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 CS012_HUMAN Reviewed; 141 AA. AC Q9NSK7; B3KQ16; Q0D2Q0; Q6P4C5; Q9BSL7; DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot. DT 29-MAY-2024, sequence version 4. DT 28-JAN-2026, entry version 140. DE RecName: Full=Protein C19orf12; GN Name=C19orf12; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] {ECO:0000312|EMBL:BAG51878.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Stomach, and Teratocarcinoma; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [2] {ECO:0000312|EMBL:AC010513} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [3] {ECO:0000312|EMBL:AAH04957.1, ECO:0000312|EMBL:AAH09946.1, ECO:0000312|EMBL:AAH17211.2, ECO:0000312|EMBL:AAH63518.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC TISSUE=Brain, Lymph, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] {ECO:0000312|EMBL:CAB82403.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 23-130 (ISOFORMS 1/2). RC TISSUE=Melanoma; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP INVOLVEMENT IN NBIA4. RX PubMed=23521069; DOI=10.1111/cge.12137; RA Schottmann G., Stenzel W., Lutzkendorf S., Schuelke M., Knierim E.; RT "A novel frameshift mutation of C19ORF12 causes NBIA4 with cerebellar RT atrophy and manifests with severe peripheral motor axonal neuropathy."; RL Clin. Genet. 85:290-292(2014). RN [6] RP VARIANTS NBIA4 ARG-42; GLU-54 AND ARG-58, VARIANT NBIA4 MET-11 (ISOFORM 4), RP VARIANTS GLU-131 AND THR-131, SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=21981780; DOI=10.1016/j.ajhg.2011.09.007; RA Hartig M.B., Iuso A., Haack T., Kmiec T., Jurkiewicz E., Heim K., RA Roeber S., Tarabin V., Dusi S., Krajewska-Walasek M., Jozwiak S., RA Hempel M., Winkelmann J., Elstner M., Oexle K., Klopstock T., RA Mueller-Felber W., Gasser T., Trenkwalder C., Tiranti V., Kretzschmar H., RA Schmitz G., Strom T.M., Meitinger T., Prokisch H.; RT "Absence of an orphan mitochondrial protein, c19orf12, causes a distinct RT clinical subtype of neurodegeneration with brain iron accumulation."; RL Am. J. Hum. Genet. 89:543-550(2011). RN [7] RP VARIANT NBIA4 GLY-55 DEL, AND VARIANT NBIA4 MET-11 (ISOFORM 4). RX PubMed=22584950; DOI=10.1007/s00415-012-6521-7; RA Deschauer M., Gaul C., Behrmann C., Prokisch H., Zierz S., Haack T.B.; RT "C19orf12 mutations in neurodegeneration with brain iron accumulation RT mimicking juvenile amyotrophic lateral sclerosis."; RL J. Neurol. 259:2434-2439(2012). RN [8] RP VARIANT NBIA4 GLN-110. RX PubMed=22508347; DOI=10.1002/mds.24980; RA Horvath R., Holinski-Feder E., Neeve V.C., Pyle A., Griffin H., Ashok D., RA Foley C., Hudson G., Rautenstrauss B., Nurnberg G., Nurnberg P., RA Kortler J., Neitzel B., Bassmann I., Rahman T., Keavney B., Loughlin J., RA Hambleton S., Schoser B., Lochmuller H., Santibanez-Koref M., RA Chinnery P.F.; RT "A new phenotype of brain iron accumulation with dystonia, optic atrophy, RT and peripheral neuropathy."; RL Mov. Disord. 27:789-793(2012). RN [9] RP VARIANTS NBIA4 SER-47 AND PRO-85. RX PubMed=22704260; DOI=10.1016/j.spen.2012.03.006; RA Panteghini C., Zorzi G., Venco P., Dusi S., Reale C., Brunetti D., RA Chiapparini L., Zibordi F., Siegel B., Siegel B., Garavaglia B., RA Simonati A., Bertini E., Nardocci N., Tiranti V.; RT "C19orf12 and FA2H mutations are rare in Italian patients with RT neurodegeneration with brain iron accumulation."; RL Semin. Pediatr. Neurol. 19:75-81(2012). RN [10] RP VARIANT NBIA4 MET-11 (ISOFORM 4). RX PubMed=23278385; DOI=10.1111/cge.12079; RA Dogu O., Krebs C.E., Kaleagasi H., Demirtas Z., Oksuz N., Walker R.H., RA Paisan-Ruiz C.; RT "Rapid disease progression in adult-onset mitochondrial membrane protein- RT associated neurodegeneration."; RL Clin. Genet. 84:350-355(2013). RN [11] RP VARIANTS NBIA4 PHE-28; PRO-37; ARG-42; LEU-49; GLU-54; VAL-54; ARG-58; RP LEU-72; SER-87 AND PRO-123, AND VARIANTS GLU-131; THR-131 AND ARG-138. RX PubMed=23269600; DOI=10.1212/wnl.0b013e31827e07be; RA Hogarth P., Gregory A., Kruer M.C., Sanford L., Wagoner W., Natowicz M.R., RA Egel R.T., Subramony S.H., Goldman J.G., Berry-Kravis E., Foulds N.C., RA Hammans S.R., Desguerre I., Rodriguez D., Wilson C., Diedrich A., Green S., RA Tran H., Reese L., Woltjer R.L., Hayflick S.J.; RT "New NBIA subtype: genetic, clinical, pathologic, and radiographic features RT of MPAN."; RL Neurology 80:268-275(2013). RN [12] RP VARIANT SPG43 PRO-52, VARIANTS NBIA4 PRO-52 AND GLY-55 DEL, SUBCELLULAR RP LOCATION, CHARACTERIZATION OF VARIANTS SPG43 PRO-52, AND CHARACTERIZATION RP OF VARIANTS NBIA4 PRO-52; GLY-55 DEL AND ARG-58. RX PubMed=23857908; DOI=10.1002/humu.22378; RA Landoure G., Zhu P.P., Lourenco C.M., Johnson J.O., Toro C., Bricceno K.V., RA Rinaldi C., Meilleur K.G., Sangare M., Diallo O., Pierson T.M., Ishiura H., RA Tsuji S., Hein N., Fink J.K., Stoll M., Nicholson G., Gonzalez M.A., RA Speziani F., Durr A., Stevanin G., Biesecker L.G., Accardi J., Landis D.M., RA Gahl W.A., Traynor B.J., Marques W. Jr., Zuchner S., Blackstone C., RA Fischbeck K.H., Burnett B.G.; RT "Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in RT C19orf12."; RL Hum. Mutat. 34:1357-1360(2013). RN [13] RP CHARACTERIZATION OF VARIANTS NBIA4 SER-47 AND PRO-85, AND SUBCELLULAR RP LOCATION. RX PubMed=26136767; DOI=10.3389/fgene.2015.00185; RA Venco P., Bonora M., Giorgi C., Papaleo E., Iuso A., Prokisch H., RA Pinton P., Tiranti V.; RT "Mutations of C19orf12, coding for a transmembrane glycine zipper RT containing mitochondrial protein, cause mis-localization of the protein, RT inability to respond to oxidative stress and increased mitochondrial RT Ca(2)(+)."; RL Front. Genet. 6:185-185(2015). RN [14] RP VARIANT NBIA4 ARG-58, AND VARIANT NBIA4 MET-11 (ISOFORM 4). RX PubMed=25592411; DOI=10.1016/j.jns.2014.12.036; RA Tschentscher A., Dekomien G., Ross S., Cremer K., Kukuk G.M., Epplen J.T., RA Hoffjan S.; RT "Analysis of the C19orf12 and WDR45 genes in patients with RT neurodegeneration with brain iron accumulation."; RL J. Neurol. Sci. 349:105-109(2015). RN [15] RP VARIANT NBIA4 LEU-72. RX PubMed=26187298; DOI=10.1016/j.jns.2015.07.009; RA Kleffner I., Wessling C., Gess B., Korsukewitz C., Allkemper T., RA Schirmacher A., Young P., Senderek J., Husstedt I.W.; RT "Behr syndrome with homozygous C19ORF12 mutation."; RL J. Neurol. Sci. 357:115-118(2015). CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:21981780, CC ECO:0000269|PubMed:22508347, ECO:0000269|PubMed:26136767}. CC Mitochondrion membrane {ECO:0000269|PubMed:21981780, CC ECO:0000269|PubMed:26136767}; Single-pass membrane protein CC {ECO:0000255}. Endoplasmic reticulum {ECO:0000269|PubMed:22508347}. CC Cytoplasm, cytosol {ECO:0000269|PubMed:26136767}. Note=In response to CC oxidative stress, relocates to the cytosol forming aggregates that CC partially co-localize with mitochondria. {ECO:0000269|PubMed:26136767}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q9NSK7-4; Sequence=Displayed; CC Name=4; CC IsoId=Q9NSK7-1; Sequence=VSP_062333; CC Name=2; CC IsoId=Q9NSK7-2; Sequence=VSP_062332; CC Name=3; CC IsoId=Q9NSK7-3; Sequence=VSP_062334, VSP_062335; CC -!- INDUCTION: Up-regulated during adipocyte differentiation in an in vitro CC preadipocyte differentiation model. {ECO:0000269|PubMed:21981780}. CC -!- DISEASE: Neurodegeneration with brain iron accumulation 4 (NBIA4) CC [MIM:614298]: A neurodegenerative disorder associated with iron CC accumulation in the brain, primarily in the basal ganglia. NBIA4 CC results in speech difficulty, extrapyramidal signs, oromandibular and CC generalized dystonia, and parkinsonism. Most patients have progressive CC involvement of the corticospinal tract, with spasticity, hyperreflexia, CC and extensor plantar responses. {ECO:0000269|PubMed:21981780, CC ECO:0000269|PubMed:22508347, ECO:0000269|PubMed:22584950, CC ECO:0000269|PubMed:22704260, ECO:0000269|PubMed:23269600, CC ECO:0000269|PubMed:23278385, ECO:0000269|PubMed:23521069, CC ECO:0000269|PubMed:23857908, ECO:0000269|PubMed:25592411, CC ECO:0000269|PubMed:26136767, ECO:0000269|PubMed:26187298}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Spastic paraplegia 43, autosomal recessive (SPG43) CC [MIM:615043]: 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. SP43 is characterized CC by childhood onset of progressive spasticity affecting the lower and CC upper limbs. {ECO:0000269|PubMed:23857908}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the C19orf12 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH17211.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK057185; BAG51878.1; -; mRNA. DR EMBL; DA708831; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AC010513; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC004957; AAH04957.1; -; mRNA. DR EMBL; BC009946; AAH09946.1; -; mRNA. DR EMBL; BC017211; AAH17211.2; ALT_INIT; mRNA. DR EMBL; BC063518; AAH63518.1; -; mRNA. DR EMBL; AL162066; CAB82403.1; -; mRNA. DR CCDS; CCDS12418.2; -. [Q9NSK7-4] DR CCDS; CCDS59373.1; -. [Q9NSK7-3] DR CCDS; CCDS74325.1; -. [Q9NSK7-2] DR PIR; T47169; T47169. DR RefSeq; NP_001026896.3; NM_001031726.4. [Q9NSK7-4] DR RefSeq; NP_001242975.1; NM_001256046.3. [Q9NSK7-3] DR RefSeq; NP_001242976.1; NM_001256047.2. [Q9NSK7-4] DR RefSeq; NP_001269858.1; NM_001282929.1. [Q9NSK7-2] DR RefSeq; NP_001269859.1; NM_001282930.3. [Q9NSK7-2] DR RefSeq; NP_001269860.1; NM_001282931.3. [Q9NSK7-2] DR RefSeq; NP_113636.2; NM_031448.6. [Q9NSK7-4] DR RefSeq; XP_024307503.1; XM_024451735.2. [Q9NSK7-4] DR RefSeq; XP_047295453.1; XM_047439497.1. [Q9NSK7-2] DR RefSeq; XP_054178270.1; XM_054322295.1. [Q9NSK7-4] DR RefSeq; XP_054178271.1; XM_054322296.1. [Q9NSK7-2] DR AlphaFoldDB; Q9NSK7; -. DR SMR; Q9NSK7; -. DR BioGRID; 123700; 2. DR FunCoup; Q9NSK7; 1030. DR IntAct; Q9NSK7; 2. DR STRING; 9606.ENSP00000376103; -. DR iPTMnet; Q9NSK7; -. DR PhosphoSitePlus; Q9NSK7; -. DR BioMuta; C19orf12; -. DR DMDM; 374095505; -. DR jPOST; Q9NSK7; -. DR MassIVE; Q9NSK7; -. DR PaxDb; 9606-ENSP00000376103; -. DR PeptideAtlas; Q9NSK7; -. DR ProteomicsDB; 82566; -. [Q9NSK7-1] DR ProteomicsDB; 82567; -. [Q9NSK7-2] DR ProteomicsDB; 82568; -. [Q9NSK7-3] DR ProteomicsDB; 82569; -. [Q9NSK7-4] DR Pumba; Q9NSK7; -. DR Antibodypedia; 47936; 39 antibodies from 14 providers. DR DNASU; 83636; -. DR Ensembl; ENST00000323670.14; ENSP00000313332.9; ENSG00000131943.21. [Q9NSK7-4] DR Ensembl; ENST00000392275.1; ENSP00000507573.1; ENSG00000131943.21. [Q9NSK7-2] DR Ensembl; ENST00000392276.1; ENSP00000376102.1; ENSG00000131943.21. [Q9NSK7-2] DR Ensembl; ENST00000592153.5; ENSP00000467117.1; ENSG00000131943.21. [Q9NSK7-3] DR Ensembl; ENST00000623113.3; ENSP00000485413.2; ENSG00000131943.21. [Q9NSK7-4] DR GeneID; 83636; -. DR KEGG; hsa:83636; -. DR MANE-Select; ENST00000323670.14; ENSP00000313332.9; NM_031448.6; NP_113636.2. DR UCSC; uc002nsj.4; human. [Q9NSK7-4] DR AGR; HGNC:25443; -. DR ClinPGx; PA134981038; -. DR CTD; 83636; -. DR DisGeNET; 83636; -. DR GeneCards; C19orf12; -. DR GeneReviews; C19orf12; -. DR HGNC; HGNC:25443; C19orf12. DR HPA; ENSG00000131943; Tissue enhanced (adipose tissue, tongue). DR MalaCards; C19orf12; -. DR MIM; 614297; gene. DR MIM; 614298; phenotype. DR MIM; 615043; phenotype. DR OpenTargets; ENSG00000131943; -. DR Orphanet; 320370; Autosomal recessive spastic paraplegia type 43. DR Orphanet; 289560; Mitochondrial membrane protein-associated neurodegeneration. DR VEuPathDB; HostDB:ENSG00000131943; -. DR eggNOG; ENOG502RZQC; Eukaryota. DR GeneTree; ENSGT00390000009077; -. DR HOGENOM; CLU_2460310_0_0_1; -. DR InParanoid; Q9NSK7; -. DR OrthoDB; 5976774at2759; -. DR PAN-GO; Q9NSK7; 0 GO annotations based on evolutionary models. DR PhylomeDB; Q9NSK7; -. DR PathwayCommons; Q9NSK7; -. DR SignaLink; Q9NSK7; -. DR Agora; ENSG00000131943; -. DR BioGRID-ORCS; 83636; 24 hits in 1143 CRISPR screens. DR ChiTaRS; C19orf12; human. DR GenomeRNAi; 83636; -. DR Pharos; Q9NSK7; Tbio. DR PRO; PR:Q9NSK7; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q9NSK7; protein. DR Bgee; ENSG00000131943; Expressed in endothelial cell and 186 other cell types or tissues. DR ExpressionAtlas; Q9NSK7; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:0051560; P:mitochondrial calcium ion homeostasis; IMP:UniProtKB. DR GO; GO:0006979; P:response to oxidative stress; IMP:UniProtKB. DR InterPro; IPR033369; C19orf12. DR PANTHER; PTHR31493; NAZO FAMILY MEMBER; 1. DR PANTHER; PTHR31493:SF1; PROTEIN C19ORF12; 1. DR Pfam; PF20721; C19orf12; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasm; Disease variant; Endoplasmic reticulum; KW Hereditary spastic paraplegia; Membrane; Mitochondrion; Neurodegeneration; KW Proteomics identification; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..141 FT /note="Protein C19orf12" FT /id="PRO_0000296662" FT TRANSMEM 40..60 FT /note="Helical" FT /evidence="ECO:0000255" FT VAR_SEQ 1..64 FT /note="Missing (in isoform 2)" FT /id="VSP_062332" FT VAR_SEQ 1 FT /note="M -> MERLKSHKPATM (in isoform 4)" FT /id="VSP_062333" FT VAR_SEQ 98..107 FT /note="HLEWTDAVQL -> PCSSSCWPCW (in isoform 3)" FT /id="VSP_062334" FT VAR_SEQ 108..141 FT /note="Missing (in isoform 3)" FT /id="VSP_062335" FT VARIANT 28 FT /note="S -> F (in NBIA4; dbSNP:rs1204865094)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069756" FT VARIANT 37 FT /note="A -> P (in NBIA4)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069757" FT VARIANT 42 FT /note="G -> R (in NBIA4; dbSNP:rs200133991)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066618" FT VARIANT 47 FT /note="G -> S (in NBIA4; predominantly cytosolic FT distribution with a localization also seen in the FT mitochondrial matrix; no cytosolic redistribution seen in FT response to oxidative stress; patient fibroblasts FT accumulate high levels of mitochondrial calcium and are FT more prone to oxidative stress-induced apoptosis; FT dbSNP:rs1358503478)" FT /evidence="ECO:0000269|PubMed:22704260, FT ECO:0000269|PubMed:26136767" FT /id="VAR_076803" FT VARIANT 49 FT /note="P -> L (in NBIA4; dbSNP:rs1424999393)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069758" FT VARIANT 52 FT /note="A -> P (in NBIA4 and SPG43; impairs subcellular FT localization to the endoplasmic reticulum or mitochondrion; FT dbSNP:rs376103979)" FT /evidence="ECO:0000269|PubMed:23857908" FT /id="VAR_070668" FT VARIANT 54 FT /note="G -> E (in NBIA4; dbSNP:rs752450983)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066619" FT VARIANT 54 FT /note="G -> V (in NBIA4; dbSNP:rs752450983)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069759" FT VARIANT 55 FT /note="Missing (in NBIA4; impairs subcellular localization FT to the endoplasmic reticulum or mitochondrion)" FT /evidence="ECO:0000269|PubMed:22584950, FT ECO:0000269|PubMed:23857908" FT /id="VAR_070669" FT VARIANT 58 FT /note="G -> R (in NBIA4; impairs subcellular localization FT to the endoplasmic reticulum or mitochondrion; FT dbSNP:rs515726205)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600, ECO:0000269|PubMed:23857908, FT ECO:0000269|PubMed:25592411" FT /id="VAR_066620" FT VARIANT 72 FT /note="P -> L (in NBIA4; dbSNP:rs201987973)" FT /evidence="ECO:0000269|PubMed:23269600, FT ECO:0000269|PubMed:26187298" FT /id="VAR_069760" FT VARIANT 85 FT /note="Q -> P (in NBIA4; no effect on its subcellular FT localization; no cytosolic redistribution seen in response FT to oxidative stress)" FT /evidence="ECO:0000269|PubMed:22704260, FT ECO:0000269|PubMed:26136767" FT /id="VAR_076804" FT VARIANT 87 FT /note="R -> S (in NBIA4; dbSNP:rs1384930997)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069761" FT VARIANT 110 FT /note="L -> Q (in NBIA4)" FT /evidence="ECO:0000269|PubMed:22508347" FT /id="VAR_069762" FT VARIANT 123 FT /note="A -> P (in NBIA4; uncertain significance; FT dbSNP:rs1264612218)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069763" FT VARIANT 131 FT /note="K -> E (found in families with neurodegeneration FT with brain iron accumulation; uncertain significance; FT dbSNP:rs146170087)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066621" FT VARIANT 131 FT /note="K -> T (in dbSNP:rs79915936)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:23269600" FT /id="VAR_066622" FT VARIANT 138 FT /note="Q -> R (in dbSNP:rs73023451)" FT /evidence="ECO:0000269|PubMed:23269600" FT /id="VAR_069764" FT VARIANT Q9NSK7-1:11 FT /note="T -> M (in NBIA4; dbSNP:rs397514477)" FT /evidence="ECO:0000269|PubMed:21981780, FT ECO:0000269|PubMed:22584950, ECO:0000269|PubMed:23278385, FT ECO:0000269|PubMed:25592411" FT /id="VAR_089160" SQ SEQUENCE 141 AA; 15007 MW; C6EEA8C17A909E7F CRC64; MTIMVEDIMK LLCSLSGERK MKAAVKHSGK GALVTGAMAF VGGLVGGPPG LAVGGAVGGL LGAWMTSGQF KPVPQILMEL PPAEQQRLFN EAAAIIRHLE WTDAVQLTAL VMGSEALQQQ LLAMLVNYVT KELRAEIQYD D // ID DDIT4_HUMAN Reviewed; 232 AA. AC Q9NX09; Q9H0S3; DT 23-OCT-2007, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 28-JAN-2026, entry version 175. DE RecName: Full=DNA damage-inducible transcript 4 protein; DE AltName: Full=HIF-1 responsive protein RTP801; DE AltName: Full=Protein regulated in development and DNA damage response 1; DE Short=REDD-1; GN Name=DDIT4; Synonyms=REDD1, RTP801; 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], TISSUE SPECIFICITY, INDUCTION BY DNA DAMAGE, RP AND SUBCELLULAR LOCATION. RC TISSUE=Fetal brain; RX PubMed=12453409; DOI=10.1016/s1097-2765(02)00706-2; RA Ellisen L.W., Ramsayer K.D., Johannessen C.M., Yang A., Beppu H., Minda K., RA Oliner J.D., McKeon F., Haber D.A.; RT "REDD1, a developmentally regulated transcriptional target of p63 and p53, RT links p63 to regulation of reactive oxygen species."; RL Mol. Cell 10:995-1005(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=11884613; DOI=10.1128/mcb.22.7.2283-2293.2002; RA Shoshani T., Faerman A., Mett I., Zelin E., Tenne T., Gorodin S., RA Moshel Y., Elbaz S., Budanov A., Chajut A., Kalinski H., Kamer I., RA Rozen A., Mor O., Keshet E., Leshkowitz D., Einat P., Skaliter R., RA Feinstein E.; RT "Identification of a novel hypoxia-inducible factor 1-responsive gene, RT RTP801, involved in apoptosis."; RL Mol. Cell. Biol. 22:2283-2293(2002). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=11230166; DOI=10.1101/gr.gr1547r; RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B., RA Klein M., Poustka A.; RT "Towards a catalog of human genes and proteins: sequencing and analysis of RT 500 novel complete protein coding human cDNAs."; RL Genome Res. 11:422-435(2001). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Kidney, 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 INDUCTION. RX PubMed=14646594; DOI=10.1038/emm.2003.53; RA Kim J.-R., Lee S.-R., Chung H.J., Kim S., Baek S.-H., Kim J.H., Kim Y.-S.; RT "Identification of amyloid beta-peptide responsive genes by cDNA microarray RT technology: involvement of RTP801 in amyloid beta-peptide toxicity."; RL Exp. Mol. Med. 35:403-411(2003). RN [9] RP FUNCTION. RX PubMed=15545625; DOI=10.1101/gad.1256804; RA Brugarolas J., Lei K., Hurley R.L., Manning B.D., Reiling J.H., Hafen E., RA Witters L.A., Ellisen L.W., Kaelin W.G. Jr.; RT "Regulation of mTOR function in response to hypoxia by REDD1 and the RT TSC1/TSC2 tumor suppressor complex."; RL Genes Dev. 18:2893-2904(2004). RN [10] RP INDUCTION. RX PubMed=15751966; DOI=10.1021/bi047574r; RA Lin L., Qian Y., Shi X., Chen Y.; RT "Induction of a cell stress response gene RTP801 by DNA damaging agent RT methyl methanesulfonate through CCAAT/enhancer binding protein."; RL Biochemistry 44:3909-3914(2005). RN [11] RP FUNCTION. RX PubMed=15632201; DOI=10.1074/jbc.c400557200; RA Corradetti M.N., Inoki K., Guan K.-L.; RT "The stress-inducted proteins RTP801 and RTP801L are negative regulators of RT the mammalian target of rapamycin pathway."; RL J. Biol. Chem. 280:9769-9772(2005). RN [12] RP FUNCTION. RX PubMed=15988001; DOI=10.1128/mcb.25.14.5834-5845.2005; RA Sofer A., Lei K., Johannessen C.M., Ellisen L.W.; RT "Regulation of mTOR and cell growth in response to energy stress by RT REDD1."; RL Mol. Cell. Biol. 25:5834-5845(2005). RN [13] RP INDUCTION. RX PubMed=15592522; DOI=10.1038/sj.onc.1208236; RA Schwarzer R., Tondera D., Arnold W., Giese K., Klippel A., Kaufmann J.; RT "REDD1 integrates hypoxia-mediated survival signaling downstream of RT phosphatidylinositol 3-kinase."; RL Oncogene 24:1138-1149(2005). RN [14] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=17005863; DOI=10.1523/jneurosci.3292-06.2006; RA Malagelada C., Ryu E.J., Biswas S.C., Jackson-Lewis V., Greene L.A.; RT "RTP801 is elevated in Parkinson brain substantia nigral neurons and RT mediates death in cellular models of Parkinson's disease by a mechanism RT involving mammalian target of rapamycin inactivation."; RL J. Neurosci. 26:9996-10005(2006). RN [15] RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=17379067; DOI=10.1016/j.exphem.2007.01.049; RA Gery S., Park D.J., Vuong P.T., Virk R.K., Muller C.I., Hofmann W.-K., RA Koeffler H.P.; RT "RTP801 is a novel retinoic acid-responsive gene associated with myeloid RT differentiation."; RL Exp. Hematol. 35:572-578(2007). RN [16] RP FUNCTION, UBIQUITINATION, INTERACTION WITH BTRC, IDENTIFICATION IN A RP COMPLEX WITH CUL4A; DDB1 AND BTRC, IDENTIFICATION BY MASS SPECTROMETRY, RP PARTIAL PROTEIN SEQUENCE, MUTAGENESIS OF SER-19; THR-23 AND THR-25, AND RP PHOSPHORYLATION AT SER-19; THR-23; THR-25 AND SER-121. RX PubMed=19557001; DOI=10.1038/embor.2009.93; RA Katiyar S., Liu E., Knutzen C.A., Lang E.S., Lombardo C.R., Sankar S., RA Toth J.I., Petroski M.D., Ronai Z., Chiang G.G.; RT "REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 RT ubiquitin ligase."; RL EMBO Rep. 10:866-872(2009). RN [17] RP INTERACTION WITH TXNIP, AND FUNCTION. RX PubMed=21460850; DOI=10.1038/onc.2011.102; RA Jin H.O., Seo S.K., Kim Y.S., Woo S.H., Lee K.H., Yi J.Y., Lee S.J., RA Choe T.B., Lee J.H., An S., Hong S.I., Park I.C.; RT "TXNIP potentiates Redd1-induced mTOR suppression through stabilization of RT Redd1."; RL Oncogene 30:3792-3801(2011). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [19] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 89-226, FUNCTION, SUBUNIT, RP INDUCTION, AND MUTAGENESIS OF SER-103; ARG-133; SER-137; PRO-139; CYS-140; RP LYS-219; LEU-221 AND TYR-222. RX PubMed=20166753; DOI=10.1021/bi902135e; RA Vega-Rubin-de-Celis S., Abdallah Z., Kinch L., Grishin N.V., Brugarolas J., RA Zhang X.; RT "Structural analysis and functional implications of the negative mTORC1 RT regulator REDD1."; RL Biochemistry 49:2491-2501(2010). CC -!- FUNCTION: Regulates cell growth, proliferation and survival via CC inhibition of the activity of the mammalian target of rapamycin complex CC 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves CC DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an CC important role in responses to cellular energy levels and cellular CC stress, including responses to hypoxia and DNA damage. Regulates CC p53/TP53-mediated apoptosis in response to DNA damage via its effect on CC mTORC1 activity. Its role in the response to hypoxia depends on the CC cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, CC but not in hepatocytes (By similarity). Required for mTORC1-mediated CC defense against viral protein synthesis and virus replication (By CC similarity). Inhibits neuronal differentiation and neurite outgrowth CC mediated by NGF via its effect on mTORC1 activity. Required for normal CC neuron migration during embryonic brain development. Plays a role in CC neuronal cell death. {ECO:0000250, ECO:0000269|PubMed:15545625, CC ECO:0000269|PubMed:15632201, ECO:0000269|PubMed:15988001, CC ECO:0000269|PubMed:17005863, ECO:0000269|PubMed:17379067, CC ECO:0000269|PubMed:19557001, ECO:0000269|PubMed:20166753, CC ECO:0000269|PubMed:21460850}. CC -!- SUBUNIT: Monomer. Interacts with BTRC. Identified in a complex with CC CUL4A, DDB1 and BTRC. Interacts with TXNIP; this inhibits the CC proteasomal degradation of DDIT4. {ECO:0000269|PubMed:19557001, CC ECO:0000269|PubMed:20166753, ECO:0000269|PubMed:21460850}. CC -!- INTERACTION: CC Q9NX09; Q3SYB3: FOXD4L6; NbExp=3; IntAct=EBI-715104, EBI-6425864; CC Q9NX09; Q14145: KEAP1; NbExp=3; IntAct=EBI-715104, EBI-751001; CC Q9NX09; P57682: KLF3; NbExp=3; IntAct=EBI-715104, EBI-8472267; CC Q9NX09; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-715104, EBI-10698053; CC Q9NX09; P16284: PECAM1; NbExp=3; IntAct=EBI-715104, EBI-716404; CC Q9NX09; Q6P1K2: PMF1; NbExp=3; IntAct=EBI-715104, EBI-713832; CC Q9NX09; P61086: UBE2K; NbExp=3; IntAct=EBI-715104, EBI-473850; CC Q9NX09; P40337-2: VHL; NbExp=3; IntAct=EBI-715104, EBI-12157263; CC Q9NX09; P58304: VSX2; NbExp=3; IntAct=EBI-715104, EBI-6427899; CC Q9NX09; Q96MN9-2: ZNF488; NbExp=3; IntAct=EBI-715104, EBI-25831733; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:12453409}. CC -!- TISSUE SPECIFICITY: Broadly expressed, with lowest levels in brain, CC skeletal muscle and intestine. Up-regulated in substantia nigra neurons CC from Parkinson disease patients (at protein level). CC {ECO:0000269|PubMed:11884613, ECO:0000269|PubMed:12453409, CC ECO:0000269|PubMed:17005863, ECO:0000269|PubMed:17379067}. CC -!- INDUCTION: Up-regulated in fibroblasts upon ionizing radiation, via a CC TP53-dependent pathway. Up-regulated by TP63 in primary keratinocytes, CC and down-regulated during keratinocyte differentiation. Up-regulated CC upon DNA alkylation. Up-regulated by amyloid beta-peptide and retinoic CC acid. Up-regulated by hypoxia, via a PI3K and HIF1A-dependent but CC TP53/TP63-independent mechanism (at protein level). CC {ECO:0000269|PubMed:11884613, ECO:0000269|PubMed:12453409, CC ECO:0000269|PubMed:14646594, ECO:0000269|PubMed:15592522, CC ECO:0000269|PubMed:15751966, ECO:0000269|PubMed:17379067, CC ECO:0000269|PubMed:20166753}. CC -!- PTM: Phosphorylated by GSK3B; this promotes proteasomal degradation. CC {ECO:0000269|PubMed:19557001}. CC -!- PTM: Polyubiquitinated by a DCX (DDB1-CUL4A-RBX1) E3 ubiquitin-protein CC ligase complex with BTRC as substrate-recognition component, leading to CC its proteasomal degradation. {ECO:0000269|PubMed:19557001}. CC -!- SIMILARITY: Belongs to the DDIT4 family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/45802/DDIT4"; 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; AY090097; AAM10442.1; -; mRNA. DR EMBL; AF335324; AAL38424.1; -; mRNA. DR EMBL; AL136668; CAB66603.1; -; mRNA. DR EMBL; AK000507; BAA91214.1; -; mRNA. DR EMBL; AL683820; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471083; EAW54452.1; -; Genomic_DNA. DR EMBL; BC000708; AAH00708.1; -; mRNA. DR EMBL; BC007714; AAH07714.1; -; mRNA. DR EMBL; BC015236; AAH15236.1; -; mRNA. DR CCDS; CCDS7315.1; -. DR RefSeq; NP_061931.1; NM_019058.4. DR PDB; 3LQ9; X-ray; 2.00 A; A/B=89-226. DR PDB; 7MOP; EM; 3.30 A; B=1-232. DR PDBsum; 3LQ9; -. DR PDBsum; 7MOP; -. DR AlphaFoldDB; Q9NX09; -. DR EMDB; EMD-23925; -. DR SMR; Q9NX09; -. DR BioGRID; 120028; 24. DR CORUM; Q9NX09; -. DR FunCoup; Q9NX09; 1418. DR IntAct; Q9NX09; 25. DR MINT; Q9NX09; -. DR STRING; 9606.ENSP00000307305; -. DR DrugBank; DB06048; RTP-801i. DR iPTMnet; Q9NX09; -. DR PhosphoSitePlus; Q9NX09; -. DR BioMuta; DDIT4; -. DR DMDM; 74753036; -. DR jPOST; Q9NX09; -. DR MassIVE; Q9NX09; -. DR PaxDb; 9606-ENSP00000307305; -. DR PeptideAtlas; Q9NX09; -. DR ProteomicsDB; 83020; -. DR Pumba; Q9NX09; -. DR Antibodypedia; 29243; 330 antibodies from 38 providers. DR DNASU; 54541; -. DR Ensembl; ENST00000307365.4; ENSP00000307305.3; ENSG00000168209.7. DR Ensembl; ENST00000491934.3; ENSP00000506356.1; ENSG00000168209.7. DR GeneID; 54541; -. DR KEGG; hsa:54541; -. DR MANE-Select; ENST00000307365.4; ENSP00000307305.3; NM_019058.4; NP_061931.1. DR UCSC; uc001jsx.2; human. DR AGR; HGNC:24944; -. DR ClinPGx; PA134977994; -. DR CTD; 54541; -. DR DisGeNET; 54541; -. DR GeneCards; DDIT4; -. DR HGNC; HGNC:24944; DDIT4. DR HPA; ENSG00000168209; Low tissue specificity. DR MIM; 607729; gene. DR OpenTargets; ENSG00000168209; -. DR VEuPathDB; HostDB:ENSG00000168209; -. DR eggNOG; ENOG502RB72; Eukaryota. DR GeneTree; ENSGT00530000063652; -. DR HOGENOM; CLU_086145_1_0_1; -. DR InParanoid; Q9NX09; -. DR OMA; MPGLWER; -. DR OrthoDB; 10018535at2759; -. DR PAN-GO; Q9NX09; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q9NX09; -. DR PathwayCommons; Q9NX09; -. DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes. DR SignaLink; Q9NX09; -. DR SIGNOR; Q9NX09; -. DR Agora; ENSG00000168209; -. DR BioGRID-ORCS; 54541; 26 hits in 1170 CRISPR screens. DR CD-CODE; B5B9A610; PML body. DR ChiTaRS; DDIT4; human. DR EvolutionaryTrace; Q9NX09; -. DR GeneWiki; DDIT4; -. DR GenomeRNAi; 54541; -. DR Pharos; Q9NX09; Tbio. DR PRO; PR:Q9NX09; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q9NX09; protein. DR Bgee; ENSG00000168209; Expressed in pericardium and 210 other cell types or tissues. DR ExpressionAtlas; Q9NX09; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell. DR GO; GO:0071889; F:14-3-3 protein binding; IBA:GO_Central. DR GO; GO:0006915; P:apoptotic process; IBA:GO_Central. DR GO; GO:0007420; P:brain development; ISS:UniProtKB. DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl. DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB. DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; ISS:UniProtKB. DR GO; GO:0045820; P:negative regulation of glycolytic process; IEA:Ensembl. DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:UniProtKB. DR GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB. DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0032984; P:protein-containing complex disassembly; IEA:Ensembl. DR GO; GO:0072593; P:reactive oxygen species metabolic process; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR FunFam; 3.90.470.40:FF:000001; DNA damage-inducible transcript 4 protein; 1. DR Gene3D; 3.90.470.40; RTP801-like; 1. DR InterPro; IPR012918; RTP801-like. DR InterPro; IPR038281; RTP801-like_C_sf. DR PANTHER; PTHR12478:SF7; DNA DAMAGE-INDUCIBLE TRANSCRIPT 4 PROTEIN; 1. DR PANTHER; PTHR12478; DNA-DAMAGE-INDUCIBLE TRANSCRIPT 4 PROTEIN DDIT4; 1. DR Pfam; PF07809; RTP801_C; 1. PE 1: Evidence at protein level; KW 3D-structure; Antiviral defense; Apoptosis; Cytoplasm; KW Direct protein sequencing; Mitochondrion; Phosphoprotein; KW Proteomics identification; Reference proteome; Ubl conjugation. FT CHAIN 1..232 FT /note="DNA damage-inducible transcript 4 protein" FT /id="PRO_0000307197" FT REGION 1..71 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 9..22 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 19 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:19557001" FT MOD_RES 23 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:19557001" FT MOD_RES 25 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:19557001" FT MOD_RES 121 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:19557001" FT MUTAGEN 19 FT /note="S->A: Strongly inhibits proteasomal degradation." FT /evidence="ECO:0000269|PubMed:19557001" FT MUTAGEN 23 FT /note="T->A: Strongly inhibits proteasomal degradation. FT Strongly inhibits proteasomal degradation; when associated FT with A-25." FT /evidence="ECO:0000269|PubMed:19557001" FT MUTAGEN 25 FT /note="T->A: Strongly inhibits proteasomal degradation; FT when associated with A-23." FT /evidence="ECO:0000269|PubMed:19557001" FT MUTAGEN 103 FT /note="S->L,W: No effect on inhibition of mTORC1." FT /evidence="ECO:0000269|PubMed:20166753" FT MUTAGEN 133 FT /note="R->A: No effect on inhibition of mTORC1." FT /evidence="ECO:0000269|PubMed:20166753" FT MUTAGEN 137 FT /note="S->A,D: No effect on inhibition of mTORC1." FT /evidence="ECO:0000269|PubMed:20166753" FT MUTAGEN 139 FT /note="P->A: Abolishes inhibition of mTORC1." FT /evidence="ECO:0000269|PubMed:20166753" FT MUTAGEN 140 FT /note="C->S: Mildly reduces inhibition of mTORC1." FT /evidence="ECO:0000269|PubMed:20166753" FT MUTAGEN 219 FT /note="K->A: Reduces inhibition of mTORC1. Abolishes FT inhibition of mTORC1; when associated with A-222." FT /evidence="ECO:0000269|PubMed:20166753" FT MUTAGEN 221 FT /note="L->A: Reduces inhibition of mTORC1." FT /evidence="ECO:0000269|PubMed:20166753" FT MUTAGEN 222 FT /note="Y->A: Reduces inhibition of mTORC1. Abolishes FT inhibition of mTORC1; when associated with A-219." FT /evidence="ECO:0000269|PubMed:20166753" FT CONFLICT 228 FT /note="L -> P (in Ref. 3; CAB66603)" FT /evidence="ECO:0000305" FT TURN 6..8 FT /evidence="ECO:0007829|PDB:7MOP" FT HELIX 90..104 FT /evidence="ECO:0007829|PDB:3LQ9" FT STRAND 107..112 FT /evidence="ECO:0007829|PDB:3LQ9" FT HELIX 121..135 FT /evidence="ECO:0007829|PDB:3LQ9" FT HELIX 141..144 FT /evidence="ECO:0007829|PDB:3LQ9" FT STRAND 145..153 FT /evidence="ECO:0007829|PDB:3LQ9" FT STRAND 156..165 FT /evidence="ECO:0007829|PDB:3LQ9" FT STRAND 173..180 FT /evidence="ECO:0007829|PDB:3LQ9" FT STRAND 214..220 FT /evidence="ECO:0007829|PDB:3LQ9" SQ SEQUENCE 232 AA; 25371 MW; 774E941EBDD08198 CRC64; MPSLWDRFSS SSTSSSPSSL PRTPTPDRPP RSAWGSATRE EGFDRSTSLE SSDCESLDSS NSGFGPEEDT AYLDGVSLPD FELLSDPEDE HLCANLMQLL QESLAQARLG SRRPARLLMP SQLVSQVGKE LLRLAYSEPC GLRGALLDVC VEQGKSCHSV GQLALDPSLV PTFQLTLVLR LDSRLWPKIQ GLFSSANSPF LPGFSQSLTL STGFRVIKKK LYSSEQLLIE EC // ID HTRA2_HUMAN Reviewed; 458 AA. AC O43464; Q9HBZ4; Q9P0Y3; Q9P0Y4; DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 2. DT 28-JAN-2026, entry version 241. DE RecName: Full=Serine protease HTRA2, mitochondrial; DE EC=3.4.21.108; DE AltName: Full=High temperature requirement protein A2; DE Short=HtrA2; DE AltName: Full=Omi stress-regulated endoprotease; DE AltName: Full=Serine protease 25; DE AltName: Full=Serine proteinase OMI; DE Flags: Precursor; GN Name=HTRA2; Synonyms=OMI, PRSS25; 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), SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND MUTAGENESIS OF SER-306. RX PubMed=10644717; DOI=10.1074/jbc.275.4.2581; RA Faccio L., Fusco C., Chen A., Martinotti S., Bonventre J.V., Zervos A.S.; RT "Characterization of a novel human serine protease that has extensive RT homology to bacterial heat shock endoprotease HtrA and is regulated by RT kidney ischemia."; RL J. Biol. Chem. 275:2581-2588(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3 AND 4), AND CHARACTERIZATION. RC TISSUE=Brain; RX PubMed=10971580; DOI=10.1046/j.1432-1327.2000.01589.x; RA Gray C.W., Ward R.V., Karran E.H., Turconi S., Rowles A., Viglienghi D., RA Southan C., Barton A., Fantom K.G., West A., Savopoulos J.W., Hassan N.J., RA Clinkenbeard H., Hanning C., Amegadzie B., Davis J.B., Dingwall C., RA Livi G.P., Creasy C.L.; RT "Characterization of human HtrA2, a novel serine protease involved in the RT mammalian cellular stress response."; RL Eur. J. Biochem. 267:5699-5710(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Kidney; RX PubMed=10995577; DOI=10.1006/geno.2000.6263; RA Faccio L., Fusco C., Viel A., Zervos A.S.; RT "Tissue-specific splicing of Omi stress-regulated endoprotease leads to an RT inactive protease with a modified PDZ motif."; RL Genomics 68:343-347(2000). RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 134-458, INTERACTION WITH XIAP, AND MUTAGENESIS OF RP ALA-134. RX PubMed=11583623; DOI=10.1016/s1097-2765(01)00341-0; RA Suzuki Y., Imai Y., Nakayama H., Takahashi K., Takio K., Takahashi R.; RT "A serine protease, HtrA2, is released from the mitochondria and interacts RT with XIAP, inducing cell death."; RL Mol. Cell 8:613-621(2001). RN [7] RP CHARACTERIZATION, AND PHOSPHORYLATION. RX PubMed=10873535; DOI=10.1006/prep.2000.1240; RA Savopoulos J.W., Carter P.S., Turconi S., Pettman G.R., Karran E.H., RA Gray C.W., Ward R.V., Jenkins O., Creasy C.L.; RT "Expression, purification, and functional analysis of the human serine RT protease HtrA2."; RL Protein Expr. Purif. 