: INA; NbExp=3; IntAct=EBI-985879, EBI-366258; CC P37840; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-985879, EBI-21911304; CC P37840; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-985879, EBI-2127319; CC P37840; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-985879, EBI-2796400; CC P37840; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-985879, EBI-714379; CC P37840; Q92876: KLK6; NbExp=3; IntAct=EBI-985879, EBI-2432309; CC P37840; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-985879, EBI-1044640; CC P37840; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-985879, EBI-11985629; CC P37840; P13473-2: LAMP2; NbExp=3; IntAct=EBI-985879, EBI-21591415; CC P37840; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-985879, EBI-1108377; CC P37840; Q9H2C1: LHX5; NbExp=3; IntAct=EBI-985879, EBI-25835523; CC P37840; Q9UPM6: LHX6; NbExp=3; IntAct=EBI-985879, EBI-10258746; CC P37840; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-985879, EBI-739832; CC P37840; Q8N448: LNX2; NbExp=3; IntAct=EBI-985879, EBI-2340947; CC P37840; A2RU56: LOC401296; NbExp=3; IntAct=EBI-985879, EBI-9088215; CC P37840; Q5S007: LRRK2; NbExp=6; IntAct=EBI-985879, EBI-5323863; CC P37840; O95777: LSM8; NbExp=3; IntAct=EBI-985879, EBI-347779; CC P37840; P07948: LYN; NbExp=3; IntAct=EBI-985879, EBI-79452; CC P37840; Q8TD91-2: MAGEC3; NbExp=3; IntAct=EBI-985879, EBI-10694180; CC P37840; P10636-6: MAPT; NbExp=3; IntAct=EBI-985879, EBI-7796455; CC P37840; P10636-8: MAPT; NbExp=12; IntAct=EBI-985879, EBI-366233; CC P37840; Q8N6F8: METTL27; NbExp=3; IntAct=EBI-985879, EBI-8487781; CC P37840; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-985879, EBI-4397720; CC P37840; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-985879, EBI-21250407; CC P37840; Q8N594: MPND; NbExp=3; IntAct=EBI-985879, EBI-2512452; CC P37840; Q9Y3D2: MSRB2; NbExp=3; IntAct=EBI-985879, EBI-9092052; CC P37840; P00414: MT-CO3; NbExp=3; IntAct=EBI-985879, EBI-3932264; CC P37840; P02795: MT2A; NbExp=3; IntAct=EBI-985879, EBI-996616; CC P37840; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-985879, EBI-10698053; CC P37840; O00746: NME4; NbExp=3; IntAct=EBI-985879, EBI-744871; CC P37840; O15381-5: NVL; NbExp=3; IntAct=EBI-985879, EBI-18577082; CC P37840; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-985879, EBI-25888682; CC P37840; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-985879, EBI-1058491; CC P37840; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-985879, EBI-25830200; CC P37840; Q6VY07: PACS1; NbExp=3; IntAct=EBI-985879, EBI-2555014; CC P37840; O96013-2: PAK4; NbExp=3; IntAct=EBI-985879, EBI-21659863; CC P37840; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-985879, EBI-17159452; CC P37840; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-985879, EBI-6309018; CC P37840; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-985879, EBI-716063; CC P37840; O75925: PIAS1; NbExp=3; IntAct=EBI-985879, EBI-629434; CC P37840; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-985879, EBI-12891828; CC P37840; P17252: PRKCA; NbExp=3; IntAct=EBI-985879, EBI-1383528; CC P37840; Q02156: PRKCE; NbExp=3; IntAct=EBI-985879, EBI-706254; CC P37840; O60260-5: PRKN; NbExp=8; IntAct=EBI-985879, EBI-21251460; CC P37840; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-985879, EBI-5280197; CC P37840; P62191: PSMC1; NbExp=3; IntAct=EBI-985879, EBI-357598; CC P37840; P17980: PSMC3; NbExp=6; IntAct=EBI-985879, EBI-359720; CC P37840; Q9UI14: RABAC1; NbExp=4; IntAct=EBI-985879, EBI-712367; CC P37840; Q9UJ41-4: RABGEF1; NbExp=3; IntAct=EBI-985879, EBI-14093916; CC P37840; P62826: RAN; NbExp=3; IntAct=EBI-985879, EBI-286642; CC P37840; Q13702-2: RAPSN; NbExp=3; IntAct=EBI-985879, EBI-22012855; CC P37840; P57052: RBM11; NbExp=3; IntAct=EBI-985879, EBI-741332; CC P37840; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-985879, EBI-714023; CC P37840; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-985879, EBI-21535400; CC P37840; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-985879, EBI-25829984; CC P37840; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-985879, EBI-749039; CC P37840; Q8IYW5: RNF168; NbExp=3; IntAct=EBI-985879, EBI-914207; CC P37840; Q96D59: RNF183; NbExp=3; IntAct=EBI-985879, EBI-743938; CC P37840; Q8N488: RYBP; NbExp=3; IntAct=EBI-985879, EBI-752324; CC P37840; O75446: SAP30; NbExp=3; IntAct=EBI-985879, EBI-632609; CC P37840; O00560: SDCBP; NbExp=3; IntAct=EBI-985879, EBI-727004; CC P37840; O43236: SEPTIN4; NbExp=3; IntAct=EBI-985879, EBI-1047513; CC P37840; O75920-2: SERF1B; NbExp=4; IntAct=EBI-985879, EBI-21283682; CC P37840; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-985879, EBI-10182463; CC P37840; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-985879, EBI-358545; CC P37840; Q01959: SLC6A3; NbExp=3; IntAct=EBI-985879, EBI-6661445; CC P37840; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-985879, EBI-9845742; CC P37840; P37840: SNCA; NbExp=51; IntAct=EBI-985879, EBI-985879; CC P37840; Q9Y6H5: SNCAIP; NbExp=22; IntAct=EBI-985879, EBI-717182; CC P37840; Q9Y6H5-2: SNCAIP; NbExp=2; IntAct=EBI-985879, EBI-15577909; CC P37840; Q16143: SNCB; NbExp=3; IntAct=EBI-985879, EBI-727106; CC P37840; P00441: SOD1; NbExp=9; IntAct=EBI-985879, EBI-990792; CC P37840; P23497-2: SP100; NbExp=3; IntAct=EBI-985879, EBI-6589365; CC P37840; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-985879, EBI-11959123; CC P37840; Q8NHS9: SPATA22; NbExp=3; IntAct=EBI-985879, EBI-7067260; CC P37840; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-985879, EBI-8345366; CC P37840; Q13501: SQSTM1; NbExp=3; IntAct=EBI-985879, EBI-307104; CC P37840; O75886: STAM2; NbExp=3; IntAct=EBI-985879, EBI-373258; CC P37840; Q16623: STX1A; NbExp=2; IntAct=EBI-985879, EBI-712466; CC P37840; Q9BR01-2: SULT4A1; NbExp=3; IntAct=EBI-985879, EBI-25831443; CC P37840; Q92797-2: SYMPK; NbExp=3; IntAct=EBI-985879, EBI-21560407; CC P37840; Q16650: TBR1; NbExp=3; IntAct=EBI-985879, EBI-1047158; CC P37840; Q13569: TDG; NbExp=3; IntAct=EBI-985879, EBI-348333; CC P37840; P28347-2: TEAD1; NbExp=3; IntAct=EBI-985879, EBI-12151837; CC P37840; Q15554-4: TERF2; NbExp=3; IntAct=EBI-985879, EBI-25840535; CC P37840; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-985879, EBI-74615; CC P37840; O94811: TPPP; NbExp=8; IntAct=EBI-985879, EBI-3927802; CC P37840; P19474: TRIM21; NbExp=3; IntAct=EBI-985879, EBI-81290; CC P37840; P68363: TUBA1B; NbExp=3; IntAct=EBI-985879, EBI-487083; CC P37840; P07437: TUBB; NbExp=3; IntAct=EBI-985879, EBI-350864; CC P37840; Q8WVJ9: TWIST2; NbExp=3; IntAct=EBI-985879, EBI-1797313; CC P37840; P62987: UBA52; NbExp=3; IntAct=EBI-985879, EBI-357304; CC P37840; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-985879, EBI-749370; CC P37840; O15205: UBD; NbExp=3; IntAct=EBI-985879, EBI-6657186; CC P37840; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-985879, EBI-11530712; CC P37840; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-985879, EBI-17761788; CC P37840; O75604-3: USP2; NbExp=3; IntAct=EBI-985879, EBI-10696113; CC P37840; P63027: VAMP2; NbExp=5; IntAct=EBI-985879, EBI-520113; CC P37840; P40337-2: VHL; NbExp=3; IntAct=EBI-985879, EBI-12157263; CC P37840; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-985879, EBI-11141397; CC P37840; O00308: WWP2; NbExp=3; IntAct=EBI-985879, EBI-743923; CC P37840; Q04917: YWHAH; NbExp=4; IntAct=EBI-985879, EBI-306940; CC P37840; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-985879, EBI-25842419; CC P37840; Q96NC0: ZMAT2; NbExp=3; IntAct=EBI-985879, EBI-2682299; CC P37840; Q8WUU4: ZNF296; NbExp=3; IntAct=EBI-985879, EBI-8834821; CC P37840; Q8N895: ZNF366; NbExp=3; IntAct=EBI-985879, EBI-2813661; CC P37840; Q8N988-2: ZNF557; NbExp=3; IntAct=EBI-985879, EBI-10699005; CC P37840; Q68EA5: ZNF57; NbExp=3; IntAct=EBI-985879, EBI-8490788; CC P37840; Q8NBB4-2: ZSCAN1; NbExp=3; IntAct=EBI-985879, EBI-12021938; CC P37840; A8K878; NbExp=3; IntAct=EBI-985879, EBI-25831303; CC P37840; P0DTC9: N; Xeno; NbExp=2; IntAct=EBI-985879, EBI-25475856; CC P37840; Q61327: Slc6a3; Xeno; NbExp=5; IntAct=EBI-985879, EBI-7839708; CC P37840-1; P37840-1: SNCA; NbExp=21; IntAct=EBI-9684465, EBI-9684465; CC P37840-1; Q04917: YWHAH; NbExp=9; IntAct=EBI-9684465, EBI-306940; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:26442590, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. Membrane {ECO:0000269|PubMed:24936070}. CC Nucleus {ECO:0000269|PubMed:12859192, ECO:0000269|PubMed:24936070}. CC Synapse {ECO:0000269|PubMed:15282274}. Secreted CC {ECO:0000269|PubMed:24936070}. Cell projection, axon CC {ECO:0000250|UniProtKB:O55042}. Note=Membrane-bound in dopaminergic CC neurons (PubMed:15282274). Expressed and colocalized with SEPTIN4 in CC dopaminergic axon terminals, especially at the varicosities (By CC similarity). {ECO:0000250|UniProtKB:O55042, CC ECO:0000269|PubMed:15282274}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=NACP140; CC IsoId=P37840-1; Sequence=Displayed; CC Name=2-4; Synonyms=NACP112; CC IsoId=P37840-2; Sequence=VSP_006364; CC Name=2-5; CC IsoId=P37840-3; Sequence=VSP_006363; CC -!- TISSUE SPECIFICITY: Highly expressed in presynaptic terminals in the CC central nervous system. Expressed principally in brain. CC {ECO:0000269|PubMed:8194594}. CC -!- DOMAIN: The 'non A-beta component of Alzheimer disease amyloid plaque' CC domain (NAC domain) is involved in fibrils formation. The middle CC hydrophobic region forms the core of the filaments. The C-terminus may CC regulate aggregation and determine the diameter of the filaments. CC {ECO:0000269|PubMed:19722699}. CC -!- PTM: Phosphorylated, predominantly on serine residues. Phosphorylation CC by CK1 appears to occur on residues distinct from the residue CC phosphorylated by other kinases. Phosphorylation of Ser-129 is CC selective and extensive in synucleinopathy lesions. In vitro, CC phosphorylation at Ser-129 promoted insoluble fibril formation. CC Phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic CC stress. {ECO:0000269|PubMed:10617630, ECO:0000269|PubMed:10852916, CC ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11813001, CC ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:24936070}. CC -!- PTM: Hallmark lesions of neurodegenerative synucleinopathies contain CC alpha-synuclein that is modified by nitration of tyrosine residues and CC possibly by dityrosine cross-linking to generated stable oligomers. CC -!- PTM: Ubiquitinated. The predominant conjugate is the diubiquitinated CC form. {ECO:0000250|UniProtKB:P37377}. CC -!- PTM: Acetylation at Met-1 seems to be important for proper folding and CC native oligomeric structure. {ECO:0000269|PubMed:22407793}. CC -!- DISEASE: Note=Genetic alterations of SNCA resulting in aberrant CC polymerization into fibrils, are associated with several CC neurodegenerative diseases (synucleinopathies). SNCA fibrillar CC aggregates represent the major non A-beta component of Alzheimer CC disease amyloid plaque, and a major component of Lewy body inclusions. CC They are also found within Lewy body (LB)-like intraneuronal CC inclusions, glial inclusions and axonal spheroids in neurodegeneration CC with brain iron accumulation type 1. CC -!- DISEASE: Parkinson disease 1, autosomal dominant (PARK1) [MIM:168601]: CC A complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability. Additional CC features are characteristic postural abnormalities, dysautonomia, CC dystonic cramps, and dementia. The pathology of Parkinson disease CC involves the loss of dopaminergic neurons in the substantia nigra and CC the presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. The CC disease is progressive and usually manifests after the age of 50 years, CC although early-onset cases (before 50 years) are known. The majority of CC the cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:14755719, CC ECO:0000269|PubMed:23427326, ECO:0000269|PubMed:23457019, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:9197268, ECO:0000269|PubMed:9462735}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 4, autosomal dominant (PARK4) [MIM:605543]: CC A complex neurodegenerative disorder with manifestations ranging from CC typical Parkinson disease to dementia with Lewy bodies. Clinical CC features include parkinsonian symptoms (resting tremor, rigidity, CC postural instability and bradykinesia), dementia, diffuse Lewy body CC pathology, autonomic dysfunction, hallucinations and paranoia. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Dementia, Lewy body (DLB) [MIM:127750]: A neurodegenerative CC disorder characterized by mental impairment leading to dementia, CC parkinsonism, fluctuating cognitive function, visual hallucinations, CC falls, syncopal episodes, and sensitivity to neuroleptic medication. CC Brainstem or cortical intraneuronal accumulations of aggregated CC proteins (Lewy bodies) are the only essential pathologic features. CC Patients may also have hippocampal and neocortical senile plaques, CC sometimes in sufficient number to fulfill the diagnostic criteria for CC Alzheimer disease. {ECO:0000269|PubMed:14755719}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the synuclein 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; L08850; AAA16117.1; -; mRNA. DR EMBL; L36674; AAA98493.1; -; mRNA. DR EMBL; L36675; AAA98487.1; -; mRNA. DR EMBL; D31839; BAA06625.1; -; mRNA. DR EMBL; U46901; AAC02114.1; -; Genomic_DNA. DR EMBL; U46897; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46898; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46899; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; AF163864; AAG30302.1; -; Genomic_DNA. DR EMBL; AF163864; AAG30303.1; -; Genomic_DNA. DR EMBL; AY049786; AAL15443.1; -; mRNA. DR EMBL; AK290169; BAF82858.1; -; mRNA. DR EMBL; CR457058; CAG33339.1; -; mRNA. DR EMBL; DQ088379; AAY88735.1; -; Genomic_DNA. DR EMBL; CH471057; EAX06036.1; -; Genomic_DNA. DR EMBL; BC013293; AAH13293.1; -; mRNA. DR EMBL; BC108275; AAI08276.1; -; mRNA. DR CCDS; CCDS3634.1; -. [P37840-1] DR CCDS; CCDS43252.1; -. [P37840-2] DR PIR; A49669; A49669. DR PIR; S56746; S56746. DR RefSeq; NP_000336.1; NM_000345.4. [P37840-1] DR RefSeq; NP_001139526.1; NM_001146054.2. [P37840-1] DR RefSeq; NP_001139527.1; NM_001146055.2. [P37840-1] DR RefSeq; NP_001362214.1; NM_001375285.1. [P37840-1] DR RefSeq; NP_001362215.1; NM_001375286.1. [P37840-1] DR RefSeq; NP_001362216.1; NM_001375287.1. [P37840-1] DR RefSeq; NP_001362217.1; NM_001375288.1. [P37840-1] DR RefSeq; NP_009292.1; NM_007308.3. [P37840-2] DR PDB; 1XQ8; NMR; -; A=1-140. DR PDB; 2JN5; NMR; -; A=1-12. DR PDB; 2KKW; NMR; -; A=1-140. DR PDB; 2M55; NMR; -; B=1-19. DR PDB; 2N0A; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 2X6M; X-ray; 1.62 A; B=132-140. DR PDB; 3Q25; X-ray; 1.90 A; A=1-19. DR PDB; 3Q26; X-ray; 1.54 A; A=10-42. DR PDB; 3Q27; X-ray; 1.30 A; A=32-57. DR PDB; 3Q28; X-ray; 1.60 A; A=58-79. DR PDB; 3Q29; X-ray; 2.30 A; A/C=1-19. DR PDB; 4BXL; NMR; -; C=35-56. DR PDB; 4R0U; X-ray; 1.38 A; A=72-78. DR PDB; 4R0W; X-ray; 1.50 A; A=70-76. DR PDB; 4RIK; X-ray; 1.85 A; A=69-77. DR PDB; 4RIL; EM; 1.43 A; A=68-78. DR PDB; 4ZNN; EM; 1.41 A; A=47-56. DR PDB; 5CRW; X-ray; 1.60 A; B=31-41. DR PDB; 6A6B; EM; 3.07 A; A/B/C/D/E/F/G/H/I/J/K/L=37-99. DR PDB; 6CT7; X-ray; 1.90 A; S/T=1-10. DR PDB; 6CU7; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6CU8; EM; 3.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6H6B; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-121. DR PDB; 6I42; X-ray; 1.38 A; B=48-60. DR PDB; 6L1T; EM; 3.22 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6L1U; EM; 3.37 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=1-140. DR PDB; 6L4S; EM; 3.37 A; A/B/C/D/E/F=45-99. DR PDB; 6LRQ; EM; 3.49 A; A/B/C/D/E/F=1-140. DR PDB; 6OSJ; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSL; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSM; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6PEO; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 6PES; EM; 3.60 A; A/B/C/D/E/V/W/X/Y/Z=1-140. DR PDB; 6RT0; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6RTB; EM; 3.46 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SST; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SSX; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6UFR; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYO; EM; 2.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYP; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYQ; EM; 3.09 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7C1D; EM; 3.80 A; A/B/C/D/E/F=1-140. DR PDB; 7E0F; EM; 3.02 A; A/B/C/D/E/F=1-140. DR PDB; 7L7H; EM; 4.00 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7LC9; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J/K/L=41-140. DR PDB; 7NCA; EM; 3.47 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCG; EM; 3.43 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCH; EM; 3.84 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCI; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCJ; EM; 4.23 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCK; EM; 3.18 A; A/B/C/D/E/F=1-140. DR PDB; 7OZG; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7OZH; EM; 3.02 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7STX; EM; 3.14 A; C=1-5. DR PDB; 7UAK; EM; 3.38 A; A/B/C/D/E/F=1-140. DR PDB; 7V47; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7V48; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7V49; EM; 3.40 A; A/B/C=1-140. DR PDB; 7V4A; EM; 3.20 A; A/B/C=1-140. DR PDB; 7V4B; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7V4C; EM; 3.30 A; A/B/F=1-140. DR PDB; 7V4D; EM; 3.50 A; A/B/C/D/E/F=1-140. DR PDB; 7WMM; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7WNZ; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=36-100. DR PDB; 7WO0; EM; 2.70 A; A/B/C/D/E/F/G/O/P/Q/R/S/T/U=35-99. DR PDB; 7XJX; EM; 2.70 A; A/B/C/D/E/F=1-140. DR PDB; 7XO0; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO1; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO2; EM; 3.00 A; A/B/C/D/E/I=1-140. DR PDB; 7XO3; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7YK2; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YK8; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7YNF; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 7YNG; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7YNL; EM; 2.60 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7YNM; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNN; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNO; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNP; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNQ; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNR; EM; 2.90 A; A/B/C/D/E/F=1-140. DR PDB; 7YNS; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7YNT; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8A4L; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J/K/L/M/O/P=1-140. DR PDB; 8A9L; EM; 2.16 A; A=1-140. DR PDB; 8ADS; EM; 3.05 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADU; EM; 3.24 A; A/B/C/D/E=1-140. DR PDB; 8ADV; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADW; EM; 2.95 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8AEX; EM; 2.76 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8B9V; X-ray; 2.16 A; A=110-119. DR PDB; 8BQV; EM; 2.00 A; A=1-140. DR PDB; 8BQW; EM; 2.30 A; A/C=1-140. DR PDB; 8CE7; EM; 2.70 A; A/C=1-140. DR PDB; 8CEB; EM; 2.70 A; A/C=1-140. DR PDB; 8CYR; EM; 4.