19:227-234(2000). RN [8] RP FUNCTION, AND INTERACTION WITH BIRC6/BRUCE. RX PubMed=15200957; DOI=10.1016/j.molcel.2004.05.018; RA Bartke T., Pohl C., Pyrowolakis G., Jentsch S.; RT "Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin RT ligase."; RL Mol. Cell 14:801-811(2004). RN [9] RP FUNCTION, AND INTERACTION WITH THAP5. RX PubMed=19502560; DOI=10.1152/ajpheart.00234.2009; RA Balakrishnan M.P., Cilenti L., Mashak Z., Popat P., Alnemri E.S., RA Zervos A.S.; RT "THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved RT by the proapoptotic Omi/HtrA2 protease during cell death."; RL Am. J. Physiol. 297:H643-H653(2009). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP INTERACTION WITH AREL1. RX PubMed=23479728; DOI=10.1074/jbc.m112.436113; RA Kim J.B., Kim S.Y., Kim B.M., Lee H., Kim I., Yun J., Jo Y., Oh T., Jo Y., RA Chae H.D., Shin D.Y.; RT "Identification of a novel anti-apoptotic E3 ubiquitin ligase that RT ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, RT and ARTS."; RL J. Biol. Chem. 288:12014-12021(2013). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [14] {ECO:0007744|PDB:1LCY} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 134-458, SUBUNIT, AND ACTIVE SITE. RX PubMed=11967569; DOI=10.1038/nsb795; RA Li W., Srinivasula S.M., Chai J., Li P., Wu J.W., Zhang Z., Alnemri E.S., RA Shi Y.; RT "Structural insights into the pro-apoptotic function of mitochondrial RT serine protease HtrA2/Omi."; RL Nat. Struct. Biol. 9:436-441(2002). RN [15] {ECO:0007744|PDB:8E2K} RP STRUCTURE BY ELECTRON MICROSCOPY (3.21 ANGSTROMS) OF 134-458 IN COMPLEX RP WITH BIRC6, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND UBIQUITINATION BY RP BIRC6. RX PubMed=36758104; DOI=10.1126/science.ade5750; RA Hunkeler M., Jin C.Y., Fischer E.S.; RT "Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated RT release of caspases."; RL Science 379:1105-1111(2023). RN [16] {ECO:0007744|PDB:8AUK} RP STRUCTURE BY ELECTRON MICROSCOPY (6.20 ANGSTROMS) OF 134-458 IN COMPLEX RP WITH BIRC6, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND UBIQUITINATION BY RP BIRC6. RX PubMed=36758105; DOI=10.1126/science.ade8873; RA Ehrmann J.F., Grabarczyk D.B., Heinke M., Deszcz L., Kurzbauer R., RA Hudecz O., Shulkina A., Gogova R., Meinhart A., Versteeg G.A., Clausen T.; RT "Structural basis for regulation of apoptosis and autophagy by the RT BIRC6/SMAC complex."; RL Science 379:1117-1123(2023). RN [17] RP INVOLVEMENT IN PARK13, VARIANTS SER-141 AND SER-399, AND CHARACTERIZATION RP OF VARIANTS SER-141 AND SER-399. RX PubMed=15961413; DOI=10.1093/hmg/ddi215; RA Strauss K.M., Martins L.M., Plun-Favreau H., Marx F.P., Kautzmann S., RA Berg D., Gasser T., Wszolek Z., Mueller T., Bornemann A., Wolburg H., RA Downward J., Riess O., Schulz J.B., Krueger R.; RT "Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's RT disease."; RL Hum. Mol. Genet. 14:2099-2111(2005). RN [18] RP INVOLVEMENT IN PARK13, VARIANTS PRO-72 AND SER-141, AND VARIANT PARK13 RP TRP-404. RX PubMed=18401856; DOI=10.1002/humu.20713; RA Bogaerts V., Nuytemans K., Reumers J., Pals P., Engelborghs S., Pickut B., RA Corsmit E., Peeters K., Schymkowitz J., De Deyn P.P., Cras P., Rousseau F., RA Theuns J., Van Broeckhoven C.; RT "Genetic variability in the mitochondrial serine protease HTRA2 contributes RT to risk for Parkinson disease."; RL Hum. Mutat. 29:832-840(2008). RN [19] RP VARIANTS CYS-12; LEU-128; SER-141; SER-227 AND SER-399. RX PubMed=18364387; DOI=10.1093/hmg/ddn096; RA Simon-Sanchez J., Singleton A.B.; RT "Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic RT mutations in neurologically normal controls."; RL Hum. Mol. Genet. 17:1988-1993(2008). RN [20] RP VARIANT SER-399. RX PubMed=25422467; DOI=10.1073/pnas.1419581111; RA Unal Gulsuner H., Gulsuner S., Mercan F.N., Onat O.E., Walsh T., Shahin H., RA Lee M.K., Dogu O., Kansu T., Topaloglu H., Elibol B., Akbostanci C., RA King M.C., Ozcelik T., Tekinay A.B.; RT "Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential RT tremor and Parkinson disease."; RL Proc. Natl. Acad. Sci. U.S.A. 111:18285-18290(2014). RN [21] RP INVOLVEMENT IN MGCA8, VARIANT MGCA8 GLN-404, AND CHARACTERIZATION OF RP VARIANT MGCA8 GLN-404. RX PubMed=27208207; DOI=10.1136/jmedgenet-2016-103922; RA Mandel H., Saita S., Edvardson S., Jalas C., Shaag A., Goldsher D., RA Vlodavsky E., Langer T., Elpeleg O.; RT "Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and RT 3-methylglutaconic aciduria."; RL J. Med. Genet. 53:690-696(2016). RN [22] RP VARIANT SER-399. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [23] RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER, AND CHARACTERIZATION OF RP VARIANT MGCA8 243-LEU-PRO-244 DELINS PRO-SER. RX PubMed=27696117; DOI=10.1007/s10545-016-9977-2; RA Olahova M., Thompson K., Hardy S.A., Barbosa I.A., Besse A., RA Anagnostou M.E., White K., Davey T., Simpson M.A., Champion M., Enns G., RA Schelley S., Lightowlers R.N., Chrzanowska-Lightowlers Z.M., McFarland R., RA Deshpande C., Bonnen P.E., Taylor R.W.; RT "Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome RT associated with 3-methylglutaconic aciduria."; RL J. Inherit. Metab. Dis. 40:121-130(2017). CC -!- FUNCTION: [Isoform 1]: Serine protease that shows proteolytic activity CC against a non-specific substrate beta-casein (PubMed:10873535). CC Promotes apoptosis by either relieving the inhibition of BIRC proteins CC on caspases, leading to an increase in caspase activity; or by a BIRC CC inhibition-independent, caspase-independent and serine protease CC activity-dependent mechanism (PubMed:15200957). Cleaves BIRC6 and CC relieves its inhibition on CASP3, CASP7 and CASP9, but it is also prone CC to inhibition by BIRC6 (PubMed:36758104, PubMed:36758105). Cleaves CC THAP5 and promotes its degradation during apoptosis (PubMed:19502560). CC {ECO:0000269|PubMed:10873535, ECO:0000269|PubMed:15200957, CC ECO:0000269|PubMed:19502560, ECO:0000269|PubMed:36758104, CC ECO:0000269|PubMed:36758105}. CC -!- FUNCTION: [Isoform 2]: Seems to be proteolytically inactive. CC {ECO:0000269|PubMed:10995577}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Cleavage of non-polar aliphatic amino-acids at the P1 CC position, with a preference for Val, Ile and Met. At the P2 and P3 CC positions, Arg is selected most strongly with a secondary preference CC for other hydrophilic residues.; EC=3.4.21.108; CC -!- ACTIVITY REGULATION: Inhibited by BIRC6. {ECO:0000269|PubMed:36758104, CC ECO:0000269|PubMed:36758105}. CC -!- SUBUNIT: Homotrimer (PubMed:36758104, PubMed:36758105). Interacts with CC MXI2. Interacts with THAP5 under apoptotic conditions. The mature CC protein, but not the precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and CC XIAP/BIRC4. Interacts with AREL1 (via HECT domain); in the cytoplasm CC following induction of apoptosis (PubMed:23479728). CC {ECO:0000269|PubMed:11583623, ECO:0000269|PubMed:11967569, CC ECO:0000269|PubMed:15200957, ECO:0000269|PubMed:19502560, CC ECO:0000269|PubMed:23479728}. CC -!- INTERACTION: CC O43464; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-517086, EBI-25840993; CC O43464; Q8IUR7: ARMC8; NbExp=6; IntAct=EBI-517086, EBI-1049469; CC O43464; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-517086, EBI-25844820; CC O43464; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-517086, EBI-14199987; CC O43464; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-517086, EBI-25843552; CC O43464; Q96FT7-4: ASIC4; NbExp=3; IntAct=EBI-517086, EBI-9089489; CC O43464; Q13490: BIRC2; NbExp=4; IntAct=EBI-517086, EBI-514538; CC O43464; Q96CA5: BIRC7; NbExp=5; IntAct=EBI-517086, EBI-517623; CC O43464; Q7Z7K6: CENPV; NbExp=3; IntAct=EBI-517086, EBI-1210604; CC O43464; P02489: CRYAA; NbExp=3; IntAct=EBI-517086, EBI-6875961; CC O43464; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-517086, EBI-25842815; CC O43464; O00303: EIF3F; NbExp=3; IntAct=EBI-517086, EBI-711990; CC O43464; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-517086, EBI-9246952; CC O43464; Q13216-2: ERCC8; NbExp=3; IntAct=EBI-517086, EBI-16466949; CC O43464; Q99871: HAUS7; NbExp=3; IntAct=EBI-517086, EBI-395719; CC O43464; Q02363: ID2; NbExp=3; IntAct=EBI-517086, EBI-713450; CC O43464; Q8IY31-2: IFT20; NbExp=3; IntAct=EBI-517086, EBI-11742277; CC O43464; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-517086, EBI-743960; CC O43464; Q6P597: KLC3; NbExp=3; IntAct=EBI-517086, EBI-1643885; CC O43464; P57682: KLF3; NbExp=3; IntAct=EBI-517086, EBI-8472267; CC O43464; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-517086, EBI-714379; CC O43464; P08727: KRT19; NbExp=3; IntAct=EBI-517086, EBI-742756; CC O43464; Q14525: KRT33B; NbExp=3; IntAct=EBI-517086, EBI-1049638; CC O43464; Q1L5Z9: LONRF2; NbExp=3; IntAct=EBI-517086, EBI-2510853; CC O43464; Q99683: MAP3K5; NbExp=3; IntAct=EBI-517086, EBI-476263; CC O43464; Q8NA82: MARCHF10; NbExp=3; IntAct=EBI-517086, EBI-2341554; CC O43464; Q8N594: MPND; NbExp=3; IntAct=EBI-517086, EBI-2512452; CC O43464; Q8WY64: MYLIP; NbExp=3; IntAct=EBI-517086, EBI-6952711; CC O43464; Q9P0J0: NDUFA13; NbExp=8; IntAct=EBI-517086, EBI-372742; CC O43464; Q13562: NEUROD1; NbExp=3; IntAct=EBI-517086, EBI-3908303; CC O43464; O15381-5: NVL; NbExp=3; IntAct=EBI-517086, EBI-18577082; CC O43464; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-517086, EBI-1058491; CC O43464; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-517086, EBI-25830200; CC O43464; Q9NUU6: OTULINL; NbExp=3; IntAct=EBI-517086, EBI-6916492; CC O43464; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-517086, EBI-11022007; CC O43464; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-517086, EBI-6309018; CC O43464; O14813: PHOX2A; NbExp=3; IntAct=EBI-517086, EBI-25844430; CC O43464; O75925: PIAS1; NbExp=3; IntAct=EBI-517086, EBI-629434; CC O43464; Q8WWB5: PIH1D2; NbExp=3; IntAct=EBI-517086, EBI-10232538; CC O43464; Q96T49: PPP1R16B; NbExp=3; IntAct=EBI-517086, EBI-10293968; CC O43464; Q6ZMI0-5: PPP1R21; NbExp=3; IntAct=EBI-517086, EBI-25835994; CC O43464; P17980: PSMC3; NbExp=3; IntAct=EBI-517086, EBI-359720; CC O43464; P57052: RBM11; NbExp=3; IntAct=EBI-517086, EBI-741332; CC O43464; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-517086, EBI-749039; CC O43464; Q96D59: RNF183; NbExp=3; IntAct=EBI-517086, EBI-743938; CC O43464; Q15287: RNPS1; NbExp=2; IntAct=EBI-517086, EBI-395959; CC O43464; Q96GQ5: RUSF1; NbExp=3; IntAct=EBI-517086, EBI-8636004; CC O43464; Q8N488: RYBP; NbExp=3; IntAct=EBI-517086, EBI-752324; CC O43464; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-517086, EBI-11528848; CC O43464; Q9NR46: SH3GLB2; NbExp=3; IntAct=EBI-517086, EBI-749607; CC O43464; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-517086, EBI-358489; CC O43464; Q16637-3: SMN2; NbExp=3; IntAct=EBI-517086, EBI-395447; CC O43464; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-517086, EBI-3942425; CC O43464; Q5VWN6: TASOR2; NbExp=3; IntAct=EBI-517086, EBI-745958; CC O43464; Q86WV5: TEN1; NbExp=3; IntAct=EBI-517086, EBI-2562799; CC O43464; O95150: TNFSF15; NbExp=3; IntAct=EBI-517086, EBI-16355546; CC O43464; Q6DKK2: TTC19; NbExp=4; IntAct=EBI-517086, EBI-948354; CC O43464; Q495M9: USH1G; NbExp=3; IntAct=EBI-517086, EBI-8601749; CC O43464; O75604-3: USP2; NbExp=3; IntAct=EBI-517086, EBI-10696113; CC O43464; Q8NEZ2: VPS37A; NbExp=3; IntAct=EBI-517086, EBI-2850578; CC O43464; Q15007-2: WTAP; NbExp=3; IntAct=EBI-517086, EBI-25840023; CC O43464; O00308: WWP2; NbExp=3; IntAct=EBI-517086, EBI-743923; CC O43464; P98170: XIAP; NbExp=23; IntAct=EBI-517086, EBI-517127; CC O43464; P24278: ZBTB25; NbExp=3; IntAct=EBI-517086, EBI-739899; CC O43464; Q9UNY5: ZNF232; NbExp=3; IntAct=EBI-517086, EBI-749023; CC O43464; Q8N0Y2-2: ZNF444; NbExp=3; IntAct=EBI-517086, EBI-12010736; CC O43464; O60304: ZNF500; NbExp=3; IntAct=EBI-517086, EBI-18234077; CC O43464; O15535: ZSCAN9; NbExp=3; IntAct=EBI-517086, EBI-751531; CC O43464; Q86V28; NbExp=3; IntAct=EBI-517086, EBI-10259496; CC O43464; P02666: CSN2; Xeno; NbExp=7; IntAct=EBI-517086, EBI-5260183; CC O43464; Q60855: Ripk1; Xeno; NbExp=2; IntAct=EBI-517086, EBI-529119; CC PRO_0000026946; P02666: CSN2; Xeno; NbExp=2; IntAct=EBI-5271862, EBI-5260183; CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space. Mitochondrion CC membrane {ECO:0000305}; Single-pass membrane protein {ECO:0000305}. CC Note=Predominantly present in the intermembrane space. Released into CC the cytosol following apoptotic stimuli, such as UV treatment, and CC stimulation of mitochondria with caspase-8 truncated BID/tBID. CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum CC {ECO:0000269|PubMed:10644717}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=13B; CC IsoId=O43464-1; Sequence=Displayed; CC Name=2; Synonyms=D-Omi; CC IsoId=O43464-2; Sequence=VSP_005359, VSP_005361; CC Name=3; Synonyms=p7; CC IsoId=O43464-3; Sequence=VSP_005360, VSP_005361; CC Name=4; Synonyms=p4; CC IsoId=O43464-4; Sequence=VSP_005362; CC -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed. CC {ECO:0000269|PubMed:10644717}. CC -!- DOMAIN: The mature N-terminus is involved in the interaction with XIAP. CC -!- DOMAIN: The PDZ domain mediates interaction with MXI2. CC -!- PTM: Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC. CC {ECO:0000269|PubMed:36758104, ECO:0000269|PubMed:36758105}. CC -!- PTM: Autoproteolytically activated. {ECO:0000269|PubMed:10873535}. CC -!- DISEASE: 3-methylglutaconic aciduria 8 (MGCA8) [MIM:617248]: An CC autosomal recessive inborn error of metabolism resulting in early CC death. Clinical features include extreme hypertonia observed at birth, CC alternating with hypotonia, subsequent appearance of extrapyramidal CC symptoms, lack of psychomotor development, microcephaly, and CC intractable seizures. Patients show lactic acidemia, 3-methylglutaconic CC aciduria, intermittent neutropenia, and progressive brain atrophy. CC {ECO:0000269|PubMed:27208207, ECO:0000269|PubMed:27696117}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 13 (PARK13) [MIM:610297]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability, as well as by a CC clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. {ECO:0000269|PubMed:15961413, ECO:0000269|PubMed:18401856}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41879/HTRA2"; 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; AF020760; AAB94569.2; -; mRNA. DR EMBL; AF141305; AAF66596.1; -; mRNA. DR EMBL; AF141306; AAF66597.1; -; mRNA. DR EMBL; AF141307; AAF66598.1; -; mRNA. DR EMBL; AF184911; AAG13126.1; -; mRNA. DR EMBL; AC006544; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000096; AAH00096.1; -; mRNA. DR CCDS; CCDS1951.1; -. [O43464-1] DR CCDS; CCDS1952.1; -. [O43464-2] DR CCDS; CCDS92785.1; -. [O43464-3] DR RefSeq; NP_001308656.1; NM_001321727.1. [O43464-3] DR RefSeq; NP_037379.1; NM_013247.5. [O43464-1] DR RefSeq; NP_659540.1; NM_145074.2. [O43464-2] DR PDB; 1LCY; X-ray; 2.00 A; A=134-458. DR PDB; 2PZD; X-ray; 2.75 A; A/B=359-458. DR PDB; 5FHT; X-ray; 1.95 A; A=134-458. DR PDB; 5M3N; X-ray; 1.65 A; A=134-458. DR PDB; 5M3O; X-ray; 1.70 A; A=134-458. DR PDB; 5TNY; X-ray; 1.70 A; A=134-458. DR PDB; 5TNZ; X-ray; 1.75 A; A=134-458. DR PDB; 5TO0; X-ray; 1.90 A; A=134-458. DR PDB; 5TO1; X-ray; 1.69 A; A=134-458. DR PDB; 5WYN; X-ray; 2.05 A; A=134-458. DR PDB; 7VGE; X-ray; 4.00 A; A/B/C=140-342, D/F=140-341, E=140-340. DR PDB; 8AUK; EM; 6.20 A; C/D/E=134-458. DR PDB; 8E2K; EM; 3.21 A; X/Y/Z=134-458. DR PDBsum; 1LCY; -. DR PDBsum; 2PZD; -. DR PDBsum; 5FHT; -. DR PDBsum; 5M3N; -. DR PDBsum; 5M3O; -. DR PDBsum; 5TNY; -. DR PDBsum; 5TNZ; -. DR PDBsum; 5TO0; -. DR PDBsum; 5TO1; -. DR PDBsum; 5WYN; -. DR PDBsum; 7VGE; -. DR PDBsum; 8AUK; -. DR PDBsum; 8E2K; -. DR AlphaFoldDB; O43464; -. DR EMDB; EMD-15672; -. DR EMDB; EMD-27841; -. DR SASBDB; O43464; -. DR SMR; O43464; -. DR BioGRID; 118165; 304. DR CORUM; O43464; -. DR ELM; O43464; -. DR FunCoup; O43464; 1709. DR IntAct; O43464; 313. DR MINT; O43464; -. DR STRING; 9606.ENSP00000258080; -. DR BindingDB; O43464; -. DR ChEMBL; CHEMBL4523137; -. DR MEROPS; S01.278; -. DR MoonDB; O43464; Predicted. DR TCDB; 8.A.217.1.1; the apoptosis cell death regulator (acdr) family. DR iPTMnet; O43464; -. DR PhosphoSitePlus; O43464; -. DR BioMuta; HTRA2; -. DR OGP; O43464; -. DR jPOST; O43464; -. DR MassIVE; O43464; -. DR PaxDb; 9606-ENSP00000258080; -. DR PeptideAtlas; O43464; -. DR ProteomicsDB; 48958; -. [O43464-1] DR ProteomicsDB; 48959; -. [O43464-2] DR ProteomicsDB; 48960; -. [O43464-3] DR ProteomicsDB; 48961; -. [O43464-4] DR Pumba; O43464; -. DR TopDownProteomics; O43464-2; -. [O43464-2] DR ABCD; O43464; 1 sequenced antibody. DR Antibodypedia; 3554; 772 antibodies from 43 providers. DR DNASU; 27429; -. DR Ensembl; ENST00000258080.8; ENSP00000258080.3; ENSG00000115317.14. [O43464-1] DR Ensembl; ENST00000352222.7; ENSP00000312893.3; ENSG00000115317.14. [O43464-2] DR Ensembl; ENST00000437202.2; ENSP00000399166.2; ENSG00000115317.14. [O43464-3] DR GeneID; 27429; -. DR KEGG; hsa:27429; -. DR MANE-Select; ENST00000258080.8; ENSP00000258080.3; NM_013247.5; NP_037379.1. DR UCSC; uc002smi.2; human. [O43464-1] DR AGR; HGNC:14348; -. DR ClinPGx; PA33836; -. DR CTD; 27429; -. DR DisGeNET; 27429; -. DR GeneCards; HTRA2; -. DR HGNC; HGNC:14348; HTRA2. DR HPA; ENSG00000115317; Low tissue specificity. DR MalaCards; HTRA2; -. DR MIM; 168600; phenotype. DR MIM; 606441; gene. DR MIM; 610297; phenotype. DR MIM; 617248; phenotype. DR OpenTargets; ENSG00000115317; -. DR Orphanet; 505208; 3-methylglutaconic aciduria type 8. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000115317; -. DR eggNOG; KOG1320; Eukaryota. DR GeneTree; ENSGT00940000155108; -. DR HOGENOM; CLU_020120_6_0_1; -. DR InParanoid; O43464; -. DR OMA; MDNYRDE; -. DR OrthoDB; 4217619at2759; -. DR PAN-GO; O43464; 5 GO annotations based on evolutionary models. DR PhylomeDB; O43464; -. DR BRENDA; 3.4.21.108; 2681. DR PathwayCommons; O43464; -. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR Reactome; R-HSA-9841251; Mitochondrial unfolded protein response (UPRmt). DR SignaLink; O43464; -. DR SIGNOR; O43464; -. DR Agora; ENSG00000115317; -. DR BioGRID-ORCS; 27429; 97 hits in 1167 CRISPR screens. DR ChiTaRS; HTRA2; human. DR EvolutionaryTrace; O43464; -. DR GeneWiki; HtrA_serine_peptidase_2; -. DR GenomeRNAi; 27429; -. DR Pharos; O43464; Tbio. DR PRO; PR:O43464; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; O43464; protein. DR Bgee; ENSG00000115317; Expressed in cortical plate and 199 other cell types or tissues. DR ExpressionAtlas; O43464; baseline and differential. DR GO; GO:0035631; C:CD40 receptor complex; ISS:BHF-UCL. DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:BHF-UCL. DR GO; GO:0005856; C:cytoskeleton; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; NAS:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:MGI. DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:1905370; C:serine-type endopeptidase complex; IMP:CAFA. DR GO; GO:0042802; F:identical protein binding; IPI:CAFA. DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB. DR GO; GO:0030291; F:protein serine/threonine kinase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0008236; F:serine-type peptidase activity; IDA:UniProtKB. DR GO; GO:1990948; F:ubiquitin ligase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0051082; F:unfolded protein binding; NAS:UniProtKB. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IMP:UniProtKB. DR GO; GO:0034605; P:cellular response to heat; IDA:UniProtKB. DR GO; GO:0035458; P:cellular response to interferon-beta; IDA:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0071300; P:cellular response to retinoic acid; IDA:ParkinsonsUK-UCL. DR GO; GO:0006672; P:ceramide metabolic process; IEA:Ensembl. DR GO; GO:0097194; P:execution phase of apoptosis; TAS:UniProtKB. DR GO; GO:0030900; P:forebrain development; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:ParkinsonsUK-UCL. DR GO; GO:0035694; P:mitochondrial protein catabolic process; TAS:Reactome. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0045786; P:negative regulation of cell cycle; TAS:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:1905090; P:negative regulation of type 2 mitophagy; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0019742; P:pentacyclic triterpenoid metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:1900119; P:positive regulation of execution phase of apoptosis; IDA:ParkinsonsUK-UCL. DR GO; GO:2001241; P:positive regulation of extrinsic apoptotic signaling pathway in absence of ligand; IMP:UniProtKB. DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL. DR GO; GO:0012501; P:programmed cell death; IBA:GO_Central. DR GO; GO:0016540; P:protein autoprocessing; TAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0006508; P:proteolysis; IMP:UniProtKB. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl. DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl. DR CDD; cd06785; cpPDZ_HtrA-like; 1. DR DisProt; DP00315; -. DR FunFam; 2.40.10.120:FF:000004; Serine protease HTRA2, mitochondrial; 1. DR FunFam; 2.30.42.10:FF:000145; serine protease HTRA2, mitochondrial; 1. DR Gene3D; 2.30.42.10; -; 1. DR Gene3D; 2.40.10.120; -; 1. DR InterPro; IPR001478; PDZ. DR InterPro; IPR041489; PDZ_6. DR InterPro; IPR036034; PDZ_sf. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR001940; Peptidase_S1C. DR PANTHER; PTHR22939; SERINE PROTEASE FAMILY S1C HTRA-RELATED; 1. DR PANTHER; PTHR22939:SF127; SERINE PROTEASE HTRA2, MITOCHONDRIAL; 1. DR Pfam; PF17820; PDZ_6; 1. DR Pfam; PF13365; Trypsin_2; 1. DR PRINTS; PR00834; PROTEASES2C. DR SMART; SM00228; PDZ; 1. DR SUPFAM; SSF50156; PDZ domain-like; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS50106; PDZ; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Autocatalytic cleavage; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Epilepsy; Hydrolase; Membrane; Mitochondrion; Neurodegeneration; KW Parkinson disease; Parkinsonism; Protease; Proteomics identification; KW Reference proteome; Serine protease; Transit peptide; Transmembrane; KW Transmembrane helix; Ubl conjugation; Zymogen. FT TRANSIT 1..31 FT /note="Mitochondrion" FT PROPEP 32..133 FT /evidence="ECO:0000269|PubMed:11583623" FT /id="PRO_0000026945" FT CHAIN 134..458 FT /note="Serine protease HTRA2, mitochondrial" FT /id="PRO_0000026946" FT TRANSMEM 105..125 FT /note="Helical" FT /evidence="ECO:0000255" FT DOMAIN 364..445 FT /note="PDZ" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT REGION 166..342 FT /note="Serine protease" FT MOTIF 134..137 FT /note="IAP-binding motif" FT ACT_SITE 198 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT ACT_SITE 228 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT ACT_SITE 306 FT /note="Charge relay system" FT /evidence="ECO:0000269|PubMed:11967569" FT VAR_SEQ 238..302 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10995577" FT /id="VSP_005359" FT VAR_SEQ 313 FT /note="L -> LARELGAVSLQ (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10971580" FT /id="VSP_005360" FT VAR_SEQ 314..458 FT /note="DGEVIGVNTMKVTAGISFAIPSDRLREFLHRGEKKNSSSGISGSQRRYIGVM FT MLTLSPSILAELQLREPSFPDVQHGVLIHKVILGSPAHRAGLRPGDVILAIGEQMVQNA FT EDVYEAVRTQSQLAVQIRRGRETLTLYVTPEVTE -> VSETSFLPRIPAPGQCGKGRF FT PLIQGCLVKFLSSSLLAISQYPTRSPQHLLVLLFGCPHPLLFV (in isoform 4)" FT /evidence="ECO:0000303|PubMed:10971580" FT /id="VSP_005362" FT VAR_SEQ 372..403 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:10971580, FT ECO:0000303|PubMed:10995577" FT /id="VSP_005361" FT VARIANT 12 FT /note="W -> C (in dbSNP:rs775840965)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076967" FT VARIANT 72 FT /note="L -> P (in dbSNP:rs150047108)" FT /evidence="ECO:0000269|PubMed:18401856" FT /id="VAR_046134" FT VARIANT 128 FT /note="P -> L (in dbSNP:rs757704467)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076968" FT VARIANT 141 FT /note="A -> S (may be a risk factor for Parkinson disease; FT reduced protease activity; dbSNP:rs72470544)" FT /evidence="ECO:0000269|PubMed:15961413, FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:18401856" FT /id="VAR_027349" FT VARIANT 227 FT /note="A -> S (in dbSNP:rs375322953)" FT /evidence="ECO:0000269|PubMed:18364387" FT /id="VAR_076969" FT VARIANT 243..244 FT /note="LP -> PS (in MGCA8; loss of protein expression; FT dbSNP:rs1057519082)" FT /evidence="ECO:0000269|PubMed:27696117" FT /id="VAR_077960" FT VARIANT 399 FT /note="G -> S (may be a risk factor for Parkinson disease; FT reduced protease activity; dbSNP:rs72470545)" FT /evidence="ECO:0000269|PubMed:15961413, FT ECO:0000269|PubMed:18364387, ECO:0000269|PubMed:25422467, FT ECO:0000269|PubMed:27535533" FT /id="VAR_027350" FT VARIANT 404 FT /note="R -> Q (in MGCA8; may lead to skipping of exon 7 and FT the resultant protein may be truncated; loss of protein FT expression in patient cells homozygous for the mutation; FT dbSNP:rs767006508)" FT /evidence="ECO:0000269|PubMed:27208207" FT /id="VAR_077961" FT VARIANT 404 FT /note="R -> W (in PARK13; dbSNP:rs1380794702)" FT /evidence="ECO:0000269|PubMed:18401856" FT /id="VAR_046135" FT MUTAGEN 134 FT /note="A->M: Loss of interaction with XIAP. Loss of FT inhibition of XIAP activity." FT /evidence="ECO:0000269|PubMed:11583623" FT MUTAGEN 306 FT /note="S->A: Loss of protease activity." FT /evidence="ECO:0000269|PubMed:10644717" FT HELIX 143..147 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 149..157 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 158..160 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 161..170 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 171..174 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 175..188 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 189..191 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 192..195 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 198..200 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 204..209 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 211..213 FT /evidence="ECO:0007829|PDB:5TO0" FT STRAND 215..224 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 225..228 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 229..233 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 248..250 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 256..259 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 265..268 FT /evidence="ECO:0007829|PDB:5FHT" FT STRAND 271..275 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 295..299 FT /evidence="ECO:0007829|PDB:5M3N" FT TURN 303..307 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 308..311 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 317..326 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 329..334 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 335..342 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 359..361 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 364..368 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 371..380 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 382..384 FT /evidence="ECO:0007829|PDB:5WYN" FT STRAND 391..396 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 401..405 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 412..416 FT /evidence="ECO:0007829|PDB:5M3N" FT HELIX 424..433 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 435..443 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 446..452 FT /evidence="ECO:0007829|PDB:5M3N" FT STRAND 455..457 FT /evidence="ECO:0007829|PDB:5M3N" SQ SEQUENCE 458 AA; 48841 MW; CEA955A7D0DD8C0D CRC64; MAAPRAGRGA GWSLRAWRAL GGIRWGRRPR LTPDLRALLT SGTSDPRARV TYGTPSLWAR LSVGVTEPRA CLTSGTPGPR AQLTAVTPDT RTREASENSG TRSRAWLAVA LGAGGAVLLL LWGGGRGPPA VLAAVPSPPP ASPRSQYNFI ADVVEKTAPA VVYIEILDRH PFLGREVPIS NGSGFVVAAD GLIVTNAHVV ADRRRVRVRL LSGDTYEAVV TAVDPVADIA TLRIQTKEPL PTLPLGRSAD VRQGEFVVAM GSPFALQNTI TSGIVSSAQR PARDLGLPQT NVEYIQTDAA IDFGNSGGPL VNLDGEVIGV NTMKVTAGIS FAIPSDRLRE FLHRGEKKNS SSGISGSQRR YIGVMMLTLS PSILAELQLR EPSFPDVQHG VLIHKVILGS PAHRAGLRPG DVILAIGEQM VQNAEDVYEA VRTQSQLAVQ IRRGRETLTL YVTPEVTE // ID LRRK2_HUMAN Reviewed; 2527 AA. AC Q5S007; A6NJU2; Q6ZS50; Q8NCX9; DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot. DT 20-APR-2010, sequence version 2. DT 28-JAN-2026, entry version 200. DE RecName: Full=Leucine-rich repeat serine/threonine-protein kinase 2; DE EC=2.7.11.1 {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421}; DE EC=3.6.5.- {ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815}; DE AltName: Full=Dardarin; GN Name=LRRK2; Synonyms=PARK8; 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], TISSUE SPECIFICITY, AND VARIANTS PARK8 RP VAL-1122; CYS-1441; CYS-1699 AND THR-2020. RC TISSUE=Brain; RX PubMed=15541309; DOI=10.1016/j.neuron.2004.11.005; RA Zimprich A., Biskup S., Leitner P., Lichtner P., Farrer M., Lincoln S.J., RA Kachergus J.M., Hulihan M.M., Uitti R.J., Calne D.B., Stoessl A.J., RA Pfeiffer R.F., Patenge N., Carballo Carbajal I., Vieregge P., Asmus F., RA Mueller-Myhsok B., Dickson D.W., Meitinger T., Strom T.M., Wszolek Z.K., RA Gasser T.; RT "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic RT pathology."; RL Neuron 44:601-607(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2128-2527. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP DISEASE. RX PubMed=16081470; DOI=10.1093/brain/awh607; RA Adams J.R., van Netten H., Schulzer M., Mak E., McKenzie J., Strongosky A., RA Sossi V., Ruth T.J., Lee C.S., Farrer M., Gasser T., Uitti R.J., RA Calne D.B., Wszolek Z.K., Stoessl A.J.; RT "PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and RT evidence for presymptomatic compensation."; RL Brain 128:2777-2785(2005). RN [5] RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT PARK8 THR-2020. RX PubMed=16321986; DOI=10.1093/hmg/ddi439; RA Gloeckner C.J., Kinkl N., Schumacher A., Braun R.J., O'Neill E., RA Meitinger T., Kolch W., Prokisch H., Ueffing M.; RT "The Parkinson disease causing LRRK2 mutation I2020T is associated with RT increased kinase activity."; RL Hum. Mol. Genet. 15:223-232(2006). RN [6] RP DISEASE. RX PubMed=16087219; DOI=10.1016/j.mad.2005.06.010; RA Toft M., Sando S.B., Melquist S., Ross O.A., White L.R., Aasly J.O., RA Farrer M.J.; RT "LRRK2 mutations are not common in Alzheimer's disease."; RL Mech. Ageing Dev. 126:1201-1205(2005). RN [7] RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK8 CYS-1441 AND RP SER-2019. RX PubMed=16269541; DOI=10.1073/pnas.0507360102; RA West A.B., Moore D.J., Biskup S., Bugayenko A., Smith W.W., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 RT augment kinase activity."; RL Proc. Natl. Acad. Sci. U.S.A. 102:16842-16847(2005). RN [8] RP SUBCELLULAR LOCATION, AND INTERACTION WITH PRKN. RX PubMed=16352719; DOI=10.1073/pnas.0508052102; RA Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B., Dawson V.L., RA Dawson T.M., Ross C.A.; RT "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant RT LRRK2 induces neuronal degeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 102:18676-18681(2005). RN [9] RP TISSUE SPECIFICITY. RX PubMed=16532471; DOI=10.1002/ana.20808; RA Galter D., Westerlund M., Carmine A., Lindqvist E., Sydow O., Olson L.; RT "LRRK2 expression linked to dopamine-innervated areas."; RL Ann. Neurol. 59:714-719(2006). RN [10] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=17120249; DOI=10.1002/ana.21019; RA Biskup S., Moore D.J., Celsi F., Higashi S., West A.B., Andrabi S.A., RA Kurkinen K., Yu S.W., Savitt J.M., Waldvogel H.J., Faull R.L., Emson P.C., RA Torp R., Ottersen O.P., Dawson T.M., Dawson V.L.; RT "Localization of LRRK2 to membranous and vesicular structures in mammalian RT brain."; RL Ann. Neurol. 60:557-569(2006). RN [11] RP FUNCTION, CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; CYS-1699; SER-2019 RP AND THR-2020, AND VARIANT MET-1906. RX PubMed=17114044; DOI=10.1016/j.neuron.2006.10.008; RA MacLeod D., Dowman J., Hammond R., Leete T., Inoue K., Abeliovich A.; RT "The familial Parkinsonism gene LRRK2 regulates neurite process RT morphology."; RL Neuron 52:587-593(2006). RN [12] RP FUNCTION. RX PubMed=20949042; DOI=10.1371/journal.pone.0013191; RA Zach S., Felk S., Gillardon F.; RT "Signal transduction protein array analysis links LRRK2 to Ste20 kinases RT and PKC zeta that modulate neuronal plasticity."; RL PLoS ONE 5:E13191-E13191(2010). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PRDX3, AND RP CHARACTERIZATION OF VARIANT PARK8 SER-2019. RX PubMed=21850687; DOI=10.1002/humu.21582; RA Angeles D.C., Gan B.H., Onstead L., Zhao Y., Lim K.L., Dachsel J., RA Melrose H., Farrer M., Wszolek Z.K., Dickson D.W., Tan E.K.; RT "Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 RT exacerbating oxidative stress-induced neuronal death."; RL Hum. Mutat. 32:1390-1397(2011). RN [14] RP FUNCTION, AND INTERACTION WITH TPCN2. RX PubMed=22012985; DOI=10.1093/hmg/ddr481; RA Gomez-Suaga P., Luzon-Toro B., Churamani D., Zhang L., Bloor-Young D., RA Patel S., Woodman P.G., Churchill G.C., Hilfiker S.; RT "Leucine-rich repeat kinase 2 regulates autophagy through a calcium- RT dependent pathway involving NAADP."; RL Hum. Mol. Genet. 21:511-525(2012). RN [15] RP SUBUNIT, AND AUTOPHOSPHORYLATION. RX PubMed=22952686; DOI=10.1371/journal.pone.0043472; RA Civiero L., Vancraenenbroeck R., Belluzzi E., Beilina A., Lobbestael E., RA Reyniers L., Gao F., Micetic I., De Maeyer M., Bubacco L., Baekelandt V., RA Cookson M.R., Greggio E., Taymans J.M.; RT "Biochemical characterization of highly purified leucine-rich repeat RT kinases 1 and 2 demonstrates formation of homodimers."; RL PLoS ONE 7:E43472-E43472(2012). RN [16] RP FUNCTION IN RETROGRADE TRANSPORT, INTERACTION WITH RAB29 AND VPS35, RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT PARK8 SER-2019, AND RP CHARACTERIZATION OF VARIANT MET-1906. RX PubMed=23395371; DOI=10.1016/j.neuron.2012.11.033; RA MacLeod D.A., Rhinn H., Kuwahara T., Zolin A., Di Paolo G., McCabe B.D., RA MacCabe B.D., Marder K.S., Honig L.S., Clark L.N., Small S.A., RA Abeliovich A.; RT "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and RT Parkinson's disease risk."; RL Neuron 77:425-439(2013). RN [17] RP WD REPEATS. RX PubMed=23776530; DOI=10.1371/journal.pone.0065705; RA Wang Y., Jiang F., Zhuo Z., Wu X.H., Wu Y.D.; RT "A method for WD40 repeat detection and secondary structure prediction."; RL PLoS ONE 8:E65705-E65705(2013). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [19] RP FUNCTION, SUBCELLULAR LOCATION, ELECTRON MICROSCOPY, WD REPEATS, AND RP CHARACTERIZATION OF VARIANT ARG-2385. RX PubMed=24687852; DOI=10.1128/mcb.00914-13; RA Piccoli G., Onofri F., Cirnaru M.D., Kaiser C.J., Jagtap P., RA Kastenmuller A., Pischedda F., Marte A., von Zweydorf F., Vogt A., RA Giesert F., Pan L., Antonucci F., Kiel C., Zhang M., Weinkauf S., RA Sattler M., Sala C., Matteoli M., Ueffing M., Gloeckner C.J.; RT "Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein RT interactions mediated by its C-terminal WD40 domain."; RL Mol. Cell. Biol. 34:2147-2161(2014). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY REGULATION, INTERACTION RP WITH RAB8A; RAB10 AND RAB12, CHARACTERIZATION OF VARIANTS PARK8 HIS-1441; RP CYS-1441; GLY-1441; CYS-1699; HIS-1728; SER-2019; THR-2020; SER-2031 AND RP ARG-2385, AND MUTAGENESIS OF ASP-1994. RX PubMed=26824392; DOI=10.7554/elife.12813; RA Steger M., Tonelli F., Ito G., Davies P., Trost M., Vetter M., Wachter S., RA Lorentzen E., Duddy G., Wilson S., Baptista M.A., Fiske B.K., Fell M.J., RA Morrow J.A., Reith A.D., Alessi D.R., Mann M.; RT "Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates RT a subset of Rab GTPases."; RL Elife 5:0-0(2016). RN [21] RP FUNCTION, INTERACTION WITH MAPT, SUBCELLULAR LOCATION, CHARACTERIZATION OF RP VARIANT PAR8 SER-2019, AND MUTAGENESIS OF LYS-1906; ASP-1994 AND ASP-2017. 