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYS; EM; 3.10 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYT; EM; 3.00 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYV; EM; 3.50 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYW; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYX; EM; 3.00 A; A/B/C/D/E/I/J/K/L/M=1-140. DR PDB; 8CYY; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ0; EM; 2.90 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ1; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ2; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ3; EM; 3.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ6; EM; 3.20 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8FPT; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8G0L; EM; 3.39 A; C=1-5. DR PDB; 8GF7; EM; 4.80 A; A/B/C/D/E/F=7-96. DR PDB; 8H03; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8H04; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8H05; EM; 3.40 A; A/B/C=1-140. DR PDB; 8HZB; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZC; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZS; EM; 3.30 A; A/B/C/D/E/F=1-140. DR PDB; 8JEX; EM; 3.10 A; A/B/G/H/K/P=1-140. DR PDB; 8JEY; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 8JJV; X-ray; 1.23 A; B=43-56. DR PDB; 8JLY; X-ray; 1.29 A; B=43-56. DR PDB; 8OG0; X-ray; 1.71 A; P=136-140. DR PDB; 8OJR; NMR; -; A=1-25. DR PDB; 8OL8; NMR; -; A=2-12. DR PDB; 8OQI; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PIX; EM; 3.41 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PJO; EM; 2.31 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PK2; EM; 3.26 A; A/B/C/D/E=1-140. DR PDB; 8PK4; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8QPZ; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J/K/L=8-140. DR PDB; 8RI9; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 8RQM; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8RRR; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8UKA; EM; 3.90 A; A/B/C/D/E/a/b/c/d/e=1-140. DR PDB; 8X7B; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7L; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7M; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7P; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7Q; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7R; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8XWD; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2P; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2Q; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8ZLI; EM; 3.40 A; A/B/C/D/E/F/I/J/K/L=45-99. DR PDB; 8ZLO; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/O/T=45-99. DR PDB; 8ZLP; EM; 3.50 A; A/B/C/F/G/H=1-98. DR PDB; 8ZMY; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-98. DR PDB; 8ZVY; X-ray; 1.72 A; C/D=121-140. DR PDB; 8ZWH; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWI; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWJ; EM; 3.10 A; A/B/C/D/E/G=1-140. DR PDB; 8ZWK; EM; 3.40 A; A/B/C/D/E/F=1-140. DR PDB; 9C5R; EM; 2.61 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 9CD9; EM; 3.20 A; E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z=1-140. DR PDB; 9CDA; EM; 3.30 A; K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b=1-140. DR PDB; 9CK3; EM; 2.04 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 9CX6; EM; 3.20 A; G/H=1-140. DR PDB; 9D5C; EM; 4.80 A; A/B/C/F/G/H=1-96. DR PDB; 9EUU; EM; 1.93 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9FYP; EM; 2.23 A; I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9HGR; EM; 2.70 A; A/B=1-140. DR PDB; 9HGS; EM; 3.00 A; C=1-140. DR PDB; 9HXA; EM; 3.70 A; A/C=1-140. DR PDB; 9IJP; EM; 3.10 A; B/C/E/G/I/L=1-140. DR PDB; 9O4B; EM; 2.59 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDBsum; 1XQ8; -. DR PDBsum; 2JN5; -. DR PDBsum; 2KKW; -. DR PDBsum; 2M55; -. DR PDBsum; 2N0A; -. DR PDBsum; 2X6M; -. DR PDBsum; 3Q25; -. DR PDBsum; 3Q26; -. DR PDBsum; 3Q27; -. DR PDBsum; 3Q28; -. DR PDBsum; 3Q29; -. DR PDBsum; 4BXL; -. DR PDBsum; 4R0U; -. DR PDBsum; 4R0W; -. DR PDBsum; 4RIK; -. DR PDBsum; 4RIL; -. DR PDBsum; 4ZNN; -. DR PDBsum; 5CRW; -. DR PDBsum; 6A6B; -. DR PDBsum; 6CT7; -. DR PDBsum; 6CU7; -. DR PDBsum; 6CU8; -. DR PDBsum; 6H6B; -. DR PDBsum; 6I42; -. DR PDBsum; 6L1T; -. DR PDBsum; 6L1U; -. DR PDBsum; 6L4S; -. DR PDBsum; 6LRQ; -. DR PDBsum; 6OSJ; -. DR PDBsum; 6OSL; -. DR PDBsum; 6OSM; -. DR PDBsum; 6PEO; -. DR PDBsum; 6PES; -. DR PDBsum; 6RT0; -. DR PDBsum; 6RTB; -. DR PDBsum; 6SST; -. DR PDBsum; 6SSX; -. DR PDBsum; 6UFR; -. DR PDBsum; 6XYO; -. DR PDBsum; 6XYP; -. DR PDBsum; 6XYQ; -. DR PDBsum; 7C1D; -. DR PDBsum; 7E0F; -. DR PDBsum; 7L7H; -. DR PDBsum; 7LC9; -. DR PDBsum; 7NCA; -. DR PDBsum; 7NCG; -. DR PDBsum; 7NCH; -. DR PDBsum; 7NCI; -. DR PDBsum; 7NCJ; -. DR PDBsum; 7NCK; -. DR PDBsum; 7OZG; -. DR PDBsum; 7OZH; -. DR PDBsum; 7STX; -. DR PDBsum; 7UAK; -. DR PDBsum; 7V47; -. DR PDBsum; 7V48; -. DR PDBsum; 7V49; -. DR PDBsum; 7V4A; -. DR PDBsum; 7V4B; -. DR PDBsum; 7V4C; -. DR PDBsum; 7V4D; -. DR PDBsum; 7WMM; -. DR PDBsum; 7WNZ; -. DR PDBsum; 7WO0; -. DR PDBsum; 7XJX; -. DR PDBsum; 7XO0; -. DR PDBsum; 7XO1; -. DR PDBsum; 7XO2; -. DR PDBsum; 7XO3; -. DR PDBsum; 7YK2; -. DR PDBsum; 7YK8; -. DR PDBsum; 7YNF; -. DR PDBsum; 7YNG; -. DR PDBsum; 7YNL; -. DR PDBsum; 7YNM; -. DR PDBsum; 7YNN; -. DR PDBsum; 7YNO; -. DR PDBsum; 7YNP; -. DR PDBsum; 7YNQ; -. DR PDBsum; 7YNR; -. DR PDBsum; 7YNS; -. DR PDBsum; 7YNT; -. DR PDBsum; 8A4L; -. DR PDBsum; 8A9L; -. DR PDBsum; 8ADS; -. DR PDBsum; 8ADU; -. DR PDBsum; 8ADV; -. DR PDBsum; 8ADW; -. DR PDBsum; 8AEX; -. DR PDBsum; 8B9V; -. DR PDBsum; 8BQV; -. DR PDBsum; 8BQW; -. DR PDBsum; 8CE7; -. DR PDBsum; 8CEB; -. DR PDBsum; 8CYR; -. DR PDBsum; 8CYS; -. DR PDBsum; 8CYT; -. DR PDBsum; 8CYV; -. DR PDBsum; 8CYW; -. DR PDBsum; 8CYX; -. DR PDBsum; 8CYY; -. DR PDBsum; 8CZ0; -. DR PDBsum; 8CZ1; -. DR PDBsum; 8CZ2; -. DR PDBsum; 8CZ3; -. DR PDBsum; 8CZ6; -. DR PDBsum; 8FPT; -. DR PDBsum; 8G0L; -. DR PDBsum; 8GF7; -. DR PDBsum; 8H03; -. DR PDBsum; 8H04; -. DR PDBsum; 8H05; -. DR PDBsum; 8HZB; -. DR PDBsum; 8HZC; -. DR PDBsum; 8HZS; -. DR PDBsum; 8JEX; -. DR PDBsum; 8JEY; -. DR PDBsum; 8JJV; -. DR PDBsum; 8JLY; -. DR PDBsum; 8OG0; -. DR PDBsum; 8OJR; -. DR PDBsum; 8OL8; -. DR PDBsum; 8OQI; -. DR PDBsum; 8PIX; -. DR PDBsum; 8PJO; -. DR PDBsum; 8PK2; -. DR PDBsum; 8PK4; -. DR PDBsum; 8QPZ; -. DR PDBsum; 8RI9; -. DR PDBsum; 8RQM; -. DR PDBsum; 8RRR; -. DR PDBsum; 8UKA; -. DR PDBsum; 8X7B; -. DR PDBsum; 8X7L; -. DR PDBsum; 8X7M; -. DR PDBsum; 8X7O; -. DR PDBsum; 8X7P; -. DR PDBsum; 8X7Q; -. DR PDBsum; 8X7R; -. DR PDBsum; 8XWD; -. DR PDBsum; 8Y2P; -. DR PDBsum; 8Y2Q; -. DR PDBsum; 8ZLI; -. DR PDBsum; 8ZLO; -. DR PDBsum; 8ZLP; -. DR PDBsum; 8ZMY; -. DR PDBsum; 8ZVY; -. DR PDBsum; 8ZWH; -. DR PDBsum; 8ZWI; -. DR PDBsum; 8ZWJ; -. DR PDBsum; 8ZWK; -. DR PDBsum; 9C5R; -. DR PDBsum; 9CD9; -. DR PDBsum; 9CDA; -. DR PDBsum; 9CK3; -. DR PDBsum; 9CX6; -. DR PDBsum; 9D5C; -. DR PDBsum; 9EUU; -. DR PDBsum; 9FYP; -. DR PDBsum; 9HGR; -. DR PDBsum; 9HGS; -. DR PDBsum; 9HXA; -. DR PDBsum; 9IJP; -. DR PDBsum; 9O4B; -. DR AlphaFoldDB; P37840; -. DR BMRB; P37840; -. DR EMDB; EMD-0148; -. DR EMDB; EMD-0801; -. DR EMDB; EMD-0803; -. DR EMDB; EMD-0833; -. DR EMDB; EMD-0958; -. DR EMDB; EMD-10305; -. DR EMDB; EMD-10307; -. DR EMDB; EMD-10650; -. DR EMDB; EMD-10651; -. DR EMDB; EMD-10652; -. DR EMDB; EMD-12264; -. DR EMDB; EMD-12265; -. DR EMDB; EMD-12266; -. DR EMDB; EMD-12267; -. DR EMDB; EMD-12268; -. DR EMDB; EMD-12269; -. DR EMDB; EMD-13123; -. DR EMDB; EMD-13124; -. DR EMDB; EMD-15148; -. DR EMDB; EMD-15285; -. DR EMDB; EMD-15369; -. DR EMDB; EMD-15370; -. DR EMDB; EMD-15371; -. DR EMDB; EMD-15372; -. DR EMDB; EMD-15388; -. DR EMDB; EMD-16188; -. DR EMDB; EMD-16189; -. DR EMDB; EMD-16600; -. DR EMDB; EMD-16603; -. DR EMDB; EMD-17111; -. DR EMDB; EMD-17693; -. DR EMDB; EMD-17714; -. DR EMDB; EMD-17723; -. DR EMDB; EMD-17726; -. DR EMDB; EMD-18570; -. DR EMDB; EMD-19184; -. DR EMDB; EMD-19446; -. DR EMDB; EMD-19462; -. DR EMDB; EMD-19986; -. DR EMDB; EMD-20183; -. DR EMDB; EMD-20185; -. DR EMDB; EMD-20186; -. DR EMDB; EMD-20328; -. DR EMDB; EMD-20331; -. DR EMDB; EMD-20759; -. DR EMDB; EMD-23212; -. DR EMDB; EMD-23270; -. DR EMDB; EMD-25438; -. DR EMDB; EMD-26427; -. DR EMDB; EMD-27082; -. DR EMDB; EMD-27083; -. DR EMDB; EMD-27084; -. DR EMDB; EMD-27085; -. DR EMDB; EMD-27086; -. DR EMDB; EMD-27087; -. DR EMDB; EMD-27088; -. DR EMDB; EMD-27089; -. DR EMDB; EMD-27090; -. DR EMDB; EMD-27091; -. DR EMDB; EMD-27092; -. DR EMDB; EMD-27093; -. DR EMDB; EMD-29657; -. DR EMDB; EMD-29980; -. DR EMDB; EMD-30269; -. DR EMDB; EMD-30931; -. DR EMDB; EMD-3094; -. DR EMDB; EMD-3095; -. DR EMDB; EMD-31702; -. DR EMDB; EMD-31703; -. DR EMDB; EMD-31704; -. DR EMDB; EMD-31705; -. DR EMDB; EMD-31706; -. DR EMDB; EMD-31707; -. DR EMDB; EMD-31708; -. DR EMDB; EMD-32615; -. DR EMDB; EMD-32636; -. DR EMDB; EMD-32637; -. DR EMDB; EMD-33236; -. DR EMDB; EMD-33332; -. DR EMDB; EMD-33333; -. DR EMDB; EMD-33334; -. DR EMDB; EMD-33335; -. DR EMDB; EMD-33884; -. DR EMDB; EMD-33890; -. DR EMDB; EMD-33960; -. DR EMDB; EMD-33961; -. DR EMDB; EMD-33965; -. DR EMDB; EMD-33966; -. DR EMDB; EMD-33967; -. DR EMDB; EMD-33968; -. DR EMDB; EMD-33969; -. DR EMDB; EMD-33970; -. DR EMDB; EMD-33971; -. DR EMDB; EMD-35087; -. DR EMDB; EMD-35088; -. DR EMDB; EMD-35090; -. DR EMDB; EMD-36202; -. DR EMDB; EMD-36203; -. DR EMDB; EMD-38097; -. DR EMDB; EMD-38103; -. DR EMDB; EMD-38104; -. DR EMDB; EMD-38105; -. DR EMDB; EMD-38106; -. DR EMDB; EMD-38107; -. DR EMDB; EMD-38108; -. DR EMDB; EMD-38733; -. DR EMDB; EMD-38862; -. DR EMDB; EMD-38863; -. DR EMDB; EMD-42350; -. DR EMDB; EMD-45221; -. DR EMDB; EMD-45464; -. DR EMDB; EMD-45465; -. DR EMDB; EMD-45639; -. DR EMDB; EMD-45650; -. DR EMDB; EMD-45651; -. DR EMDB; EMD-45979; -. DR EMDB; EMD-47820; -. DR EMDB; EMD-4994; -. DR EMDB; EMD-4996; -. DR EMDB; EMD-50077; -. DR EMDB; EMD-50860; -. DR EMDB; EMD-50888; -. DR EMDB; EMD-52165; -. DR EMDB; EMD-52166; -. DR EMDB; EMD-52458; -. DR