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 [22] RP FUNCTION, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANT MET-1906. RX PubMed=27830463; DOI=10.1007/s13238-016-0326-x; RA Yan R., Liu Z.; RT "LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by RT promoting Rip2 phosphorylation."; RL Protein Cell 8:55-66(2017). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, CHARACTERIZATION OF VARIANTS PARK8 RP GLY-1441; CYS-1699 AND SER-2019, AND MUTAGENESIS OF ASP-2017. RX PubMed=29125462; DOI=10.7554/elife.31012; RA Steger M., Diez F., Dhekne H.S., Lis P., Nirujogi R.S., Karayel O., RA Tonelli F., Martinez T.N., Lorentzen E., Pfeffer S.R., Alessi D.R., RA Mann M.; RT "Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation RT establishes a connection to ciliogenesis."; RL Elife 6:0-0(2017). RN [24] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, INTERACTION WITH APP, RP PHOSPHORYLATION AT SER-910 AND SER-935, CHARACTERIZATION OF VARIANTS PARK8 RP GLY-1441 AND SER-2019, AND MUTAGENESIS OF ASP-1994. RX PubMed=28720718; DOI=10.1126/scisignal.aam6790; RA Chen Z.C., Zhang W., Chua L.L., Chai C., Li R., Lin L., Cao Z., RA Angeles D.C., Stanton L.W., Peng J.H., Zhou Z.D., Lim K.L., Zeng L., RA Tan E.K.; RT "Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD RT activity and neurotoxicity in Parkinson's disease."; RL Sci. Signal. 10:0-0(2017). RN [25] {ECO:0000305} RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS PARK8 RP CYS-1441; GLY-1441; CYS-1699; SER-2019 AND THR-2020, AND CHARACTERIZATION RP OF VARIANT MET-1906. RX PubMed=30209220; DOI=10.1073/pnas.1812196115; RA Eguchi T., Kuwahara T., Sakurai M., Komori T., Fujimoto T., Ito G., RA Yoshimura S.I., Harada A., Fukuda M., Koike M., Iwatsubo T.; RT "LRRK2 and its substrate Rab GTPases are sequentially targeted onto RT stressed lysosomes and maintain their homeostasis."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E9115-E9124(2018). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, TISSUE SPECIFICITY, RP CHARACTERIZATION OF VARIANT PARK8 SER-2019, AND PHOSPHORYLATION AT SER-935. RX PubMed=29127255; DOI=10.1042/bcj20170803; RA Fan Y., Howden A.J.M., Sarhan A.R., Lis P., Ito G., Martinez T.N., RA Brockmann K., Gasser T., Alessi D.R., Sammler E.M.; RT "Interrogating Parkinson's disease LRRK2 kinase pathway activity by RT assessing Rab10 phosphorylation in human neutrophils."; RL Biochem. J. 475:23-44(2018). RN [27] RP FUNCTION, CATALYTIC ACTIVITY, AND VARIANTS PARK8 GLY-1441 AND SER-2019. RX PubMed=30398148; DOI=10.7554/elife.40202; RA Dhekne H.S., Yanatori I., Gomez R.C., Tonelli F., Diez F., Schuele B., RA Steger M., Alessi D.R., Pfeffer S.R.; RT "A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and RT Sonic hedgehog signaling in the brain."; RL Elife 7:0-0(2018). RN [28] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP PHOSPHORYLATION AT SER-910; SER-935; SER-955; SER-973 AND SER-1292, RP CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; CYS-1699; RP HIS-1728; SER-2019; THR-2020; SER-2031 AND ARG-2385, AND MUTAGENESIS OF RP CYS-727; LEU-728; LEU-729; LEU-760; LEU-761; LEU-762; LEU-789; LEU-790; RP LEU-791; THR-1348; ARG-1441; TYR-1699; ASP-2017 AND GLY-2019. RX PubMed=29212815; DOI=10.15252/embj.201798099; RA Purlyte E., Dhekne H.S., Sarhan A.R., Gomez R., Lis P., Wightman M., RA Martinez T.N., Tonelli F., Pfeffer S.R., Alessi D.R.; RT "Rab29 activation of the Parkinson's disease-associated LRRK2 kinase."; RL EMBO J. 37:1-18(2018). RN [29] RP ERRATUM OF PUBMED:29212815. RX PubMed=30647193; DOI=10.15252/embj.2018101237; RA Purlyte E., Dhekne H.S., Sarhan A.R., Gomez R., Lis P., Wightman M., RA Martinez T.N., Tonelli F., Pfeffer S.R., Alessi D.R.; RL EMBO J. 38:0-0(2019). RN [30] RP SUBCELLULAR LOCATION, AND UBIQUITINATION BY TRIM1. RX PubMed=35266954; DOI=10.1083/jcb.202010065; RA Stormo A.E.D., Shavarebi F., FitzGibbon M., Earley E.M., Ahrendt H., RA Lum L.S., Verschueren E., Swaney D.L., Skibinski G., Ravisankar A., RA van Haren J., Davis E.J., Johnson J.R., Von Dollen J., Balen C., Porath J., RA Crosio C., Mirescu C., Iaccarino C., Dauer W.T., Nichols R.J., Wittmann T., RA Cox T.C., Finkbeiner S., Krogan N.J., Oakes S.A., Hiniker A.; RT "The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, RT degradation, and toxicity."; RL J. Cell Biol. 221:0-0(2022). RN [31] {ECO:0000305} RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=38227290; DOI=10.1083/jcb.202302067; RA Eguchi T., Sakurai M., Wang Y., Saito C., Yoshii G., Wileman T., RA Mizushima N., Kuwahara T., Iwatsubo T.; RT "The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate the lysosomal RT stress response."; RL J. Cell Biol. 223:0-0(2024). RN [32] {ECO:0007744|PDB:2ZEJ, ECO:0007744|PDB:3D6T} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1333-1516 IN COMPLEX WITH GDP, RP FUNCTION, GTPASE ACTIVITY, ACTIVITY REGULATION, SUBUNIT, DOMAIN ROC, AND RP MUTAGENESIS OF THR-1343 AND ARG-1398. RX PubMed=18230735; DOI=10.1073/pnas.0709098105; RA Deng J., Lewis P.A., Greggio E., Sluch E., Beilina A., Cookson M.R.; RT "Structure of the ROC domain from the Parkinson's disease-associated RT leucine-rich repeat kinase 2 reveals a dimeric GTPase."; RL Proc. Natl. Acad. Sci. U.S.A. 105:1499-1504(2008). RN [33] {ECO:0007744|PDB:5MY9, ECO:0007744|PDB:5MYC} RP X-RAY CRYSTALLOGRAPHY (1.33 ANGSTROMS) OF 929-941 IN COMPLEX WITH SFN, RP INTERACTION WITH YWHAG, PHOSPHORYLATION AT SER-910; SER-935; SER-955; RP SER-973 AND SER-1444, AND CHARACTERIZATION OF VARIANT PARK8 CYS-1441. RX PubMed=28202711; DOI=10.1042/bcj20161078; RA Stevers L.M., de Vries R.M., Doveston R.G., Milroy L.G., Brunsveld L., RA Ottmann C.; RT "Structural interface between LRRK2 and 14-3-3 protein."; RL Biochem. J. 474:1273-1287(2017). RN [34] {ECO:0007744|PDB:6DLO, ECO:0007744|PDB:6DLP} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 2142-2527, FUNCTION, CATALYTIC RP ACTIVITY, SUBUNIT, DOMAIN, PHOSPHORYLATION AT SER-935 AND SER-1292, RP CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; SER-2019; ASP-2175; TYR-2189; RP ILE-2356; ARG-2385; MET-2390 AND ILE-2439, AND MUTAGENESIS OF ASP-2017; RP LEU-2343; PHE-2344; SER-2345; TYR-2346; HIS-2391; ARG-2394; GLU-2395; RP MET-2408 AND SER-2409. RX PubMed=30635421; DOI=10.1073/pnas.1817889116; RA Zhang P., Fan Y., Ru H., Wang L., Magupalli V.G., Taylor S.S., Alessi D.R., RA Wu H.; RT "Crystal structure of the WD40 domain dimer of LRRK2."; RL Proc. Natl. Acad. Sci. U.S.A. 116:1579-1584(2019). RN [35] {ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9, ECO:0007744|PDB:8SMC} RP STRUCTURE BY ELECTRON MICROSCOPY (3.48 ANGSTROMS) IN COMPLEX WITH RAB29; RP ATP AND GDP, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBUNIT, RP INTERACTION WITH RAB29 AND RAB32, SUBCELLULAR LOCATION, DOMAIN, RP AUTOPHOSPHORYLATION AT SER-1292, LRR REPEATS, WD REPEATS, AND MUTAGENESIS RP OF ARG-399; LEU-403; PRO-1588; ASN-1710; TRP-1791 AND ASP-2017. RX PubMed=38127736; DOI=10.1126/science.adi9926; RA Zhu H., Tonelli F., Turk M., Prescott A., Alessi D.R., Sun J.; RT "Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2."; RL Science 382:1404-1411(2023). RN [36] RP VARIANTS PARK8 GLY-1441 AND CYS-1699, AND TISSUE SPECIFICITY. RX PubMed=15541308; DOI=10.1016/j.neuron.2004.10.023; RA Paisan-Ruiz C., Jain S., Evans E.W., Gilks W.P., Simon J., van der Brug M., RA Lopez de Munain A., Aparicio S., Gil A.M., Khan N.L., Johnson J., RA Martinez J.R., Nicholl D., Carrera I.M., Pena A.S., de Silva R., Lees A.J., RA Marti-Masso J.F., Perez-Tur J., Wood N.W., Singleton A.B.; RT "Cloning of the gene containing mutations that cause PARK8-linked RT Parkinson's disease."; RL Neuron 44:595-600(2004). RN [37] RP VARIANT PARK8 SER-2019. RX PubMed=15726496; DOI=10.1086/429256; RA Kachergus J.M., Mata I.F., Hulihan M., Taylor J.P., Lincoln S., Aasly J.O., RA Gibson J.M., Ross O.A., Lynch T., Wiley J., Payami H., Nutt J., RA Maraganore D.M., Czyzewski K., Styczynska M., Wszolek Z.K., Farrer M.J., RA Toft M.; RT "Identification of a novel LRRK2 mutation linked to autosomal dominant RT parkinsonism: evidence of a common founder across European populations."; RL Am. J. Hum. Genet. 76:672-680(2005). RN [38] RP VARIANT PARK8 SER-2019. RX PubMed=15732108; DOI=10.1002/ana.20401; RA Hernandez D.G., Paisan-Ruiz C., McInerney-Leo A., Jain S., RA Meyer-Lindenberg A., Evans E.W., Berman K.F., Johnson J., Auburger G., RA Schaeffer A.A., Lopez G.J., Nussbaum R.L., Singleton A.B.; RT "Clinical and positron emission tomography of Parkinson's disease caused by RT LRRK2."; RL Ann. Neurol. 57:453-456(2005). RN [39] RP VARIANT PARK8/PD SER-2019. RX PubMed=15852371; DOI=10.1002/ana.20456; RA Aasly J.O., Toft M., Fernandez-Mata I., Kachergus J.M., Hulihan M., RA White L.R., Farrer M.J.; RT "Clinical features of LRRK2-associated Parkinson's disease in central RT Norway."; RL Ann. Neurol. 57:762-765(2005). RN [40] RP VARIANT PARK8 SER-2019. RX PubMed=16240353; DOI=10.1002/ana.20636; RG French Parkinson's disease genetics study group; RA Lesage S., Ibanez P., Lohmann E., Pollak P., Tison F., Tazir M., RA Leutenegger A.-L., Guimaraes J., Bonnet A.-M., Agid Y., Duerr A., Brice A.; RT "G2019S LRRK2 mutation in French and North African families with RT Parkinson's disease."; RL Ann. Neurol. 58:784-787(2005). RN [41] RP VARIANT PARK8 THR-2020. RX PubMed=15880653; DOI=10.1002/ana.20484; RA Funayama M., Hasegawa K., Ohta E., Kawashima N., Komiyama M., Kowa H., RA Tsuji S., Obata F.; RT "An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 RT family."; RL Ann. Neurol. 57:918-921(2005). RN [42] RP VARIANT PARK8 SER-2019. RX PubMed=15929036; DOI=10.1002/ana.20510; RA Deng H., Le W., Guo Y., Hunter C.B., Xie W., Jankovic J.; RT "Genetic and clinical identification of Parkinson's disease patients with RT LRRK2 G2019S mutation."; RL Ann. Neurol. 57:933-934(2005). RN [43] RP VARIANTS PARK8 MET-793; ARG-930; CYS-1096; THR-1228; SER-2019 AND THR-2020, RP AND VARIANT LYS-551. RX PubMed=16251215; DOI=10.1093/brain/awh666; RA Berg D., Schweitzer K., Leitner P., Zimprich A., Lichtner P., Belcredi P., RA Bruessel T., Schulte C., Maass S., Naegele T.; RT "Type and frequency of mutations in the LRRK2 gene in familial and sporadic RT Parkinson's disease."; RL Brain 128:3000-3011(2005). RN [44] RP VARIANTS PARK8 CYS-1699; HIS-1941; SER-2019 AND ILE-2356. RX PubMed=16272164; DOI=10.1093/brain/awh667; RA Khan N.L., Jain S., Lynch J.M., Pavese N., Abou-Sleiman P.M., Holton J.L., RA Healy D.G., Gilks W.P., Sweeney M.G., Ganguly M., Gibbons V., Gandhi S., RA Vaughan J., Eunson L.H., Katzenschlager R., Gayton J., Lennox G., RA Revesz T., Nicholl D., Bhatia K.P., Quinn N., Brooks D., Lees A.J., RA Davis M.B., Piccini P., Singleton A.B., Wood N.W.; RT "Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial RT Parkinson's disease: clinical, pathological, olfactory and functional RT imaging and genetic data."; RL Brain 128:2786-2796(2005). RN [45] RP VARIANTS PARK8 VAL-1371; CYS-1441 AND SER-2019. RX PubMed=16333314; DOI=10.1038/sj.ejhg.5201539; RA Di Fonzo A., Tassorelli C., De Mari M., Chien H.F., Ferreira J., Rohe C.F., RA Riboldazzi G., Antonini A., Albani G., Mauro A., Marconi R., Abbruzzese G., RA Lopiano L., Fincati E., Guidi M., Marini P., Stocchi F., Onofrj M., RA Toni V., Tinazzi M., Fabbrini G., Lamberti P., Vanacore N., Meco G., RA Leitner P., Uitti R.J., Wszolek Z.K., Gasser T., Simons E.J., RA Breedveld G.J., Goldwurm S., Pezzoli G., Sampaio C., Barbosa E., RA Martignoni E., Oostra B.A., Bonifati V.; RT "Comprehensive analysis of the LRRK2 gene in sixty families with RT Parkinson's disease."; RL Eur. J. Hum. Genet. 14:322-331(2006). RN [46] RP VARIANT PARK8 SER-2019. RX PubMed=16272257; DOI=10.1136/jmg.2005.035568; RA Goldwurm S., Di Fonzo A., Simons E.J., Rohe C.F., Zini M., Canesi M., RA Tesei S., Zecchinelli A., Antonini A., Mariani C., Meucci N., Sacilotto G., RA Sironi F., Salani G., Ferreira J., Chien H.F., Fabrizio E., Vanacore N., RA Dalla Libera A., Stocchi F., Diroma C., Lamberti P., Sampaio C., Meco G., RA Barbosa E., Bertoli-Avella A.M., Breedveld G.J., Oostra B.A., Pezzoli G., RA Bonifati V.; RT "The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late RT onset Parkinson's disease and originates from a common ancestor."; RL J. Med. Genet. 42:E65-E65(2005). RN [47] RP VARIANT PARK8 SER-2019. RX PubMed=15680455; DOI=10.1016/s0140-6736(05)17828-3; RG The Parkinson study group-PROGENI investigators; RA Nichols W.C., Pankratz N., Hernandez D., Paisan-Ruiz C., Jain S., RA Halter C.A., Michaels V.E., Reed T., Rudolph A., Shults C.W., Singleton A., RA Foroud T.; RT "Genetic screening for a single common LRRK2 mutation in familial RT Parkinson's disease."; RL Lancet 365:410-412(2005). RN [48] RP VARIANT PARK8 SER-2019. RX PubMed=15680456; DOI=10.1016/s0140-6736(05)17829-5; RG The Italian Parkinson genetics network; RA Di Fonzo A., Rohe C.F., Ferreira J., Chien H.F., Vacca L., Stocchi F., RA Guedes L., Fabrizio E., Manfredi M., Vanacore N., Goldwurm S., RA Breedveld G.J., Sampaio C., Meco G., Barbosa E., Oostra B.A., Bonifati V.; RT "A frequent LRRK2 gene mutation associated with autosomal dominant RT Parkinson's disease."; RL Lancet 365:412-415(2005). RN [49] RP VARIANT PARK8 SER-2019. RX PubMed=15680457; DOI=10.1016/s0140-6736(05)17830-1; RA Gilks W.P., Abou-Sleiman P.M., Gandhi S., Jain S., Singleton A., Lees A.J., RA Shaw K., Bhatia K.P., Bonifati V., Quinn N.P., Lynch J.M., Healy D.G., RA Holton J.L., Revesz T., Wood N.W.; RT "A common LRRK2 mutation in idiopathic Parkinson's disease."; RL Lancet 365:415-416(2005). RN [50] RP VARIANT PARK8 SER-2019. RX PubMed=15811454; DOI=10.1016/s0140-6736(05)74809-1; RA Toft M., Mata I.F., Kachergus J.M., Ross O.A., Farrer M.J.; RT "LRRK2 mutations and Parkinsonism."; RL Lancet 365:1229-1230(2005). RN [51] RP VARIANT SER-2019. RX PubMed=16001413; DOI=10.1002/mds.20618; RA Kay D.M., Kramer P., Higgins D.S., Zabetian C.P., Payami H.; RT "Escaping Parkinson's disease: a neurologically healthy octogenarian with RT the LRRK2 G2019S mutation."; RL Mov. Disord. 20:1077-1078(2005). RN [52] RP VARIANT PARK8 SER-2019. RX PubMed=16250030; DOI=10.1002/mds.20751; RA Kay D.M., Zabetian C.P., Factor S.A., Nutt J.G., Samii A., Griffith A., RA Bird T.D., Kramer P., Higgins D.S., Payami H.; RT "Parkinson's disease and LRRK2: frequency of a common mutation in U.S. RT movement disorder clinics."; RL Mov. Disord. 21:519-523(2006). RN [53] RP VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; GLN-1514; SER-1542; GLU-1598; RP PRO-1628; CYS-1699; THR-1869; THR-2012; SER-2019; THR-2020 AND ARG-2385, RP AND VARIANTS PRO-119; LYS-551; VAL-723; MET-793; VAL-1122; ALA-1262; RP HIS-1398; THR-1646; THR-1647; ASP-2081; LEU-2119; ILE-2261 AND THR-2397. RX PubMed=16172858; DOI=10.1007/s10048-005-0005-1; RA Mata I.F., Kachergus J.M., Taylor J.P., Lincoln S., Aasly J., Lynch T., RA Hulihan M.M., Cobb S.A., Wu R.-M., Lu C.-S., Lahoz C., Wszolek Z.K., RA Farrer M.J.; RT "Lrrk2 pathogenic substitutions in Parkinson's disease."; RL Neurogenetics 6:171-177(2005). RN [54] RP VARIANTS PARK8 VAL-1371 AND SER-2019, AND VARIANTS HIS-1398 AND THR-2397. RX PubMed=16157901; DOI=10.1212/01.wnl.0000167552.79769.b3; RA Paisan-Ruiz C., Lang A.E., Kawarai T., Sato C., Salehi-Rad S., Fisman G.K., RA Al-Khairallah T., St George-Hyslop P.H., Singleton A., Rogaeva E.; RT "LRRK2 gene in Parkinson disease: mutation analysis and case control RT association study."; RL Neurology 65:696-700(2005). RN [55] RP VARIANT PARK8 GLN-1067. RX PubMed=16247070; DOI=10.1212/01.wnl.0000180517.70572.37; RA Skipper L., Shen H., Chua E., Bonnard C., Kolatkar P., Tan L.C.S., RA Jamora R.D., Puvan K., Puong K.Y., Zhao Y., Pavanni R., Wong M.C., Yuen Y., RA Farrer M., Liu J.J., Tan E.K.; RT "Analysis of LRRK2 functional domains in nondominant Parkinson disease."; RL Neurology 65:1319-1321(2005). RN [56] RP VARIANTS PARK8 MET-793; THR-1869 AND SER-2019. RX PubMed=16157908; DOI=10.1212/01.wnl.0000169023.51764.b0; RA Farrer M., Stone J., Mata I.F., Lincoln S., Kachergus J., Hulihan M., RA Strain K.J., Maraganore D.M.; RT "LRRK2 mutations in Parkinson disease."; RL Neurology 65:738-740(2005). RN [57] RP VARIANTS PARK8 CYS-1441; HIS-1441 AND SER-2019. RX PubMed=16157909; DOI=10.1212/01.wnl.0000172630.22804.73; RA Zabetian C.P., Samii A., Mosley A.D., Roberts J.W., Leis B.C., Yearout D., RA Raskind W.H., Griffith A.; RT "A clinic-based study of the LRRK2 gene in Parkinson disease yields new RT mutations."; RL Neurology 65:741-744(2005). RN [58] RP VARIANT PARK8 GLY-1441. RX PubMed=15925109; DOI=10.1016/j.neulet.2005.03.033; RA Mata I.F., Taylor J.P., Kachergus J., Hulihan M., Huerta C., Lahoz C., RA Blazquez M., Guisasola L.M., Salvador C., Ribacoba R., Martinez C., RA Farrer M., Alvarez V.; RT "LRRK2 R1441G in Spanish patients with Parkinson's disease."; RL Neurosci. Lett. 382:309-311(2005). RN [59] RP VARIANT PARK8 SER-2019. RX PubMed=16298482; DOI=10.1016/j.neulet.2005.10.083; RA Infante J., Rodriguez E., Combarros O., Mateo I., Fontalba A., Pascual J., RA Oterino A., Polo J.M., Leno C., Berciano J.; RT "LRRK2 G2019S is a common mutation in Spanish patients with late-onset RT Parkinson's disease."; RL Neurosci. Lett. 395:224-226(2006). RN [60] RP VARIANT PARK8 SER-2019. RX PubMed=16102999; DOI=10.1016/j.parkreldis.2005.05.004; RA Gosal D., Ross O.A., Wiley J., Irvine G.B., Johnston J.A., Toft M., RA Mata I.F., Kachergus J., Hulihan M., Taylor J.P., Lincoln S.J., RA Farrer M.J., Lynch T., Mark Gibson J.; RT "Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link RT between familial and idiopathic PD."; RL Parkinsonism Relat. Disord. 11:349-352(2005). RN [61] RP VARIANTS PARK8 CYS-1441; GLY-1441 AND SER-2019. RX PubMed=16533964; DOI=10.1001/archneur.63.3.377; RA Gaig C., Ezquerra M., Marti M.J., Munoz E., Valldeoriola F., Tolosa E.; RT "LRRK2 mutations in Spanish patients with Parkinson disease: frequency, RT clinical features, and incomplete penetrance."; RL Arch. Neurol. 