EMDB; EMD-54402; -. DR EMDB; EMD-60226; -. DR EMDB; EMD-60231; -. DR EMDB; EMD-60232; -. DR EMDB; EMD-60262; -. DR EMDB; EMD-60527; -. DR EMDB; EMD-60528; -. DR EMDB; EMD-60529; -. DR EMDB; EMD-60530; -. DR EMDB; EMD-60637; -. DR EMDB; EMD-61330; -. DR EMDB; EMD-61355; -. DR EMDB; EMD-61356; -. DR EMDB; EMD-61357; -. DR EMDB; EMD-61383; -. DR EMDB; EMD-61384; -. DR EMDB; EMD-61394; -. DR EMDB; EMD-6482; -. DR EMDB; EMD-6988; -. DR EMDB; EMD-70093; -. DR EMDB; EMD-70295; -. DR EMDB; EMD-7618; -. DR EMDB; EMD-7619; -. DR PCDDB; P37840; -. DR SMR; P37840; -. DR BioGRID; 112506; 1553. DR CORUM; P37840; -. DR DIP; DIP-35354N; -. DR FunCoup; P37840; 336. DR IntAct; P37840; 474. DR MINT; P37840; -. DR STRING; 9606.ENSP00000500990; -. DR BindingDB; P37840; -. DR ChEMBL; CHEMBL6152; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB04209; Dequalinium. DR DrugBank; DB02709; Resveratrol. DR DrugCentral; P37840; -. DR GuidetoPHARMACOLOGY; 3285; -. DR TCDB; 1.C.77.1.1; the synuclein (synuclein) family. DR GlyConnect; 2893; 1 O-GlcNAc glycan (1 site). DR GlyCosmos; P37840; 5 sites, 1 glycan. DR GlyGen; P37840; 7 sites, 2 O-linked glycans (7 sites). DR iPTMnet; P37840; -. DR MetOSite; P37840; -. DR PhosphoSitePlus; P37840; -. DR SwissPalm; P37840; -. DR BioMuta; SNCA; -. DR DMDM; 586067; -. DR jPOST; P37840; -. DR MassIVE; P37840; -. DR PaxDb; 9606-ENSP00000338345; -. DR PeptideAtlas; P37840; -. DR ProteomicsDB; 55279; -. [P37840-1] DR ProteomicsDB; 55280; -. [P37840-2] DR ProteomicsDB; 55281; -. [P37840-3] DR Pumba; P37840; -. DR TopDownProteomics; P37840-1; -. [P37840-1] DR ABCD; P37840; 22 sequenced antibodies. DR Antibodypedia; 14688; 3097 antibodies from 56 providers. DR DNASU; 6622; -. DR Ensembl; ENST00000336904.7; ENSP00000338345.3; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000345009.8; ENSP00000343683.4; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000394986.5; ENSP00000378437.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000394989.6; ENSP00000378440.2; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000394991.8; ENSP00000378442.4; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000420646.6; ENSP00000396241.2; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000505199.5; ENSP00000421485.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000506244.5; ENSP00000422238.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000508895.5; ENSP00000426955.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000618500.4; ENSP00000484044.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000673718.1; ENSP00000500990.1; ENSG00000145335.18. [P37840-1] DR GeneID; 6622; -. DR KEGG; hsa:6622; -. DR MANE-Select; ENST00000394991.8; ENSP00000378442.4; NM_000345.4; NP_000336.1. DR UCSC; uc003hso.3; human. [P37840-1] DR AGR; HGNC:11138; -. DR ClinPGx; PA35986; -. DR CTD; 6622; -. DR DisGeNET; 6622; -. DR GeneCards; SNCA; -. DR GeneReviews; SNCA; -. DR HGNC; HGNC:11138; SNCA. DR HPA; ENSG00000145335; Group enriched (bone marrow, brain). DR MalaCards; SNCA; -. DR MIM; 127750; phenotype. DR MIM; 163890; gene. DR MIM; 168600; phenotype. DR MIM; 168601; phenotype. DR MIM; 605543; phenotype. DR OpenTargets; ENSG00000145335; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR Orphanet; 171695; Parkinsonian-pyramidal syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000145335; -. DR eggNOG; ENOG502S0Q7; Eukaryota. DR GeneTree; ENSGT00950000183175; -. DR HOGENOM; CLU_129378_1_0_1; -. DR InParanoid; P37840; -. DR OMA; LPQEGMM; -. DR OrthoDB; 9900372at2759; -. DR PAN-GO; P37840; 8 GO annotations based on evolutionary models. DR PhylomeDB; P37840; -. DR PathwayCommons; P37840; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; P37840; -. DR SIGNOR; P37840; -. DR Agora; ENSG00000145335; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 6622; 12 hits in 1150 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SNCA; human. DR EvolutionaryTrace; P37840; -. DR GeneWiki; Alpha-synuclein; -. DR GenomeRNAi; 6622; -. DR Pharos; P37840; Tchem. DR PRO; PR:P37840; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P37840; protein. DR Bgee; ENSG00000145335; Expressed in trabecular bone tissue and 205 other cell types or tissues. DR ExpressionAtlas; P37840; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:UniProtKB. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0043679; C:axon terminus; IBA:GO_Central. DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:ParkinsonsUK-UCL. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0097413; C:Lewy body; IDA:MGI. DR GO; GO:0005764; C:lysosome; TAS:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005759; C:mitochondrial matrix; IEA:Ensembl. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central. DR GO; GO:0005640; C:nuclear outer membrane; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0032991; C:protein-containing complex; IMP:UniProtKB. DR GO; GO:0005840; C:ribosome; IEA:Ensembl. DR GO; GO:0099512; C:supramolecular fiber; IDA:UniProtKB. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; IPI:ARUK-UCL. DR GO; GO:0043014; F:alpha-tubulin binding; IPI:UniProtKB. DR GO; GO:0048487; F:beta-tubulin binding; IEA:Ensembl. DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903136; F:cuprous ion binding; IMP:CAFA. DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IDA:UniProtKB. DR GO; GO:0070840; F:dynein complex binding; IPI:UniProtKB. DR GO; GO:0008047; F:enzyme activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:BHF-UCL. DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB. DR GO; GO:0042393; F:histone binding; IDA:UniProtKB. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0019894; F:kinesin binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; EXP:DisProt. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IEA:Ensembl. DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB. DR GO; GO:0043274; F:phospholipase binding; IEA:Ensembl. DR GO; GO:0005543; F:phospholipid binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0051219; F:phosphoprotein binding; IDA:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl. DR GO; GO:0004860; F:protein kinase inhibitor activity; TAS:ARUK-UCL. DR GO; GO:0140311; F:protein sequestering activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0000149; F:SNARE binding; IDA:UniProtKB. DR GO; GO:0048156; F:tau protein binding; IDA:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0141108; F:transporter regulator activity; IGI:ARUK-UCL. DR GO; GO:0015631; F:tubulin binding; EXP:DisProt. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:1990000; P:amyloid fibril formation; EXP:DisProt. DR GO; GO:0048148; P:behavioral response to cocaine; IEA:Ensembl. DR GO; GO:0071280; P:cellular response to copper ion; IDA:UniProtKB. DR GO; GO:0071872; P:cellular response to epinephrine stimulus; TAS:UniProtKB. DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; IEA:Ensembl. DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0042416; P:dopamine biosynthetic process; TAS:UniProtKB. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; TAS:UniProtKB. DR GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:0006631; P:fatty acid metabolic process; IEA:Ensembl. DR GO; GO:0006749; P:glutathione metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0042775; P:mitochondrial ATP synthesis coupled electron transport; IEA:Ensembl. DR GO; GO:0007006; P:mitochondrial membrane organization; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:1904715; P:negative regulation of chaperone-mediated autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0045963; P:negative regulation of dopamine metabolic process; IEA:Ensembl. DR GO; GO:0051585; P:negative regulation of dopamine uptake involved in synaptic transmission; IDA:UniProtKB. DR GO; GO:0045920; P:negative regulation of exocytosis; IMP:UniProtKB. DR GO; GO:0031115; P:negative regulation of microtubule polymerization; IDA:BHF-UCL. DR GO; GO:1902957; P:negative regulation of mitochondrial electron transport, NADH to ubiquinone; TAS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051622; P:negative regulation of norepinephrine uptake; IDA:UniProtKB. DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0051612; P:negative regulation of serotonin uptake; IDA:UniProtKB. DR GO; GO:0070495; P:negative regulation of thrombin-activated receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:ParkinsonsUK-UCL. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0006638; P:neutral lipid metabolic process; IEA:Ensembl. DR GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:UniProtKB. DR GO; GO:0045921; P:positive regulation of exocytosis; IMP:UniProtKB. DR GO; GO:1903285; P:positive regulation of hydrogen peroxide catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:ParkinsonsUK-UCL. DR GO; GO:0060732; P:positive regulation of inositol phosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0001956; P:positive regulation of neurotransmitter secretion; IEA:Ensembl. DR GO; GO:1904377; P:positive regulation of protein localization to cell periphery; IGI:ParkinsonsUK-UCL. DR GO; GO:0001921; P:positive regulation of receptor recycling; IDA:UniProtKB. DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:UniProtKB. DR GO; GO:0035543; P:positive regulation of SNARE complex assembly; IDA:CACAO. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB. DR GO; GO:0031623; P:receptor internalization; IDA:UniProtKB. DR GO; GO:0050812; P:regulation of acyl-CoA biosynthetic process; IEA:Ensembl. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:UniProtKB. DR GO; GO:0014048; P:regulation of glutamate secretion; IEA:Ensembl. DR GO; GO:0040012; P:regulation of locomotion; IEA:Ensembl. DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl. DR GO; GO:0043030; P:regulation of macrophage activation; IEA:Ensembl. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:BHF-UCL. DR GO; GO:0051621; P:regulation of norepinephrine uptake; IGI:ARUK-UCL. DR GO; GO:1905606; P:regulation of presynapse assembly; IGI:ARUK-UCL. DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1903421; P:regulation of synaptic vesicle recycling; TAS:ParkinsonsUK-UCL. DR GO; GO:1904307; P:response to desipramine; IEA:Ensembl. DR GO; GO:0070555; P:response to interleukin-1; IDA:UniProtKB. DR GO; GO:0010040; P:response to iron(II) ion; IDA:UniProtKB. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0032026; P:response to magnesium ion; IDA:UniProtKB. DR GO; GO:0034341; P:response to type II interferon; IDA:UniProtKB. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0035493; P:SNARE complex assembly; IDA:UniProtKB. DR GO; GO:0097435; P:supramolecular fiber organization; TAS:UniProtKB. DR GO; GO:0050808; P:synapse organization; IBA:GO_Central. DR GO; GO:0048488; P:synaptic vesicle endocytosis; ISS:UniProtKB. DR GO; GO:0016079; P:synaptic vesicle exocytosis; IDA:UniProtKB. DR GO; GO:0016082; P:synaptic vesicle priming; IMP:UniProtKB. DR GO; GO:0048489; P:synaptic vesicle transport; IEA:Ensembl. DR DisProt; DP00070; -. DR FunFam; 1.10.287.700:FF:000001; Alpha-synuclein; 1. DR Gene3D; 1.10.287.700; Helix hairpin bin; 1. DR IDEAL; IID00302; -. DR InterPro; IPR001058; Synuclein. DR InterPro; IPR002460; Synuclein_alpha. DR PANTHER; PTHR13820:SF5; ALPHA-SYNUCLEIN; 1. DR PANTHER; PTHR13820; SYNUCLEIN; 1. DR Pfam; PF01387; Synuclein; 1. DR PRINTS; PR01212; ASYNUCLEIN. DR PRINTS; PR01211; SYNUCLEIN. DR SUPFAM; SSF118375; Synuclein; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Alzheimer disease; KW Amyloid; Cell projection; Copper; Cytoplasm; Direct protein sequencing; KW Disease variant; Membrane; Metal-binding; Neurodegeneration; Nucleus; KW Parkinson disease; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Repeat; Secreted; Synapse; Ubl conjugation. FT CHAIN 1..140 FT /note="Alpha-synuclein" FT /id="PRO_0000184022" FT REPEAT 20..30 FT /note="1" FT REPEAT 31..41 FT /note="2" FT REPEAT 42..56 FT /note="3; approximate" FT REPEAT 57..67 FT /note="4" FT REGION 20..67 FT /note="4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V- FT X(4)" FT REGION 100..140 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 111..140 FT /note="Interaction with SERF1A" FT /evidence="ECO:0000269|PubMed:22854022" FT COMPBIAS 112..140 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 2 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT BINDING 50 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:22407793" FT MOD_RES 87 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:10617630" FT MOD_RES 125 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:11162638, FT ECO:0000269|PubMed:12893833" FT MOD_RES 129 FT /note="Phosphoserine; by BARK1, PLK2, CK2, CK1 and GRK5" FT /evidence="ECO:0000269|PubMed:10617630, FT ECO:0000269|PubMed:11813001, ECO:0000269|PubMed:24936070" FT VAR_SEQ 41..54 FT /note="Missing (in isoform 2-5)" FT /evidence="ECO:0000303|PubMed:7601450" FT /id="VSP_006363" FT VAR_SEQ 103..130 FT /note="Missing (in isoform 2-4)" FT /evidence="ECO:0000303|PubMed:7601450, FT ECO:0000303|PubMed:7802671" FT /id="VSP_006364" FT VARIANT 30 FT /note="A -> P (in PARK1; no effect on oligomerization; FT dbSNP:rs104893878)" FT /evidence="ECO:0000269|PubMed:25561023, FT ECO:0000269|PubMed:9462735" FT /id="VAR_007957" FT VARIANT 46 FT /note="E -> K (in PARK1 and DLB; significant increase in FT binding to negatively charged phospholipid liposomes; FT increases oligomerization; dbSNP:rs104893875)" FT /evidence="ECO:0000269|PubMed:14755719, FT ECO:0000269|PubMed:15498564, ECO:0000269|PubMed:25561023" FT /id="VAR_022703" FT VARIANT 50 FT /note="H -> Q (in PARK1; no effect on protein structure; no FT effect on phosphorylation of the protein; no effect on FT membrane- and lipid-binding; increases oligomerization; FT increases fibril formation; increases secretion of the FT protein; impairs copper-binding; dbSNP:rs201106962)" FT /evidence="ECO:0000269|PubMed:23427326, FT ECO:0000269|PubMed:23457019, ECO:0000269|PubMed:24936070, FT ECO:0000269|PubMed:25561023" FT /id="VAR_070171" FT VARIANT 53 FT /note="A -> T (in PARK1; no effect on osmotic stress- FT induced phosphorylation; increases oligomerization; FT dbSNP:rs104893877)" FT /evidence="ECO:0000269|PubMed:12893833, FT ECO:0000269|PubMed:25561023, ECO:0000269|PubMed:9197268" FT /id="VAR_007454" FT MUTAGEN 2 FT /note="D->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 35 FT /note="E->K: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 39 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 50 FT /note="H->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 57 FT /note="E->K: Increases oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 67..71 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 71..82 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76..77 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT MUTAGEN 77 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 78 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 85..94 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 125 FT /note="Y->F: Abolishes osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 133 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 136 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT HELIX 3..11 FT /evidence="ECO:0007829|PDB:3Q25" FT STRAND 16..18 FT /evidence="ECO:0007829|PDB:7YK8" FT HELIX 21..32 FT /evidence="ECO:0007829|PDB:3Q26" FT STRAND 34..36 FT /evidence="ECO:0007829|PDB:8A4L" FT STRAND 38..40 FT /evidence="ECO:0007829|PDB:7V48" FT HELIX 41..44 FT /evidence="ECO:0007829|PDB:3Q27" FT STRAND 45..49 FT /evidence="ECO:0007829|PDB:8PJO" FT STRAND 52..55 FT /evidence="ECO:0007829|PDB:8JJV" FT STRAND 57..59 FT /evidence="ECO:0007829|PDB:8RQM" FT STRAND 60..63 FT /evidence="ECO:0007829|PDB:9FYP" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:3Q28" FT STRAND 70..72 FT /evidence="ECO:0007829|PDB:7YNP" FT STRAND 73..83 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 84..86 FT /evidence="ECO:0007829|PDB:8AEX" FT STRAND 88..96 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 110..113 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 120..122 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 124..126 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 133..136 FT /evidence="ECO:0007829|PDB:2N0A" SQ SEQUENCE 140 AA; 14460 MW; 6BB2F12128931663 CRC64; MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP DNEAYEMPSE EGYQDYEPEA // 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 UCHL1_HUMAN Reviewed; 223 AA. AC P09936; Q4W5K6; Q71UM0; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1990, sequence version 2. DT 28-JAN-2026, entry version 248. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1; DE Short=UCH-L1; DE EC=3.4.19.12 {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; DE AltName: Full=Neuron cytoplasmic protein 9.5; DE AltName: Full=PGP 9.5; DE Short=PGP9.5; DE AltName: Full=Ubiquitin thioesterase L1; DE Flags: Precursor; GN Name=UCHL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, and Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-15. RX PubMed=2163617; DOI=10.1042/bj2680521; RA Day I.N.M., Hinks L.J., Thompson R.J.; RT "The structure of the human gene encoding protein gene product 9.5 RT (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase."; RL Biochem. J. 268:521-524(1990). RN [5] RP PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION, RP IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY. RX PubMed=14722078; DOI=10.1074/jbc.m314124200; RA Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S., RA Li L.; RT "Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal RT hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's RT diseases."; RL J. Biol. Chem. 279:13256-13264(2004). RN [6] RP PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE. RX PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3; RA Day I.N.M., Thompson R.J.; RT "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel RT cytoplasmic marker for neurones and neuroendocrine cells."; RL FEBS Lett. 210:157-160(1987). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, VARIANT PARK5 MET-93, AND CHARACTERIZATION RP OF VARIANT PARK5 MET-93. RX PubMed=9774100; DOI=10.1038/26652; RA Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., RA Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C., RA Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.; RT "The ubiquitin pathway in Parkinson's disease."; RL Nature 395:451-452(1998). RN [9] RP PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151. RX PubMed=1849484; DOI=10.1016/0014-5793(91)80300-r; RA Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.; RT "Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured RT human MRC-5 fibroblasts of normal origin and is strongly down-regulated in RT their SV40 transformed counterparts."; RL FEBS Lett. 280:235-240(1991). RN [10] RP PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151. RX PubMed=1286667; DOI=10.1002/elps.11501301199; RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E., RA Vandekerckhove J.; RT "Microsequences of 145 proteins recorded in the two-dimensional gel protein RT database of normal human epidermal keratinocytes."; RL Electrophoresis 13:960-969(1992). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90; RP HIS-97; HIS-161 AND ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=8639624; DOI=10.1021/bi960099f; RA Larsen C.N., Price J.S., Wilkinson K.D.; RT "Substrate binding and catalysis by ubiquitin C-terminal hydrolases: RT identification of two active site residues."; RL Biochemistry 35:6735-6744(1996). RN [12] RP TISSUE SPECIFICITY. RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532; RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.; RT "Cleavage of the C-terminus of NEDD8 by UCH-L3."; RL Biochem. Biophys. Res. Commun. 251:688-692(1998). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND RP CHARACTERIZATION OF VARIANT TYR-18. RX PubMed=12408865; DOI=10.1016/s0092-8674(02)01012-7; RA Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.; RT "The UCH-L1 gene encodes two opposing enzymatic activities that affect RT alpha-synuclein degradation and Parkinson's disease susceptibility."; RL Cell 111:209-218(2002). RN [14] RP INTERACTION WITH COPS5. RX PubMed=12082530; DOI=10.1038/sj.onc.1205390; RA Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J., RA Yochem R., Ratovitski E., Sidransky D., Jen J.; RT "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)."; RL Oncogene 21:3003-3010(2002). RN [15] RP CATALYTIC ACTIVITY, AND ACTIVE SITE. RX PubMed=16475834; DOI=10.1021/bi052135t; RA Case A., Stein R.L.; RT "Mechanistic studies of ubiquitin C-terminal hydrolase L1."; RL Biochemistry 45:2443-2452(2006). RN [16] RP SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220. RX PubMed=19261853; DOI=10.1073/pnas.0806474106; RA Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A., Cookson M.R., RA Liu Y., Logan T., Lansbury P.T. Jr.; RT "Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein RT neurotoxicity and is a therapeutic target for Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP FUNCTION. RX PubMed=22212137; DOI=10.1111/j.1471-4159.2011.07644.x; RA Zhang M., Deng Y., Luo Y., Zhang S., Zou H., Cai F., Wada K., Song W.; RT "Control of BACE1 degradation and APP processing by ubiquitin carboxyl- RT terminal hydrolase L1."; RL J. Neurochem. 120:1129-1138(2012). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS SPG79B ALA-7 AND MET-93, RP CHARACTERIZATION OF VARIANT SPG79B ALA-7, AND MUTAGENESIS OF CYS-90. RX PubMed=23359680; DOI=10.1073/pnas.1222732110; RA Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M., Choi M., RA Delil S., Caglayan A.O., Baranoski J.F., Erturk O., Yalcinkaya C., RA Karacorlu M., Dincer A., Johnson M.H., Mane S., Chandra S.S., Louvi A., RA Boggon T.J., Lifton R.P., Horwich A.L., Gunel M.; RT "Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads RT to early-onset progressive neurodegeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013). RN [21] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-90. RX PubMed=25615526; DOI=10.1038/ncomms7153; RA Goto Y., Zeng L., Yeom C.J., Zhu Y., Morinibu A., Shinomiya K., RA Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M., RA Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond E.M., RA Hiraoka M., Harada H.; RT "UCHL1 provides diagnostic and antimetastatic strategies due to its RT deubiquitinating effect on HIF-1alpha."; RL Nat. Commun. 6:6153-6153(2015). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY (ISOFORMS 2 AND 3), AND ACETYLATION AT RP MET-1 (ISOFORMS 1; 2 AND 3). RX PubMed=37316325; DOI=10.26508/lsa.202301972; RA Bogaert A., Fijalkowska D., Staes A., Van de Steene T., Vuylsteke M., RA Stadler C., Eyckerman S., Spirohn K., Hao T., Calderwood M.A., Gevaert K.; RT "N-terminal proteoforms may engage in different protein complexes."; RL Life. Sci Alliance 6:0-0(2023). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT. RX PubMed=16537382; DOI=10.1073/pnas.0510403103; RA Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K., Ray S.S., RA Lansbury P.T., Ringe D., Petsko G.A.; RT "Structural basis for conformational plasticity of the Parkinson's disease- RT associated ubiquitin hydrolase UCH-L1."; RL Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN RP COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF RP CYS-90 AND PHE-204. RX PubMed=20439756; DOI=10.1073/pnas.0910870107; RA Boudreaux D.A., Maiti T.K., Davies C.W., Das C.; RT "Ubiquitin vinyl methyl ester binding orients the misaligned active site of RT the ubiquitin hydrolase UCHL1 into productive conformation."; RL Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010). RN [25] RP CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT RP TYR-18, MUTAGENESIS OF CYS-90, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=12705903; DOI=10.1016/s0006-291x(03)00555-2; RA Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y., RA Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.; RT "Alterations of structure and hydrolase activity of parkinsonism-associated RT human ubiquitin carboxyl-terminal hydrolase L1 variants."; RL Biochem. Biophys. Res. Commun. 304:176-183(2003). RN [26] RP VARIANT MET-93. RX PubMed=10454131; DOI=10.1016/s0304-3940(99)00465-6; RA Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G., RA De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B., RA Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.; RT "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene RT is not observed in European cases with familial Parkinson's disease."; RL Neurosci. Lett. 270:1-4(1999). RN [27] RP VARIANT TYR-18. RX PubMed=10203348; DOI=10.1097/00001756-199902050-00040; RA Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K., RA Lynch T., Hardy J., Farrer M.; RT "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal RT hydrolase gene in familial Parkinson's disease."; RL NeuroReport 10:427-429(1999). RN [28] RP VARIANT TYR-18. RX PubMed=11027850; DOI=10.1016/s0304-3940(00)01510-x; RA Mellick G.D., Silburn P.A.; RT "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does RT not confer protection against idiopathic Parkinson's disease."; RL Neurosci. Lett. 293:127-130(2000). RN [29] RP VARIANT TYR-18. RX PubMed=15048890; DOI=10.1002/ana.20017; RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RT "UCHL1 is a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 55:512-521(2004). RN [30] RP ERRATUM OF PUBMED:15048890. RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RL Ann. Neurol. 55:899-899(2004). RN [31] RP VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON RP DISEASE. RX PubMed=16450370; DOI=10.1002/ana.20757; RA Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T., RA Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P., Quinn N.P., RA Lees A.J., Gibson J.M., Holton J.L., Revesz T., Goldstein D.B., Wood N.W.; RT "UCHL-1 is not a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 59:627-633(2006). RN [32] RP CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN NEURONAL RP CELLS. RX PubMed=18411255; DOI=10.1093/hmg/ddn115; RA Kyratzi E., Pavlaki M., Stefanis L.; RT "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to RT neuronal cells."; RL Hum. Mol. Genet. 17:2160-2171(2008). RN [33] RP VARIANT TYR-18. RX PubMed=21268678; DOI=10.3109/13816810.2010.544360; RA Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A., Andreasen N., RA Tasa G., Juronen E., Blennow K., Zetterberg H., Zetterberg M.; RT "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in RT patients with cataracts."; RL Ophthalmic Genet. 32:75-79(2011). RN [34] RP VARIANTS SPG79B GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS RP SPG79B GLN-178 AND ASP-216. RX PubMed=28007905; DOI=10.1093/hmg/ddw391; RA Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y., RA Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D., Bjoeraas M., RA Tallaksen C.M., Selmer K.K.; RT "Novel UCHL1 mutations reveal new insights into ubiquitin processing."; RL Hum. Mol. Genet. 26:1031-1040(2017). RN [35] RP VARIANTS SPG79A 2-GLN--ALA-223 DEL; 25-GLN--ALA-223 DEL; LEU-52 INS; RP 178-ARG--ALA-223 DEL AND 211-GLU--ALA-223 DEL, AND INVOLVEMENT IN SPG79A. RX PubMed=35986737; DOI=10.1016/j.gim.2022.07.006; RG Genomics England Research Consortium; RA Park J., Tucci A., Cipriani V., Demidov G., Rocca C., Senderek J., RA Butryn M., Velic A., Lam T., Galanaki E., Cali E., Vestito L., RA Maroofian R., Deininger N., Rautenberg M., Admard J., Hahn G.A., RA Bartels C., van Os N.J.H., Horvath R., Chinnery P.F., Tiet M.Y., RA Hewamadduma C., Hadjivassiliou M., Tofaris G.K., Wood N.W., Hayer S.N., RA Bender F., Menden B., Cordts I., Klein K., Nguyen H.P., Krauss J.K., RA Blahak C., Strom T.M., Sturm M., van de Warrenburg B., Lerche H., Macek B., RA Synofzik M., Ossowski S., Timmann D., Wolf M.E., Smedley D., Riess O., RA Schoels L., Houlden H., Haack T.B., Hengel H.; RT "Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative RT disorder with spasticity, ataxia, neuropathy, and optic atrophy."; RL Genet. Med. 24:2079-2090(2022). CC -!- FUNCTION: Deubiquitinase that plays a role in the regulation of several CC processes such as maintenance of synaptic function, cardiac function, CC inflammatory response or osteoclastogenesis (PubMed:22212137, CC PubMed:23359680). Abrogates the ubiquitination of multiple proteins CC including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor CC protein cleaving enzyme 1/BACE1 (PubMed:22212137, PubMed:25615526). In CC addition, recognizes and hydrolyzes a peptide bond at the C-terminal CC glycine of ubiquitin to maintain a stable pool of monoubiquitin that is CC a key requirement for the ubiquitin-proteasome and the autophagy- CC lysosome pathways (PubMed:12408865, PubMed:8639624, PubMed:9774100). CC Regulates amyloid precursor protein/APP processing by promoting BACE1 CC degradation resulting in decreased amyloid beta production CC (PubMed:22212137). Plays a role in the immune response by regulating CC the ability of MHC I molecules to reach cross-presentation compartments CC competent for generating Ag-MHC I complexes (By similarity). Mediates CC the 'Lys-48'-linked deubiquitination of the transcriptional coactivator CC WWTR1/TAZ leading to its stabilization and inhibition of CC osteoclastogenesis (By similarity). Deubiquitinates and stabilizes CC epidermal growth factor receptor EGFR to prevent its degradation and to CC activate its downstream mediators (By similarity). Modulates oxidative CC activity in skeletal muscle by regulating key mitochondrial oxidative CC proteins (By similarity). Enhances the activity of hypoxia-inducible CC factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated CC ubiquitination and consequently inhibiting its degradation CC (PubMed:25615526). {ECO:0000250|UniProtKB:Q9R0P9, CC ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:22212137, CC ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:25615526, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:12408865, CC ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, CC ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC KM=1.20 uM for ubiquitin ethyl ester {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC Vmax=0.47 umol/min/mg enzyme toward Ub-AMC CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity). CC Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530, CC ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}. CC -!