63:377-382(2006). RN [62] RP CHARACTERIZATION OF VARIANT ARG-2385, AND ASSOCIATION WITH PARKINSON RP DISEASE. RX PubMed=17019612; DOI=10.1007/s00439-006-0268-0; RA Tan E.K., Zhao Y., Skipper L., Tan M.G., Di Fonzo A., Sun L., RA Fook-Chong S., Tang S., Chua E., Yuen Y., Tan L., Pavanni R., Wong M.C., RA Kolatkar P., Lu C.S., Bonifati V., Liu J.J.; RT "The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: RT genetic and functional evidence."; RL Hum. Genet. 120:857-863(2007). RN [63] RP VARIANTS [LARGE SCALE ANALYSIS] PRO-119; VAL-419; LYS-551; VAL-723; RP HIS-1398; GLN-1514; SER-1542; GLN-1550 AND PRO-1723. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [64] RP VARIANTS PARK8 VAL-712; LEU-1728; HIS-1728; SER-2019; MET-2141; HIS-2143 RP AND HIS-2466, AND VARIANTS SER-228; VAL-716; GLU-871; PHE-1870 AND RP LYS-2395. RX PubMed=18213618; DOI=10.1002/humu.20668; RA Paisan-Ruiz C., Nath P., Washecka N., Gibbs J.R., Singleton A.B.; RT "Comprehensive analysis of LRRK2 in publicly available Parkinson's disease RT cases and neurologically normal controls."; RL Hum. Mutat. 29:485-490(2008). RN [65] RP VARIANT ILE-1359. 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 [66] RP VARIANTS PARK8 PRO-1628 AND ARG-2385. RX PubMed=21641266; DOI=10.1016/j.parkreldis.2010.11.008; RA Bardien S., Lesage S., Brice A., Carr J.; RT "Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated RT Parkinson's disease."; RL Parkinsonism Relat. Disord. 17:501-508(2011). RN [67] RP VARIANTS LYS-551; VAL-723; HIS-1398; GLN-1514; SER-1542; PRO-1628; RP THR-1646; THR-1647; ASP-2081 AND THR-2397. RX PubMed=22415848; DOI=10.1002/humu.22075; RA Rubio J.P., Topp S., Warren L., St Jean P.L., Wegmann D., Kessner D., RA Novembre J., Shen J., Fraser D., Aponte J., Nangle K., Cardon L.R., RA Ehm M.G., Chissoe S.L., Whittaker J.C., Nelson M.R., Mooser V.E.; RT "Deep sequencing of the LRRK2 gene in 14,002 individuals reveals evidence RT of purifying selection and independent origin of the p.Arg1628Pro mutation RT in Europe."; RL Hum. Mutat. 33:1087-1098(2012). RN [68] RP VARIANT PARK8 SER-2019. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ- RT 1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). RN [69] RP CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; CYS-1699 AND SER-2019, RP CHARACTERIZATION OF VARIANT ARG-2385, FUNCTION, SUBCELLULAR LOCATION, RP INTERACTION WITH SEC16A, AND MUTAGENESIS OF LYS-1347 AND ASP-1994. RX PubMed=25201882; DOI=10.15252/embj.201487807; RA Cho H.J., Yu J., Xie C., Rudrabhatla P., Chen X., Wu J., Parisiadou L., RA Liu G., Sun L., Ma B., Ding J., Liu Z., Cai H.; RT "Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow RT ER-Golgi export."; RL EMBO J. 33:2314-2331(2014). CC -!- FUNCTION: Serine/threonine-protein kinase which phosphorylates a broad CC range of proteins involved in multiple processes such as neuronal CC plasticity, innate immunity, autophagy, and vesicle trafficking CC (PubMed:17114044, PubMed:20949042, PubMed:21850687, PubMed:22012985, CC PubMed:23395371, PubMed:24687852, PubMed:25201882, PubMed:26014385, CC PubMed:26824392, PubMed:27830463, PubMed:28720718, PubMed:29125462, CC PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421). Is CC a key regulator of RAB GTPases by regulating the GTP/GDP exchange and CC interaction partners of RABs through phosphorylation (PubMed:26824392, CC PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, CC PubMed:30398148, PubMed:30635421). Phosphorylates RAB3A, RAB3B, RAB3C, CC RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB29, RAB35, CC and RAB43 (PubMed:23395371, PubMed:26824392, PubMed:28720718, CC PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, CC PubMed:30635421, PubMed:38127736). Regulates the RAB3IP-catalyzed CC GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on CC RAB8A (PubMed:26824392). Inhibits the interaction between RAB8A and CC GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A CC (PubMed:26824392). Regulates primary ciliogenesis through CC phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the CC brain (PubMed:29125462, PubMed:30398148). Together with RAB29, plays a CC role in the retrograde trafficking pathway for recycling proteins, such CC as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi CC apparatus in a retromer-dependent manner (PubMed:23395371). Regulates CC neuronal process morphology in the intact central nervous system (CNS) CC (PubMed:17114044). Plays a role in synaptic vesicle trafficking CC (PubMed:24687852). Plays an important role in recruiting SEC16A to CC endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi CC vesicle-mediated transport and ERES organization (PubMed:25201882). CC Positively regulates autophagy through a calcium-dependent activation CC of the CaMKK/AMPK signaling pathway (PubMed:22012985). The process CC involves activation of nicotinic acid adenine dinucleotide phosphate CC (NAADP) receptors, increase in lysosomal pH, and calcium release from CC lysosomes (PubMed:22012985). Phosphorylates PRDX3 (PubMed:21850687). By CC phosphorylating APP on 'Thr-743', which promotes the production and the CC nuclear translocation of the APP intracellular domain (AICD), regulates CC dopaminergic neuron apoptosis (PubMed:28720718). Acts as a positive CC regulator of innate immunity by mediating phosphorylation of RIPK2 CC downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation CC (PubMed:27830463). Independent of its kinase activity, inhibits the CC proteasomal degradation of MAPT, thus promoting MAPT oligomerization CC and secretion (PubMed:26014385). In addition, has GTPase activity via CC its Roc domain which regulates LRRK2 kinase activity (PubMed:18230735, CC PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29212815). CC Recruited by RAB29/RAB7L1 to overloaded lysosomes where it CC phosphorylates and stabilizes RAB8A and RAB10 which promote lysosomal CC content release and suppress lysosomal enlargement through the EHBP1 CC and EHBP1L1 effector proteins (PubMed:30209220, PubMed:38227290). CC {ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18230735, CC ECO:0000269|PubMed:20949042, ECO:0000269|PubMed:21850687, CC ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:24687852, ECO:0000269|PubMed:25201882, CC ECO:0000269|PubMed:26014385, ECO:0000269|PubMed:26824392, CC ECO:0000269|PubMed:27830463, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, CC ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220, CC ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421, CC ECO:0000269|PubMed:38127736, ECO:0000269|PubMed:38227290}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, CC ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148, CC ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:27830463, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:38127736}; CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; CC Evidence={ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, CC ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:38127736}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29125462}; CC -!- ACTIVITY REGULATION: Kinase activity is regulated by the GTPase CC activity of the ROC domain (PubMed:18230735, PubMed:29212815). GTP- CC bound LRRK2 kinase activity is stimulated by RAB29 (PubMed:29212815, CC PubMed:38127736). Phosphorylation of RAB10 'Thr-73' is stimulated by CC RAB29 and RAB32 (PubMed:38127736). Inhibited by small molecule CC inhibitor MLi-2 (PubMed:26824392, PubMed:29127255). CC {ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:38127736}. CC -!- SUBUNIT: Homodimer (PubMed:18230735, PubMed:22952686, PubMed:30635421, CC PubMed:38127736). Homotetramer; when activated by GTP-bound RAB29 CC (PubMed:38127736). Interacts with PRKN, PRDX3, and TPCN2 CC (PubMed:16352719, PubMed:21850687, PubMed:22012985). Interacts with CC VPS35 (PubMed:23395371). Interacts (via N-terminus) with RAB29; this CC interaction is direct and stimulates kinase activity (PubMed:23395371, CC PubMed:38127736). Interacts (via ROC domain) with SEC16A CC (PubMed:25201882). Interacts with APP; interaction promotes CC phosphorylation of 'Thr-743' of APP (PubMed:28720718). Interacts with CC MAPT (PubMed:26014385). Interacts with RAB8A, RAB10, and RAB12 CC (PubMed:26824392). Interacts (via N-terminus) with RAB32 CC (PubMed:38127736). Interacts with YWHAG; this interaction is dependent CC on phosphorylation of Ser-910 and either Ser-935 or Ser-1444 CC (PubMed:28202711). Interacts with SFN; this interaction is dependent on CC phosphorylation of Ser-910 and/or Ser-935 (PubMed:28202711). CC {ECO:0000269|PubMed:16352719, ECO:0000269|PubMed:18230735, CC ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22012985, CC ECO:0000269|PubMed:22952686, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:26014385, CC ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28202711, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:30635421, CC ECO:0000269|PubMed:38127736}. CC -!- INTERACTION: CC Q5S007; Q9UKV8: AGO2; NbExp=3; IntAct=EBI-5323863, EBI-528269; CC Q5S007; O43865: AHCYL1; NbExp=3; IntAct=EBI-5323863, EBI-2371423; CC Q5S007; P31749: AKT1; NbExp=6; IntAct=EBI-5323863, EBI-296087; CC Q5S007; Q8N8V4: ANKS4B; NbExp=2; IntAct=EBI-5323863, EBI-9658517; CC Q5S007; O00203: AP3B1; NbExp=2; IntAct=EBI-5323863, EBI-1044383; CC Q5S007; Q8N6T3-2: ARFGAP1; NbExp=6; IntAct=EBI-5323863, EBI-6288865; CC Q5S007; Q14155: ARHGEF7; NbExp=7; IntAct=EBI-5323863, EBI-717515; CC Q5S007; O95816: BAG2; NbExp=3; IntAct=EBI-5323863, EBI-355275; CC Q5S007; O95817: BAG3; NbExp=2; IntAct=EBI-5323863, EBI-747185; CC Q5S007; Q9UL15: BAG5; NbExp=12; IntAct=EBI-5323863, EBI-356517; CC Q5S007; P10415-1: BCL2; NbExp=2; IntAct=EBI-5323863, EBI-4370304; CC Q5S007; Q13191: CBLB; NbExp=4; IntAct=EBI-5323863, EBI-744027; CC Q5S007; Q16543: CDC37; NbExp=10; IntAct=EBI-5323863, EBI-295634; CC Q5S007; P60953: CDC42; NbExp=3; IntAct=EBI-5323863, EBI-81752; CC Q5S007; Q9UKI2: CDC42EP3; NbExp=2; IntAct=EBI-5323863, EBI-723480; CC Q5S007; Q9Y6A4: CFAP20; NbExp=3; IntAct=EBI-5323863, EBI-1046872; CC Q5S007; P05060: CHGB; NbExp=3; IntAct=EBI-5323863, EBI-712619; CC Q5S007; Q9ULV4: CORO1C; NbExp=3; IntAct=EBI-5323863, EBI-351384; CC Q5S007; P48729-1: CSNK1A1; NbExp=2; IntAct=EBI-5323863, EBI-10106282; CC Q5S007; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-5323863, EBI-9087876; CC Q5S007; Q9NWM3: CUEDC1; NbExp=2; IntAct=EBI-5323863, EBI-5838167; CC Q5S007; P53355: DAPK1; NbExp=2; IntAct=EBI-5323863, EBI-358616; CC Q5S007; Q05193: DNM1; NbExp=4; IntAct=EBI-5323863, EBI-713135; CC Q5S007; O00429: DNM1L; NbExp=16; IntAct=EBI-5323863, EBI-724571; CC Q5S007; O00429-3: DNM1L; NbExp=2; IntAct=EBI-5323863, EBI-6896746; CC Q5S007; O14640-2: DVL1; NbExp=7; IntAct=EBI-5323863, EBI-6504027; CC Q5S007; O14641: DVL2; NbExp=5; IntAct=EBI-5323863, EBI-740850; CC Q5S007; Q92997: DVL3; NbExp=4; IntAct=EBI-5323863, EBI-739789; CC Q5S007; P30084: ECHS1; NbExp=4; IntAct=EBI-5323863, EBI-719602; CC Q5S007; Q05639: EEF1A2; NbExp=3; IntAct=EBI-5323863, EBI-354943; CC Q5S007; Q13158: FADD; NbExp=4; IntAct=EBI-5323863, EBI-494804; CC Q5S007; O14976: GAK; NbExp=11; IntAct=EBI-5323863, EBI-714707; CC Q5S007; P49841: GSK3B; NbExp=7; IntAct=EBI-5323863, EBI-373586; CC Q5S007; P11142: HSPA8; NbExp=6; IntAct=EBI-5323863, EBI-351896; CC Q5S007; Q71RC2: LARP4; NbExp=3; IntAct=EBI-5323863, EBI-2878091; CC Q5S007; Q4G0J3: LARP7; NbExp=3; IntAct=EBI-5323863, EBI-2371923; CC Q5S007; P07195: LDHB; NbExp=2; IntAct=EBI-5323863, EBI-358748; CC Q5S007; O75581: LRP6; NbExp=4; IntAct=EBI-5323863, EBI-910915; CC Q5S007; Q38SD2: LRRK1; NbExp=5; IntAct=EBI-5323863, EBI-1050422; CC Q5S007; Q5S007: LRRK2; NbExp=68; IntAct=EBI-5323863, EBI-5323863; CC Q5S007; PRO_0000018605 [P46821]: MAP1B; NbExp=5; IntAct=EBI-5323863, EBI-9517186; CC Q5S007; P46734: MAP2K3; NbExp=5; IntAct=EBI-5323863, EBI-602462; CC Q5S007; P52564: MAP2K6; NbExp=4; IntAct=EBI-5323863, EBI-448135; CC Q5S007; O14733: MAP2K7; NbExp=3; IntAct=EBI-5323863, EBI-492605; CC Q5S007; P10636-2: MAPT; NbExp=3; IntAct=EBI-5323863, EBI-7796412; CC Q5S007; P10636-8: MAPT; NbExp=9; IntAct=EBI-5323863, EBI-366233; CC Q5S007; P42679: MATK; NbExp=2; IntAct=EBI-5323863, EBI-751664; CC Q5S007; O95140: MFN2; NbExp=3; IntAct=EBI-5323863, EBI-3324756; CC Q5S007; P49406: MRPL19; NbExp=3; IntAct=EBI-5323863, EBI-1188518; CC Q5S007; P26038: MSN; NbExp=19; IntAct=EBI-5323863, EBI-528768; CC Q5S007; Q7L592: NDUFAF7; NbExp=2; IntAct=EBI-5323863, EBI-2555519; CC Q5S007; Q96PY6: NEK1; NbExp=2; IntAct=EBI-5323863, EBI-373615; CC Q5S007; Q13469: NFATC2; NbExp=3; IntAct=EBI-5323863, EBI-716258; CC Q5S007; Q8WUM0: NUP133; NbExp=4; IntAct=EBI-5323863, EBI-295695; CC Q5S007; O60313: OPA1; NbExp=5; IntAct=EBI-5323863, EBI-1054131; CC Q5S007; Q9NQU5: PAK6; NbExp=2; IntAct=EBI-5323863, EBI-1053685; CC Q5S007; P62136: PPP1CA; NbExp=6; IntAct=EBI-5323863, EBI-357253; CC Q5S007; Q12972: PPP1R8; NbExp=3; IntAct=EBI-5323863, EBI-716633; CC Q5S007; P63151: PPP2R2A; NbExp=4; IntAct=EBI-5323863, EBI-1048931; CC Q5S007; P30048: PRDX3; NbExp=14; IntAct=EBI-5323863, EBI-748336; CC Q5S007; P17612: PRKACA; NbExp=6; IntAct=EBI-5323863, EBI-476586; CC Q5S007; O60260: PRKN; NbExp=3; IntAct=EBI-5323863, EBI-716346; CC Q5S007; P61026: RAB10; NbExp=7; IntAct=EBI-5323863, EBI-726075; CC Q5S007; Q6IQ22: RAB12; NbExp=2; IntAct=EBI-5323863, EBI-4289591; CC Q5S007; Q9H0U4: RAB1B; NbExp=5; IntAct=EBI-5323863, EBI-1045214; CC Q5S007; O14966: RAB29; NbExp=15; IntAct=EBI-5323863, EBI-372165; CC Q5S007; Q13637: RAB32; NbExp=12; IntAct=EBI-5323863, EBI-9837586; CC Q5S007; P57729: RAB38; NbExp=4; IntAct=EBI-5323863, EBI-6552718; CC Q5S007; P61020: RAB5B; NbExp=9; IntAct=EBI-5323863, EBI-399401; CC Q5S007; P61006: RAB8A; NbExp=9; IntAct=EBI-5323863, EBI-722293; CC Q5S007; P63000: RAC1; NbExp=5; IntAct=EBI-5323863, EBI-413628; CC Q5S007; P41220: RGS2; NbExp=6; IntAct=EBI-5323863, EBI-712388; CC Q5S007; P62906: RPL10A; NbExp=4; IntAct=EBI-5323863, EBI-356860; CC Q5S007; P26373: RPL13; NbExp=4; IntAct=EBI-5323863, EBI-356849; CC Q5S007; P50914: RPL14; NbExp=2; IntAct=EBI-5323863, EBI-356746; CC Q5S007; P62750: RPL23A; NbExp=2; IntAct=EBI-5323863, EBI-353254; CC Q5S007; P62888: RPL30; NbExp=3; IntAct=EBI-5323863, EBI-353116; CC Q5S007; P49207: RPL34; NbExp=3; IntAct=EBI-5323863, EBI-1051893; CC Q5S007; Q9BUL9: RPP25; NbExp=3; IntAct=EBI-5323863, EBI-366570; CC Q5S007; P62280: RPS11; NbExp=5; IntAct=EBI-5323863, EBI-1047710; CC Q5S007; P62277: RPS13; NbExp=3; IntAct=EBI-5323863, EBI-351850; CC Q5S007; P62841: RPS15; NbExp=9; IntAct=EBI-5323863, EBI-372635; CC Q5S007; P62249: RPS16; NbExp=4; IntAct=EBI-5323863, EBI-352480; CC Q5S007; P62269: RPS18; NbExp=3; IntAct=EBI-5323863, EBI-352451; CC Q5S007; P15880: RPS2; NbExp=4; IntAct=EBI-5323863, EBI-443446; CC Q5S007; P60866: RPS20; NbExp=4; IntAct=EBI-5323863, EBI-353105; CC Q5S007; P62266: RPS23; NbExp=2; IntAct=EBI-5323863, EBI-353072; CC Q5S007; P42677: RPS27; NbExp=4; IntAct=EBI-5323863, EBI-356336; CC Q5S007; P23396: RPS3; NbExp=4; IntAct=EBI-5323863, EBI-351193; CC Q5S007; O15027: SEC16A; NbExp=8; IntAct=EBI-5323863, EBI-357515; CC Q5S007; P60896: SEM1; NbExp=3; IntAct=EBI-5323863, EBI-79819; CC Q5S007; P31947: SFN; NbExp=5; IntAct=EBI-5323863, EBI-476295; CC Q5S007; Q99961: SH3GL1; NbExp=3; IntAct=EBI-5323863, EBI-697911; CC Q5S007; Q99962: SH3GL2; NbExp=4; IntAct=EBI-5323863, EBI-77938; CC Q5S007; P12235: SLC25A4; NbExp=2; IntAct=EBI-5323863, EBI-359074; CC Q5S007; P05141: SLC25A5; NbExp=2; IntAct=EBI-5323863, EBI-355133; CC Q5S007; P12236: SLC25A6; NbExp=2; IntAct=EBI-5323863, EBI-356254; CC Q5S007; O95295: SNAPIN; NbExp=5; IntAct=EBI-5323863, EBI-296723; CC Q5S007; P37840: SNCA; NbExp=6; IntAct=EBI-5323863, EBI-985879; CC Q5S007; Q8NHS9: SPATA22; NbExp=3; IntAct=EBI-5323863, EBI-7067260; CC Q5S007; Q13501: SQSTM1; NbExp=18; IntAct=EBI-5323863, EBI-307104; CC Q5S007; Q9UNE7: STUB1; NbExp=4; IntAct=EBI-5323863, EBI-357085; CC Q5S007; Q9UNE7-1: STUB1; NbExp=2; IntAct=EBI-5323863, EBI-15687717; CC Q5S007; Q9BQ70: TCF25; NbExp=3; IntAct=EBI-5323863, EBI-745182; CC Q5S007; Q6P3X3: TTC27; NbExp=3; IntAct=EBI-5323863, EBI-1057046; CC Q5S007; P07437: TUBB; NbExp=6; IntAct=EBI-5323863, EBI-350864; CC Q5S007; Q13885: TUBB2A; NbExp=3; IntAct=EBI-5323863, EBI-711595; CC Q5S007; P04350: TUBB4A; NbExp=6; IntAct=EBI-5323863, EBI-355007; CC Q5S007; P68371: TUBB4B; NbExp=3; IntAct=EBI-5323863, EBI-351356; CC Q5S007; Q9BUF5: TUBB6; NbExp=3; IntAct=EBI-5323863, EBI-356735; CC Q5S007; Q53GS9: USP39; NbExp=3; IntAct=EBI-5323863, EBI-1044822; CC Q5S007; P21796: VDAC1; NbExp=3; IntAct=EBI-5323863, EBI-354158; CC Q5S007; Q9Y6I7: WSB1; NbExp=5; IntAct=EBI-5323863, EBI-1171494; CC Q5S007; P31946: YWHAB; NbExp=5; IntAct=EBI-5323863, EBI-359815; CC Q5S007; P62258: YWHAE; NbExp=8; IntAct=EBI-5323863, EBI-356498; CC Q5S007; P61981: YWHAG; NbExp=26; IntAct=EBI-5323863, EBI-359832; CC Q5S007; Q04917: YWHAH; NbExp=6; IntAct=EBI-5323863, EBI-306940; CC Q5S007; P27348: YWHAQ; NbExp=10; IntAct=EBI-5323863, EBI-359854; CC Q5S007; P63104: YWHAZ; NbExp=11; IntAct=EBI-5323863, EBI-347088; CC Q5S007; O95218: ZRANB2; NbExp=2; IntAct=EBI-5323863, EBI-1051583; CC Q5S007; Q62848: Arfgap1; Xeno; NbExp=7; IntAct=EBI-5323863, EBI-4398879; CC Q5S007; O55143: Atp2a2; Xeno; NbExp=13; IntAct=EBI-5323863, EBI-770763; CC Q5S007; P30275: Ckmt1; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-773103; CC Q5S007; P39053: Dnm1; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-397785; CC Q5S007; P02687: MBP; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-908215; CC Q5S007; Q811U4: Mfn1; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-9029118; CC Q5S007; P00634: phoA; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-552958; CC Q5S007; P12369: Prkar2b; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-6096160; CC Q5S007; Q63481: Rab29; Xeno; NbExp=3; IntAct=EBI-5323863, EBI-6513837; CC Q5S007; P61021: Rab5b; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-8320093; CC Q5S007; Q58A65: Spag9; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-6530207; CC Q5S007; Q9WUD1: Stub1; Xeno; NbExp=2; IntAct=EBI-5323863, EBI-773027; CC Q5S007; P61983: Ywhag; Xeno; NbExp=6; IntAct=EBI-5323863, EBI-359821; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle {ECO:0000269|PubMed:16321986, CC ECO:0000269|PubMed:16352719, ECO:0000269|PubMed:26014385}. Perikaryon CC {ECO:0000269|PubMed:17120249}. Golgi apparatus membrane CC {ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:38127736}; Peripheral membrane protein CC {ECO:0000269|PubMed:16321986}. Cell projection, axon CC {ECO:0000269|PubMed:17120249}. Cell projection, dendrite CC {ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:21850687}. Endoplasmic CC reticulum membrane {ECO:0000269|PubMed:16321986, CC ECO:0000269|PubMed:25201882}; Peripheral membrane protein CC {ECO:0000269|PubMed:16321986}. Cytoplasmic vesicle, secretory vesicle, CC synaptic vesicle membrane {ECO:0000269|PubMed:24687852}. Endosome CC {ECO:0000250|UniProtKB:Q5S006}. Lysosome {ECO:0000269|PubMed:17120249, CC ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:38227290}. CC Mitochondrion outer membrane {ECO:0000269|PubMed:16269541, CC ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:17120249, CC ECO:0000269|PubMed:29212815}; Peripheral membrane protein CC {ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16321986, CC ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29212815}. Cytoplasm, CC cytoskeleton {ECO:0000269|PubMed:35266954}. Cytoplasmic vesicle, CC phagosome {ECO:0000250|UniProtKB:Q5S006}. Note=Colocalized with RAB29 CC along tubular structures emerging from Golgi apparatus CC (PubMed:23395371, PubMed:38127736). Localizes to endoplasmic reticulum CC exit sites (ERES), also known as transitional endoplasmic reticulum CC (tER) (PubMed:25201882). Detected on phagosomes and stressed lysosomes CC but not detected on autophagosomes induced by starvation (By CC similarity). Recruitment to stressed lysosomes is dependent on the ATG8 CC conjugation system composed of ATG5, ATG12 and ATG16L1 and leads to CC lysosomal stress-induced activation of LRRK2 (By similarity). CC {ECO:0000250|UniProtKB:Q5S006, ECO:0000269|PubMed:23395371, CC ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:38127736}. CC -!- TISSUE SPECIFICITY: Expressed in pyramidal neurons in all cortical CC laminae of the visual cortex, in neurons of the substantia nigra pars CC compacta and caudate putamen (at protein level). Expressed in CC neutrophils (at protein level) (PubMed:29127255). Expressed in the CC brain. Expressed throughout the adult brain, but at a lower level than CC in heart and liver. Also expressed in placenta, lung, skeletal muscle, CC kidney and pancreas. In the brain, expressed in the cerebellum, CC cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, CC temporal lobe and putamen. Expression is particularly high in brain CC dopaminoceptive areas. {ECO:0000269|PubMed:15541308, CC ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:16532471, CC ECO:0000269|PubMed:17120249, ECO:0000269|PubMed:29127255}. CC -!- DOMAIN: The seven-bladed WD repeat region is critical for synaptic CC vesicle trafficking and mediates interaction with multiple vesicle- CC associated presynaptic proteins (PubMed:24687852). It also mediates CC homodimerization and regulates kinase activity (PubMed:30635421). CC {ECO:0000269|PubMed:24687852, ECO:0000269|PubMed:30635421}. CC -!- DOMAIN: The COR domain mediates homodimerization; it also mediates CC homotetramerization via interaction with the protein kinase domain. CC {ECO:0000269|PubMed:38127736}. CC -!- DOMAIN: The Roc domain mediates homodimerization and regulates kinase CC activity. {ECO:0000269|PubMed:18230735}. CC -!- PTM: Autophosphorylated at Ser-1292; autophosphorylation is stimulated CC by RAB29 (PubMed:28202711, PubMed:28720718, PubMed:29127255, CC PubMed:29212815, PubMed:30635421, PubMed:38127736). Phosphorylation of CC Ser-910 and either Ser-935 or Ser-1444 facilitates interaction with CC YWHAG (PubMed:28202711). Phosphorylation of Ser-910 and/or Ser-935 CC facilitates interaction with SFN (PubMed:28202711). CC {ECO:0000269|PubMed:28202711, ECO:0000269|PubMed:28720718, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736}. CC -!- PTM: Ubiquitinated by TRIM1; undergoes 'Lys-48'-linked CC polyubiquitination leading to proteasomal degradation. CC {ECO:0000269|PubMed:35266954}. CC -!- DISEASE: Parkinson disease 8 (PARK8) [MIM:607060]: A slowly progressive CC neurodegenerative disorder characterized by bradykinesia, rigidity, CC resting tremor, postural instability, neuronal loss in the substantia CC nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy CC bodies in some patients. {ECO:0000269|PubMed:15541308, CC ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:15680455, CC ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, CC ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, CC ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, CC ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:15925109, CC ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16102999, CC ECO:0000269|PubMed:16157901, ECO:0000269|PubMed:16157908, CC ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, CC ECO:0000269|PubMed:16240353, ECO:0000269|PubMed:16247070, CC ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, CC ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16272164, CC ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, CC ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:16333314, CC ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:17114044, CC ECO:0000269|PubMed:18213618, ECO:0000269|PubMed:21641266, CC ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22956510, CC ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:25201882, CC ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28202711, CC ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, CC ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, CC ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:30398148, CC ECO:0000269|PubMed:30635421}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase 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; AY792511; AAV63975.1; -; mRNA. DR EMBL; AC079630; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC084290; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC107023; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL834529; CAD39185.1; -; mRNA. DR CCDS; CCDS31774.1; -. DR PDB; 2ZEJ; X-ray; 2.00 A; A/B=1333-1516. DR PDB; 3D6T; X-ray; 2.43 A; B=1335-1505. DR PDB; 5MY9; X-ray; 1.33 A; P=929-941. DR PDB; 5MYC; X-ray; 1.46 A; P=904-941. DR PDB; 6DLO; X-ray; 2.70 A; A/B=2142-2527. DR PDB; 6DLP; X-ray; 4.00 A; A/B=2142-2527. DR PDB; 6OJE; X-ray; 1.95 A; A/B=1329-1520. DR PDB; 6OJF; X-ray; 1.60 A; A/B=1329-1520. DR PDB; 6VNO; EM; 3.50 A; A=1327-2527. DR PDB; 6VP6; EM; 3.47 A; A/B/C=1327-2527. DR PDB; 6VP7; EM; 3.50 A; A=1327-2527. DR PDB; 6VP8; EM; 3.50 A; A=1330-2527, B=1670-1950, C=2140-2498. DR PDB; 6XAF; X-ray; 1.97 A; A/B=1329-1520. DR PDB; 6XR4; EM; 14.00 A; A/B=1-2527. DR PDB; 7LHT; EM; 3.50 A; A/B=1-2527. DR PDB; 7LHW; EM; 3.70 A; A=1-2527. DR PDB; 7LI3; EM; 3.80 A; A=1-2527. DR PDB; 7LI4; EM; 3.10 A; A=1-2527. DR PDB; 7THY; EM; 5.20 A; A=1332-1525. DR PDB; 7THZ; EM; 5.00 A; A=1332-1525. DR PDB; 8FO2; EM; 4.13 A; E=1-2527. DR PDB; 8FO7; EM; 3.52 A; C=1327-2527. DR PDB; 8FO8; EM; 3.88 A; C/E=1-2527. DR PDB; 8FO9; EM; 3.48 A; A/C/E/F=1-2527. DR PDB; 8SMC; EM; 4.02 A; C=1327-2527. DR PDB; 8TXZ; EM; 3.05 A; A=1334-2527. DR PDB; 8TYQ; EM; 2.99 A; A=1-2527. DR PDB; 8TZB; EM; 3.10 A; A=1-2527. DR PDB; 8TZC; EM; 2.70 A; A=1333-2527. DR PDB; 8TZE; EM; 2.90 A; A=1-2527. DR PDB; 8TZF; EM; 3.40 A; A=1-2527. DR PDB; 8TZG; EM; 2.70 A; A=1333-2522. DR PDB; 8TZH; EM; 3.90 A; A=1-2527. DR PDB; 8U1B; EM; 3.70 A; A=1334-2527. DR PDB; 8U7H; EM; 3.80 A; C=1327-2527. DR PDB; 8U7L; EM; 3.60 A; A/B=1-2527. DR PDB; 8U8A; EM; 3.40 A; B/C=1-2527. DR PDB; 8U8B; EM; 3.70 A; A/B=1-2527. DR PDB; 8VH4; EM; 4.10 A; A=1-2527. DR PDB; 8VH5; EM; 4.00 A; A/C=1-2527. DR PDB; 9C76; X-ray; 2.30 A; A/B=1329-1516. DR PDB; 9CHO; EM; 7.80 A; A=543-2527. DR PDB; 9CI3; EM; 3.96 A; A=1-2527. DR PDB; 9DMI; EM; 3.35 A; A=1333-2527. DR PDBsum; 2ZEJ; -. DR PDBsum; 3D6T; -. DR PDBsum; 5MY9; -. DR PDBsum; 5MYC; -. DR PDBsum; 6DLO; -. DR PDBsum; 6DLP; -. DR PDBsum; 6OJE; -. DR PDBsum; 6OJF; -. DR PDBsum; 6VNO; -. DR PDBsum; 6VP6; -. DR PDBsum; 6VP7; -. DR PDBsum; 6VP8; -. DR PDBsum; 6XAF; -. DR PDBsum; 6XR4; -. DR PDBsum; 7LHT; -. DR PDBsum; 7LHW; -. DR PDBsum; 7LI3; -. DR PDBsum; 7LI4; -. DR PDBsum; 7THY; -. DR PDBsum; 7THZ; -. DR PDBsum; 8FO2; -. DR PDBsum; 8FO7; -. DR PDBsum; 8FO8; -. DR PDBsum; 8FO9; -. DR PDBsum; 8SMC; -. DR PDBsum; 8TXZ; -. DR PDBsum; 8TYQ; -. DR PDBsum; 8TZB; -. DR PDBsum; 8TZC; -. DR PDBsum; 8TZE; -. DR PDBsum; 8TZF; -. DR PDBsum; 8TZG; -. DR PDBsum; 8TZH; -. DR PDBsum; 8U1B; -. DR PDBsum; 8U7H; -. DR PDBsum; 8U7L; -. DR PDBsum; 8U8A; -. DR PDBsum; 8U8B; -. DR PDBsum; 8VH4; -. DR PDBsum; 8VH5; -. DR PDBsum; 9C76; -. DR PDBsum; 9CHO; -. DR PDBsum; 9CI3; -. DR PDBsum; 9DMI; -. DR AlphaFoldDB; Q5S007; -. DR EMDB; EMD-20825; -. DR EMDB; EMD-20826; -. DR EMDB; EMD-21250; -. DR EMDB; EMD-21306; -. DR EMDB; EMD-21309; -. DR EMDB; EMD-21310; -. DR EMDB; EMD-21311; -. DR EMDB; EMD-21312; -. DR EMDB; EMD-23350; -. DR EMDB; EMD-23352; -. DR EMDB; EMD-23359; -. DR EMDB; EMD-23360; -. DR EMDB; EMD-25649; -. DR EMDB; EMD-25658; -. DR EMDB; EMD-25664; -. DR EMDB; EMD-25674; -. DR EMDB; EMD-25897; -. DR EMDB; EMD-25906; -. DR EMDB; EMD-25907; -. DR EMDB; EMD-29339; -. DR EMDB; EMD-29340; -. DR EMDB; EMD-29341; -. DR EMDB; EMD-29342; -. DR EMDB; EMD-41709; -. DR EMDB; EMD-41728; -. DR EMDB; EMD-41753; -. DR EMDB; EMD-41754; -. DR EMDB; EMD-41756; -. DR EMDB; EMD-41757; -. DR EMDB; EMD-41758; -. DR EMDB; EMD-41759; -. DR EMDB; EMD-41794; -. DR EMDB; EMD-41795; -. DR EMDB; EMD-41798; -. DR EMDB; EMD-41799; -. DR EMDB; EMD-41806; -. DR EMDB; EMD-41985; -. DR EMDB; EMD-42019; -. DR EMDB; EMD-42020; -. DR EMDB; EMD-43234; -. DR EMDB; EMD-43235; -. DR EMDB; EMD-45591; -. DR EMDB; EMD-45593; -. DR EMDB; EMD-45594; -. DR EMDB; EMD-45595; -. DR EMDB; EMD-45596; -. DR EMDB; EMD-45609; -. DR EMDB; EMD-47004; -. DR EMDB; EMD-47006; -. DR EMDB; EMD-47025; -. DR SMR; Q5S007; -. DR BioGRID; 125700; 512. DR CORUM; Q5S007; -. DR DIP; DIP-29684N; -. DR FunCoup; Q5S007; 660. DR IntAct; Q5S007; 2316. DR MINT; Q5S007; -. DR STRING; 9606.ENSP00000298910; -. DR BindingDB; Q5S007; -. DR ChEMBL; CHEMBL1075104; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; Q5S007; -. DR GuidetoPHARMACOLOGY; 2059; -. DR TCDB; 8.A.23.1.54; the basigin (basigin) family. DR GlyGen; Q5S007; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q5S007; -. DR PhosphoSitePlus; Q5S007; -. DR BioMuta; LRRK2; -. DR DMDM; 294862450; -. DR jPOST; Q5S007; -. DR MassIVE; Q5S007; -. DR PaxDb; 9606-ENSP00000298910; -. DR PeptideAtlas; Q5S007; -. DR ProteomicsDB; 63755; -. DR ABCD; Q5S007; 2 sequenced antibodies. DR Antibodypedia; 2109; 881 antibodies from 47 providers. DR DNASU; 120892; -. DR Ensembl; ENST00000298910.12; ENSP00000298910.7; ENSG00000188906.18. DR GeneID; 120892; -. DR KEGG; hsa:120892; -. DR MANE-Select; ENST00000298910.12; ENSP00000298910.7; NM_198578.4; NP_940980.4. DR UCSC; uc001rmg.5; human. DR AGR; HGNC:18618; -. DR ClinPGx; PA134968052; -. DR CTD; 120892; -. DR DisGeNET; 120892; -. DR GeneCards; LRRK2; -. DR GeneReviews; LRRK2; -. DR HGNC; HGNC:18618; LRRK2. DR HPA; ENSG00000188906; Tissue enriched (lung). DR MalaCards; LRRK2; -. DR MIM; 168600; phenotype. DR MIM; 607060; phenotype. DR MIM; 609007; gene. DR OpenTargets; ENSG00000188906; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000188906; -. DR eggNOG; KOG0192; Eukaryota. DR eggNOG; KOG0618; Eukaryota. DR eggNOG; KOG0619; Eukaryota. DR GeneTree; ENSGT00940000158267; -. DR HOGENOM; CLU_000815_0_0_1; -. DR InParanoid; Q5S007; -. DR OMA; FIVECMV; -. DR OrthoDB; 8940716at2759; -. DR PAN-GO; Q5S007; 31 GO annotations based on evolutionary models. DR PhylomeDB; Q5S007; -. DR PathwayCommons; Q5S007; -. DR Reactome; R-HSA-8857538; PTK6 promotes HIF1A stabilization. DR SignaLink; Q5S007; -. DR SIGNOR; Q5S007; -. DR Agora; ENSG00000188906; -. DR BioGRID-ORCS; 120892; 21 hits in 1183 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR ChiTaRS; LRRK2; human. DR EvolutionaryTrace; Q5S007; -. DR GeneWiki; LRRK2; -. DR GenomeRNAi; 120892; -. DR Pharos; Q5S007; Tchem. DR PRO; PR:Q5S007; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q5S007; protein. DR Bgee; ENSG00000188906; Expressed in buccal mucosa cell and 154 other cell types or tissues. DR ExpressionAtlas; Q5S007; baseline and differential. DR GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL. DR GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0099400; C:caveola neck; IDA:ParkinsonsUK-UCL. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0032473; C:cytoplasmic side of mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0032839; C:dendrite cytoplasm; IDA:BHF-UCL. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0070971; C:endoplasmic reticulum exit site; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005768; C:endosome; ISS:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:ParkinsonsUK-UCL. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005798; C:Golgi-associated vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0030426; C:growth cone; IDA:ParkinsonsUK-UCL. DR GO; GO:0097413; C:Lewy body; IDA:MGI. DR GO; GO:0005764; C:lysosome; ISS:UniProtKB. DR GO; GO:0005902; C:microvillus; IDA:ParkinsonsUK-UCL. DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0097487; C:multivesicular body, internal vesicle; IDA:ParkinsonsUK-UCL. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:BHF-UCL. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0043204; C:perikaryon; IDA:UniProtKB. DR GO; GO:0045335; C:phagocytic vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0099523; C:presynaptic cytosol; IEA:Ensembl. DR GO; GO:1990904; C:ribonucleoprotein complex; IEA:Ensembl. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043195; C:terminal bouton; TAS:ParkinsonsUK-UCL. DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl. DR GO; GO:1990909; C:Wnt signalosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:1904713; F:beta-catenin destruction complex binding; NAS:ParkinsonsUK-UCL. DR GO; GO:0030276; F:clathrin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0039706; F:co-receptor binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB. DR GO; GO:0034211; F:GTP-dependent protein kinase activity; IDA:BHF-UCL. DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB. DR GO; GO:0003924; F:GTPase activity; IDA:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IDA:BHF-UCL. DR GO; GO:0016301; F:kinase activity; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IMP:UniProtKB. DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IDA:BHF-UCL. DR GO; GO:0008017; F:microtubule binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0036479; F:peroxidase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0051018; F:protein kinase A binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0030159; F:signaling receptor complex adaptor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0031267; F:small GTPase binding; IPI:BHF-UCL. DR GO; GO:0000149; F:SNARE binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0017075; F:syntaxin-1 binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0044325; F:transmembrane transporter binding; IPI:UniProtKB. DR GO; GO:0015631; F:tubulin binding; IDA:BHF-UCL. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0019722; P:calcium-mediated signaling; IMP:ParkinsonsUK-UCL. DR GO; GO:0060070; P:canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:1904644; P:cellular response to curcumin; IEA:Ensembl. DR GO; GO:1903351; P:cellular response to dopamine; IMP:ParkinsonsUK-UCL. DR GO; GO:0071287; P:cellular response to manganese ion; IMP:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0034614; P:cellular response to reactive oxygen species; IMP:ParkinsonsUK-UCL. DR GO; GO:0009267; P:cellular response to starvation; IMP:ParkinsonsUK-UCL. DR GO; GO:0008340; P:determination of adult lifespan; IMP:BHF-UCL. DR GO; GO:0006897; P:endocytosis; IMP:ParkinsonsUK-UCL. DR GO; GO:0007029; P:endoplasmic reticulum organization; IMP:UniProtKB. DR GO; GO:0060079; P:excitatory postsynaptic potential; ISS:ParkinsonsUK-UCL. DR GO; GO:0035640; P:exploration behavior; IMP:BHF-UCL. DR GO; GO:0007030; P:Golgi organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0046039; P:GTP metabolic process; IDA:BHF-UCL. DR GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:BHF-UCL. DR GO; GO:0008104; P:intracellular protein localization; ISS:ParkinsonsUK-UCL. DR GO; GO:0035556; P:intracellular signal transduction; ISS:ParkinsonsUK-UCL. DR GO; GO:0007254; P:JNK cascade; IDA:BHF-UCL. DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl. DR GO; GO:0007040; P:lysosome organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB. DR GO; GO:0051646; P:mitochondrion localization; IMP:ParkinsonsUK-UCL. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:1902902; P:negative regulation of autophagosome assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IMP:ParkinsonsUK-UCL. DR GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; ISS:ParkinsonsUK-UCL. DR GO; GO:0034260; P:negative regulation of GTPase activity; IDA:MGI. DR GO; GO:1902823; P:negative regulation of late endosome to lysosome transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0016242; P:negative regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:1905504; P:negative regulation of motile cilium assembly; TAS:UniProt. DR GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl. DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IEA:Ensembl. DR GO; GO:0010955; P:negative regulation of protein processing; IDA:ParkinsonsUK-UCL. DR GO; GO:1903217; P:negative regulation of protein processing involved in protein targeting to mitochondrion; IC:ParkinsonsUK-UCL. DR GO; GO:1903215; P:negative regulation of protein targeting to mitochondrion; IDA:ParkinsonsUK-UCL. DR GO; GO:0007528; P:neuromuscular junction development; IMP:BHF-UCL. DR GO; GO:0140058; P:neuron projection arborization; IEA:Ensembl. DR GO; GO:0048812; P:neuron projection morphogenesis; IMP:UniProtKB. DR GO; GO:0021772; P:olfactory bulb development; IMP:ParkinsonsUK-UCL. DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IGI:ParkinsonsUK-UCL. DR GO; GO:0060161; P:positive regulation of dopamine receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:ParkinsonsUK-UCL. DR GO; GO:1903980; P:positive regulation of microglial cell activation; IEA:Ensembl. DR GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:BHF-UCL. DR GO; GO:1902499; P:positive regulation of protein autoubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:1900244; P:positive regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:0070973; P:protein localization to endoplasmic reticulum exit site; IMP:UniProtKB. DR GO; GO:0070585; P:protein localization to mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0006468; P:protein phosphorylation; IMP:UniProtKB. DR GO; GO:0010506; P:regulation of autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:2000172; P:regulation of branching morphogenesis of a nerve; IMP:ParkinsonsUK-UCL. DR GO; GO:1905289; P:regulation of CAMKK-AMPK signaling cascade; IMP:ParkinsonsUK-UCL. DR GO; GO:0141161; P:regulation of cAMP/PKA signal transduction; ISS:ParkinsonsUK-UCL. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; IBA:GO_Central. DR GO; GO:0031344; P:regulation of cell projection organization; IBA:GO_Central. DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; IMP:ParkinsonsUK-UCL. DR GO; GO:0060159; P:regulation of dopamine receptor signaling pathway; ISS:ParkinsonsUK-UCL. DR GO; GO:0060628; P:regulation of ER to Golgi vesicle-mediated transport; ISS:UniProtKB. DR GO; GO:0035564; P:regulation of kidney size; ISS:BHF-UCL. DR GO; GO:0040012; P:regulation of locomotion; IMP:BHF-UCL. DR GO; GO:0035751; P:regulation of lysosomal lumen pH; IMP:ParkinsonsUK-UCL. DR GO; GO:0042391; P:regulation of membrane potential; IMP:BHF-UCL. DR GO; GO:0051900; P:regulation of mitochondrial depolarization; IMP:ParkinsonsUK-UCL. DR GO; GO:0090140; P:regulation of mitochondrial fission; TAS:ParkinsonsUK-UCL. DR GO; GO:1902692; P:regulation of neuroblast proliferation; IMP:ParkinsonsUK-UCL. DR GO; GO:0014041; P:regulation of neuron maturation; IMP:ParkinsonsUK-UCL. DR GO; GO:0031647; P:regulation of protein stability; IMP:UniProtKB. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:1905279; P:regulation of retrograde transport, endosome to Golgi; IGI:ParkinsonsUK-UCL. DR GO; GO:0035542; P:regulation of SNARE complex assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; ISS:ParkinsonsUK-UCL. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IBA:GO_Central. DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; IMP:ParkinsonsUK-UCL. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; ISS:ParkinsonsUK-UCL. DR GO; GO:0006979; P:response to oxidative stress; IMP:BHF-UCL. DR GO; GO:0007266; P:Rho protein signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl. DR GO; GO:0021756; P:striatum development; IEA:Ensembl. DR GO; GO:0022028; P:tangential migration from the subventricular zone to the olfactory bulb; IMP:ParkinsonsUK-UCL. DR GO; GO:1904887; P:Wnt signalosome assembly; IPI:ParkinsonsUK-UCL. DR CDD; cd09914; RocCOR; 1. DR CDD; cd14068; STKc_LRRK2; 1. DR FunFam; 1.10.510.10:FF:001216; Leucine-rich repeat kinase 2; 1. DR FunFam; 1.25.40.20:FF:000219; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 2.130.10.10:FF:000481; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.30.200.20:FF:000313; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.30.70.1390:FF:000001; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.40.50.300:FF:000656; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.80.10.10:FF:000110; Leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 1.25.10.10:FF:000215; leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 3.80.10.10:FF:000179; leucine-rich repeat serine/threonine-protein kinase 2; 1. DR FunFam; 1.25.10.10:FF:000232; leucine-rich repeat serine/threonine-protein kinase 2 isoform X1; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR Gene3D; 1.25.10.10; Leucine-rich Repeat Variant; 2. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 2. DR Gene3D; 3.30.70.1390; ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1. DR InterPro; IPR056593; ANK_LRRK2. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR011989; ARM-like. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR056597; ARM_LRRK2. DR InterPro; IPR056602; Beta-prop_LRRK2. DR InterPro; IPR032171; COR-A. DR InterPro; IPR057263; COR-B. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR020859; ROC. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR051420; Ser_Thr_Kinases_DiverseReg. DR InterPro; IPR005225; Small_GTP-bd. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR InterPro; IPR036322; WD40_repeat_dom_sf. DR NCBIfam; TIGR00231; small_GTP; 1. DR PANTHER; PTHR48005; LEUCINE RICH REPEAT KINASE 2; 1. DR PANTHER; PTHR48005:SF13; SERINE_THREONINE-PROTEIN KINASE DDB_G0278509-RELATED; 1. DR Pfam; PF23745; ANK_LRRK2; 1. DR Pfam; PF23744; ARM_LRRK2; 1. DR Pfam; PF23748; Beta-prop_LRRK2; 1. DR Pfam; PF16095; COR-A; 1. DR Pfam; PF25497; COR-B; 1. DR Pfam; PF13855; LRR_8; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF08477; Roc; 1. DR PRINTS; PR00449; RASTRNSFRMNG. DR SMART; SM00364; LRR_BAC; 8. DR SMART; SM00369; LRR_TYP; 7. DR SMART; SM00175; RAB; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF48371; ARM repeat; 2. DR SUPFAM; SSF52058; L domain-like; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF50978; WD40 repeat-like; 1. DR PROSITE; PS51450; LRR; 11. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS51424; ROC; 1. PE 1: Evidence at protein level; KW 3D-structure; ATP-binding; Autophagy; Cell projection; Coiled coil; KW Cytoplasm; Cytoplasmic vesicle; Cytoskeleton; Differentiation; KW Disease variant; Endoplasmic reticulum; Endosome; Golgi apparatus; KW GTP-binding; GTPase activation; Hydrolase; Kinase; Leucine-rich repeat; KW Lysosome; Membrane; Mitochondrion; Mitochondrion outer membrane; KW Neurodegeneration; Nucleotide-binding; Parkinson disease; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW Serine/threonine-protein kinase; Synapse; Transferase; Ubl conjugation; KW WD repeat. FT CHAIN 1..2527 FT /note="Leucine-rich repeat serine/threonine-protein kinase FT 2" FT /id="PRO_0000086238" FT REPEAT 983..1004 FT /note="LRR 1" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1012..1033 FT /note="LRR 2" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1036..1057 FT /note="LRR 3" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1059..1080 FT /note="LRR 4" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1084..1105 FT /note="LRR 5" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1108..1129 FT /note="LRR 6" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1130..1150 FT /note="LRR 7" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1156..1171 FT /note="LRR 8" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1174..1196 FT /note="LRR 9" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1197..1218 FT /note="LRR 10" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1221..1245 FT /note="LRR 11" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1246..1267 FT /note="LRR 12" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 1269..1291 FT /note="LRR 13" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT DOMAIN 1328..1511 FT /note="Roc" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758" FT DOMAIN 1546..1740 FT /note="COR" FT /evidence="ECO:0000255" FT DOMAIN 1879..2138 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REPEAT 2139..2183 FT /note="WD 1" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2188..2228 FT /note="WD 2" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2233..2276 FT /note="WD 3" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2281..2327 FT /note="WD 4" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2333..2377 FT /note="WD 5" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2402..2438 FT /note="WD 6" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REPEAT 2443..2497 FT /note="WD 7" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8, FT ECO:0007744|PDB:8FO9" FT REGION 1..969 FT /note="Required for RAB29-mediated activation" FT /evidence="ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:38127736" FT COILED 319..348 FT /evidence="ECO:0000255" FT ACT_SITE 1994 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 1341..1348 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758, FT ECO:0000269|PubMed:18230735" FT BINDING 1885 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1887 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1888 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 1891 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8" FT BINDING 1893 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 1904 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1906 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 1947 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO2, ECO:0007744|PDB:8FO8" FT BINDING 1948 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1950 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1954 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 1957 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 1998 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO8, ECO:0007744|PDB:8FO9" FT BINDING 2001 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 2016 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 2017 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:38127736, FT ECO:0007744|PDB:8FO9" FT BINDING 2098..2121 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758" FT BINDING 2295..2298 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00758" FT MOD_RES 910 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29212815" FT MOD_RES 935 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29127255, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30635421" FT MOD_RES 955 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:29212815" FT MOD_RES 973 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:29212815" FT MOD_RES 1292 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736" FT MOD_RES 1444 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28202711" FT VARIANT 50 FT /note="R -> H (in dbSNP:rs2256408)" FT /id="VAR_024931" FT VARIANT 119 FT /note="L -> P (in dbSNP:rs33995463)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846" FT /id="VAR_024932" FT VARIANT 228 FT /note="C -> S (in dbSNP:rs56108242)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054740" FT VARIANT 419 FT /note="A -> V (in dbSNP:rs34594498)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_033903" FT VARIANT 551 FT /note="N -> K (in dbSNP:rs7308720)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024933" FT VARIANT 712 FT /note="M -> V (in PARK8; dbSNP:rs199566791)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054741" FT VARIANT 716 FT /note="A -> V (in dbSNP:rs281865043)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054742" FT VARIANT 723 FT /note="I -> V (in dbSNP:rs10878307)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:22415848" FT /id="VAR_024934" FT VARIANT 755 FT /note="P -> L (in dbSNP:rs34410987)" FT /id="VAR_033904" FT VARIANT 793 FT /note="R -> M (in PARK8; uncertain significance; FT dbSNP:rs35173587)" FT /evidence="ECO:0000269|PubMed:16157908, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16251215" FT /id="VAR_024935" FT VARIANT 871 FT /note="K -> E (in dbSNP:rs281865044)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054743" FT VARIANT 930 FT /note="Q -> R (in PARK8; uncertain significance; FT dbSNP:rs281865045)" FT /evidence="ECO:0000269|PubMed:16251215" FT /id="VAR_024936" FT VARIANT 944 FT /note="D -> Y (in dbSNP:rs17519916)" FT /id="VAR_024937" FT VARIANT 1067 FT /note="R -> Q (in PARK8; dbSNP:rs111341148)" FT /evidence="ECO:0000269|PubMed:16247070" FT /id="VAR_024938" FT VARIANT 1096 FT /note="S -> C (in PARK8; uncertain significance; FT dbSNP:rs76535406)" FT /evidence="ECO:0000269|PubMed:16251215" FT /id="VAR_024939" FT VARIANT 1122 FT /note="I -> V (in PARK8; dbSNP:rs34805604)" FT /evidence="ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:16172858" FT /id="VAR_024940" FT VARIANT 1228 FT /note="S -> T (in PARK8; dbSNP:rs60185966)" FT /evidence="ECO:0000269|PubMed:16251215" FT /id="VAR_024941" FT VARIANT 1262 FT /note="P -> A (in dbSNP:rs4640000)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024942" FT VARIANT 1359 FT /note="K -> I (found in a renal cell carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:21248752" FT /id="VAR_064728" FT VARIANT 1371 FT /note="I -> V (in PARK8; uncertain significance; FT dbSNP:rs17466213)" FT /evidence="ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16333314" FT /id="VAR_024943" FT VARIANT 1375 FT /note="D -> E (in dbSNP:rs28365226)" FT /id="VAR_047022" FT VARIANT 1398 FT /note="R -> H (in dbSNP:rs7133914)" FT /evidence="ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024944" FT VARIANT 1441 FT /note="R -> C (in PARK8; shows an increase in activity in FT both autophosphorylation and phosphorylation of a generic FT substrate; loss of interaction with SEC16A; shows an FT increase in activity in phosphorylation of RAB10; decreases FT phosphorylation-dependent binding to YWHAG; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs33939927)" FT /evidence="ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16333314, FT ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28202711, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220" FT /id="VAR_024945" FT VARIANT 1441 FT /note="R -> G (in PARK8; shows a progressive reduction in FT neurite length and branching; shows an increase in activity FT in phosphorylation of RAB8A and RAB10; decreases FT phosphorylation-dependent binding to YWHAG; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs33939927)" FT /evidence="ECO:0000269|PubMed:15541308, FT ECO:0000269|PubMed:15925109, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:17114044, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30209220, ECO:0000269|PubMed:30398148, FT ECO:0000269|PubMed:30635421" FT /id="VAR_024946" FT VARIANT 1441 FT /note="R -> H (in PARK8; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; decreases FT phosphorylation-dependent binding to YWHAG; FT dbSNP:rs34995376)" FT /evidence="ECO:0000269|PubMed:16157909, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29212815" FT /id="VAR_024947" FT VARIANT 1514 FT /note="R -> Q (in PARK8; uncertain significance; FT dbSNP:rs35507033)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:22415848" FT /id="VAR_024948" FT VARIANT 1542 FT /note="P -> S (in PARK8; uncertain significance; FT dbSNP:rs33958906)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:22415848" FT /id="VAR_024949" FT VARIANT 1550 FT /note="R -> Q (in an ovarian mucinous carcinoma sample; FT somatic mutation; dbSNP:rs200212150)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040678" FT VARIANT 1598 FT /note="V -> E (in PARK8; uncertain significance; FT dbSNP:rs721710)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024950" FT VARIANT 1628 FT /note="R -> P (in PARK8; uncertain significance; FT dbSNP:rs33949390)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:21641266, ECO:0000269|PubMed:22415848" FT /id="VAR_024951" FT VARIANT 1646 FT /note="M -> T (in dbSNP:rs35303786)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024952" FT VARIANT 1647 FT /note="S -> T (in dbSNP:rs11564148)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024953" FT VARIANT 1699 FT /note="Y -> C (in PARK8; shows no progressive reduction in FT neurite length and branching; no loss of interaction with FT SEC16A; shows an increase in activity in phosphorylation of FT RAB8A and RAB10; significantly suppresses lysosomal FT enlargement when overexpressed in LRRK2 knockout cells due FT to increased phosphorylation of Rab proteins; FT dbSNP:rs35801418)" FT /evidence="ECO:0000269|PubMed:15541308, FT ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16272164, ECO:0000269|PubMed:17114044, FT ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30209220" FT /id="VAR_024954" FT VARIANT 1723 FT /note="R -> P (in an ovarian serous carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040679" FT VARIANT 1728 FT /note="R -> H (in PARK8; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; dbSNP:rs145364431)" FT /evidence="ECO:0000269|PubMed:18213618, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:29212815" FT /id="VAR_054744" FT VARIANT 1728 FT /note="R -> L (in PARK8; dbSNP:rs145364431)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054745" FT VARIANT 1869 FT /note="M -> T (in PARK8; uncertain significance; FT dbSNP:rs35602796)" FT /evidence="ECO:0000269|PubMed:16157908, FT ECO:0000269|PubMed:16172858" FT /id="VAR