- INTERACTION: CC P09936; P63010-2: AP2B1; NbExp=3; IntAct=EBI-714860, EBI-11529439; CC P09936; P05067: APP; NbExp=5; IntAct=EBI-714860, EBI-77613; CC P09936; P05067-2: APP; NbExp=3; IntAct=EBI-714860, EBI-17264467; CC P09936; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-714860, EBI-10694449; CC P09936; P18847: ATF3; NbExp=3; IntAct=EBI-714860, EBI-712767; CC P09936; Q9H1Y0: ATG5; NbExp=4; IntAct=EBI-714860, EBI-1047414; CC P09936; O15392: BIRC5; NbExp=3; IntAct=EBI-714860, EBI-518823; CC P09936; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-714860, EBI-2837444; CC P09936; P83916: CBX1; NbExp=4; IntAct=EBI-714860, EBI-78129; CC P09936; P11802: CDK4; NbExp=4; IntAct=EBI-714860, EBI-295644; CC P09936; Q00535: CDK5; NbExp=2; IntAct=EBI-714860, EBI-1041567; CC P09936; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-714860, EBI-350590; CC P09936; Q92905: COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661; CC P09936; P00533: EGFR; NbExp=3; IntAct=EBI-714860, EBI-297353; CC P09936; O60739: EIF1B; NbExp=4; IntAct=EBI-714860, EBI-1043343; CC P09936; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-714860, EBI-9246952; CC P09936; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-714860, EBI-6448852; CC P09936; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-714860, EBI-25845242; CC P09936; Q14164: IKBKE; NbExp=4; IntAct=EBI-714860, EBI-307369; CC P09936; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-714860, EBI-21911304; CC P09936; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-714860, EBI-11985629; CC P09936; P13473-2: LAMP2; NbExp=3; IntAct=EBI-714860, EBI-21591415; CC P09936; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-714860, EBI-1108377; CC P09936; O95777: LSM8; NbExp=3; IntAct=EBI-714860, EBI-347779; CC P09936; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-714860, EBI-21250407; CC P09936; Q15843: NEDD8; NbExp=4; IntAct=EBI-714860, EBI-716247; CC P09936; O15381-5: NVL; NbExp=3; IntAct=EBI-714860, EBI-18577082; CC P09936; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-714860, EBI-22012354; CC P09936; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-714860, EBI-716063; CC P09936; P62826: RAN; NbExp=3; IntAct=EBI-714860, EBI-286642; CC P09936; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-714860, EBI-746555; CC P09936; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-714860, EBI-25829984; CC P09936; Q15554-4: TERF2; NbExp=3; IntAct=EBI-714860, EBI-25840535; CC P09936; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109; CC P09936; P04637: TP53; NbExp=3; IntAct=EBI-714860, EBI-366083; CC P09936; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-714860, EBI-359276; CC P09936; P19474: TRIM21; NbExp=3; IntAct=EBI-714860, EBI-81290; CC P09936; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-714860, EBI-749370; CC P09936; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-714860, EBI-10180829; CC P09936; P61086: UBE2K; NbExp=3; IntAct=EBI-714860, EBI-473850; CC P09936; Q9UK80: USP21; NbExp=4; IntAct=EBI-714860, EBI-373242; CC P09936; Q86WB0-2: ZC3HC1; NbExp=3; IntAct=EBI-714860, EBI-25894765; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}. CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853}; Lipid- CC anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of total UCHL1 is CC associated with membranes in brain. Localizes near and/or within CC mitochondria to potentially interact with mitochondrial proteins. CC {ECO:0000250|UniProtKB:Q9R0P9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=3; CC Name=1; CC IsoId=P09936-1; Sequence=Displayed; CC Name=2; CC IsoId=P09936-2; Sequence=VSP_062524; CC Name=3; CC IsoId=P09936-3; Sequence=VSP_062523; CC -!- TISSUE SPECIFICITY: Found in neuronal cell bodies and processes CC throughout the neocortex (at protein level). Expressed in neurons and CC cells of the diffuse neuroendocrine system and their tumors. Weakly CC expressed in ovary. Down-regulated in brains from Parkinson disease and CC Alzheimer disease patients. {ECO:0000269|PubMed:14722078, CC ECO:0000269|PubMed:9790970}. CC -!- PTM: O-glycosylated. {ECO:0000250}. CC -!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex CC neurodegenerative disorder with manifestations ranging from typical CC Parkinson disease to dementia with Lewy bodies. Clinical features CC include parkinsonian symptoms (resting tremor, rigidity, postural CC instability and bradykinesia), dementia, diffuse Lewy body pathology, CC autonomic dysfunction, hallucinations and paranoia. CC {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:9774100}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79A, autosomal dominant, with ataxia CC (SPG79A) [MIM:620221]: A form of spastic paraplegia, a CC neurodegenerative disorder characterized by a slow, gradual, CC progressive weakness and spasticity of the lower limbs. Rate of CC progression and the severity of symptoms are quite variable. Initial CC symptoms may include difficulty with balance, weakness and stiffness in CC the legs, muscle spasms, and dragging the toes when walking. In some CC forms of the disorder, bladder symptoms (such as incontinence) may CC appear, or the weakness and stiffness may spread to other parts of the CC body. SPG79A is a slowly progressive form characterized by late-onset CC spastic ataxia, neuropathy, and often optic atrophy. CC {ECO:0000269|PubMed:35986737}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79B, autosomal recessive (SPG79B) CC [MIM:615491]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. SPG79B is CC characterized by childhood onset blindness, cerebellar ataxia, CC nystagmus, dorsal column dysfunction, and spasticity with upper motor CC neuron dysfunction. {ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:28007905}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 CC to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic CC acid have been observed in brains from Alzheimer disease (AD) and CC Parkinson disease (PD) patients. In AD, UCHL1 was found to be CC associated with neurofibrillary tangles. In contrast to UCHL3, does not CC hydrolyze a peptide bond at the C-terminal glycine of NEDD8. CC -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}. CC -!- CAUTION: PubMed:9774100 reports the association of mutation Ile93Met CC with Parkinson disease. However, according to PubMed:16450370 this CC association is uncertain and UCHL1 is not a susceptibility gene for CC Parkinson disease. {ECO:0000305}. CC -!- CAUTION: The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179 CC and Cys-220 are subject of controversy and could be the artifactual CC results of sample handling. {ECO:0000305|PubMed:14722078}. CC -!- CAUTION: The homodimer may have ATP-independent ubiquitin ligase CC activity (PubMed:12408865). However, in another study, UCHL1 was shown CC to lack ubiquitin ligase activity (PubMed:23359680). CC {ECO:0000269|PubMed:23359680, ECO:0000305|PubMed:12408865}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA28443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal hydrolase CC L1 entry; CC URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1"; 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; AC095043; AAY40923.1; -; Genomic_DNA. DR EMBL; CH471069; EAW92983.1; -; Genomic_DNA. DR EMBL; BC000332; AAH00332.1; -; mRNA. DR EMBL; BC005117; AAH05117.1; -; mRNA. DR EMBL; BC006305; AAH06305.1; -; mRNA. DR EMBL; X17377; CAA35249.1; -; Genomic_DNA. DR EMBL; X04741; CAA28443.1; ALT_INIT; mRNA. DR EMBL; AH007277; AAD09172.1; -; Genomic_DNA. DR CCDS; CCDS3462.1; -. [P09936-1] DR PIR; A25856; A25856. DR RefSeq; NP_004172.2; NM_004181.4. [P09936-1] DR PDB; 2ETL; X-ray; 2.40 A; A/B=1-223. DR PDB; 2LEN; NMR; -; A=1-223. DR PDB; 3IFW; X-ray; 2.40 A; A=1-223. DR PDB; 3IRT; X-ray; 2.80 A; A/B=1-223. DR PDB; 3KVF; X-ray; 2.80 A; A=1-223. DR PDB; 3KW5; X-ray; 2.83 A; A=1-223. DR PDB; 4DM9; X-ray; 2.35 A; A/B=1-223. DR PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223. DR PDB; 7ZM0; X-ray; 2.24 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8DY8; X-ray; 2.10 A; A/B=1-223. DR PDB; 8EDE; X-ray; 1.80 A; A/B=1-223. DR PDB; 8PW1; X-ray; 2.20 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8XI7; X-ray; 1.95 A; A/B=1-223. DR PDB; 9O4M; X-ray; 2.00 A; A/B=1-223. DR PDBsum; 2ETL; -. DR PDBsum; 2LEN; -. DR PDBsum; 3IFW; -. DR PDBsum; 3IRT; -. DR PDBsum; 3KVF; -. DR PDBsum; 3KW5; -. DR PDBsum; 4DM9; -. DR PDBsum; 4JKJ; -. DR PDBsum; 7ZM0; -. DR PDBsum; 8DY8; -. DR PDBsum; 8EDE; -. DR PDBsum; 8PW1; -. DR PDBsum; 8XI7; -. DR PDBsum; 9O4M; -. DR AlphaFoldDB; P09936; -. DR BMRB; P09936; -. DR SASBDB; P09936; -. DR SMR; P09936; -. DR BioGRID; 113192; 258. DR CORUM; P09936; -. DR DIP; DIP-36620N; -. DR FunCoup; P09936; 1475. DR IntAct; P09936; 199. DR MINT; P09936; -. DR STRING; 9606.ENSP00000284440; -. DR BindingDB; P09936; -. DR ChEMBL; CHEMBL6159; -. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR GuidetoPHARMACOLOGY; 2426; -. DR MEROPS; C12.001; -. DR GlyGen; P09936; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P09936; -. DR MetOSite; P09936; -. DR PhosphoSitePlus; P09936; -. DR SwissPalm; P09936; -. DR BioMuta; UCHL1; -. DR DMDM; 136681; -. DR CPTAC; CPTAC-601; -. DR CPTAC; CPTAC-602; -. DR jPOST; P09936; -. DR MassIVE; P09936; -. DR PaxDb; 9606-ENSP00000284440; -. DR PeptideAtlas; P09936; -. DR ProteomicsDB; 52282; -. DR Pumba; P09936; -. DR Antibodypedia; 1062; 2368 antibodies from 53 providers. DR DNASU; 7345; -. DR Ensembl; ENST00000284440.9; ENSP00000284440.4; ENSG00000154277.14. [P09936-1] DR Ensembl; ENST00000503431.5; ENSP00000422542.1; ENSG00000154277.14. [P09936-1] DR GeneID; 7345; -. DR KEGG; hsa:7345; -. DR MANE-Select; ENST00000284440.9; ENSP00000284440.4; NM_004181.5; NP_004172.2. DR AGR; HGNC:12513; -. DR ClinPGx; PA37160; -. DR CTD; 7345; -. DR DisGeNET; 7345; -. DR GeneCards; UCHL1; -. DR HGNC; HGNC:12513; UCHL1. DR HPA; ENSG00000154277; Group enriched (brain, pituitary gland). DR MalaCards; UCHL1; -. DR MIM; 191342; gene. DR MIM; 613643; phenotype. DR MIM; 615491; phenotype. DR MIM; 620221; phenotype. DR OpenTargets; ENSG00000154277; -. DR Orphanet; 352654; Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000154277; -. DR eggNOG; KOG1415; Eukaryota. DR GeneTree; ENSGT00940000157306; -. DR HOGENOM; CLU_054406_2_0_1; -. DR InParanoid; P09936; -. DR OMA; AQTYSKH; -. DR OrthoDB; 427186at2759; -. DR PAN-GO; P09936; 3 GO annotations based on evolutionary models. DR PhylomeDB; P09936; -. DR BRENDA; 3.4.19.12; 2681. DR PathwayCommons; P09936; -. DR Reactome; R-HSA-5689603; UCH proteinases. DR SABIO-RK; P09936; -. DR SignaLink; P09936; -. DR SIGNOR; P09936; -. DR Agora; ENSG00000154277; -. DR BioGRID-ORCS; 7345; 9 hits in 1196 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; UCHL1; human. DR EvolutionaryTrace; P09936; -. DR GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -. DR GenomeRNAi; 7345; -. DR Pharos; P09936; Tchem. DR PRO; PR:P09936; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P09936; protein. DR Bgee; ENSG00000154277; Expressed in pons and 169 other cell types or tissues. DR ExpressionAtlas; P09936; baseline and differential. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB. DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl. DR GO; GO:0030547; F:signaling receptor inhibitor activity; IDA:BHF-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0007412; P:axon target recognition; IEA:Ensembl. DR GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0002176; P:male germ cell proliferation; IEA:Ensembl. DR GO; GO:0055001; P:muscle cell development; IEA:Ensembl. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl. DR GO; GO:0045821; P:positive regulation of glycolytic process; IMP:FlyBase. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IBA:GO_Central. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR CDD; cd09616; Peptidase_C12_UCH_L1_L3; 1. DR FunFam; 3.40.532.10:FF:000004; Ubiquitin carboxyl-terminal hydrolase; 1. DR Gene3D; 3.40.532.10; Peptidase C12, ubiquitin carboxyl-terminal hydrolase; 1. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001578; Peptidase_C12_UCH. DR InterPro; IPR036959; Peptidase_C12_UCH_sf. DR InterPro; IPR057254; UCH_AS. DR PANTHER; PTHR10589; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR10589:SF19; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L1; 1. DR Pfam; PF01088; Peptidase_C12; 1. DR PRINTS; PR00707; UBCTHYDRLASE. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00140; UCH_1; 1. DR PROSITE; PS52048; UCH_DOMAIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Cytoplasm; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Glycoprotein; Hereditary spastic paraplegia; Hydrolase; Lipoprotein; KW Membrane; Neurodegeneration; Oxidation; Parkinson disease; Parkinsonism; KW Phosphoprotein; Prenylation; Protease; Proteomics identification; KW Reference proteome; Thiol protease; Ubl conjugation pathway. FT CHAIN 1..220 FT /note="Ubiquitin carboxyl-terminal hydrolase isozyme L1" FT /id="PRO_0000211055" FT PROPEP 221..223 FT /note="Removed in mature form" FT /evidence="ECO:0000305" FT /id="PRO_0000414311" FT DOMAIN 2..221 FT /note="UCH catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT REGION 5..10 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT REGION 211..216 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT ACT_SITE 90 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT ACT_SITE 161 FT /note="Proton donor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT SITE 1 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 6 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 12 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 84 FT /note="Transition state stabilizer" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:8639624" FT SITE 124 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 176 FT /note="Important for enzyme activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT SITE 179 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 220 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES 125 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q00981" FT LIPID 220 FT /note="S-farnesyl cysteine" FT /evidence="ECO:0000269|PubMed:19261853" FT VAR_SEQ 1..11 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062523" FT VAR_SEQ 1..5 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062524" FT VARIANT 2..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087898" FT VARIANT 7 FT /note="E -> A (in SPG79B; has decreased binding to FT ubiquitin and significantly decreased hydrolase activity FT compared to wild-type; dbSNP:rs397515634)" FT /evidence="ECO:0000269|PubMed:23359680" FT /id="VAR_070875" FT VARIANT 18 FT /note="S -> Y (it confers protection from oxidative stress FT when expressed at physiological levels in neuroblastoma FT cells and primary cortical neurons; loss of dimerization FT ability; impaired ligase activity; dbSNP:rs5030732)" FT /evidence="ECO:0000269|PubMed:10203348, FT ECO:0000269|PubMed:11027850, ECO:0000269|PubMed:12408865, FT ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:15048890, FT ECO:0000269|PubMed:16450370, ECO:0000269|PubMed:18411255, FT ECO:0000269|PubMed:21268678" FT /id="VAR_015677" FT VARIANT 25..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087899" FT VARIANT 52 FT /note="L -> LL (in SPG79A; uncertain significance)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087900" FT VARIANT 93 FT /note="I -> M (in PARK5; impaired enzymatic hydrolase FT activity; has about a 50% reduction in catalytic activity FT compared to wild-type protein; dbSNP:rs121917767)" FT /evidence="ECO:0000269|PubMed:10454131, FT ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:9774100" FT /id="VAR_015678" FT VARIANT 178..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087901" FT VARIANT 178 FT /note="R -> Q (in SPG79B; increased hydrolase activity; FT decreased protein abundance; dbSNP:rs768996179)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078119" FT VARIANT 211..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087902" FT VARIANT 216 FT /note="A -> D (in SPG79B; decreased protein abundance; FT dbSNP:rs1057519600)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078120" FT MUTAGEN 73 FT /note="Q->R: No effect on enzymatic parameters." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 90 FT /note="C->S: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, FT ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624" FT MUTAGEN 97 FT /note="H->Q,N: 2-fold increase in affinity for ubiquitin FT ethyl ester, slight reduction in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->D: 10000-fold decrease in enzymatic activity; no FT change in affinity for ubiquitin ethyl ester." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->K,Q,N,Y: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 176 FT /note="D->N: 6-fold decrease in affinity for ubiquitin FT ethyl ester; 97.5% decrease in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 204 FT /note="F->A: Almost complete loss of activity." FT /evidence="ECO:0000269|PubMed:20439756" FT HELIX 10..19 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 22..25 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 27..31 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 36..41 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 46..54 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 57..70 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 71..74 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 86..88 FT /evidence="ECO:0007829|PDB:2LEN" FT HELIX 90..100 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 101..105 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 113..120 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 121..123 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 126..135 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 137..147 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 160..168 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 171..175 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 183..187 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 190..192 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 193..207 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 211..213 FT /evidence="ECO:0007829|PDB:2LEN" FT STRAND 215..220 FT /evidence="ECO:0007829|PDB:8EDE" FT MOD_RES P09936-2:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES P09936-3:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" SQ SEQUENCE 223 AA; 24824 MW; C9E972AC4DA5DA8A CRC64; MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA //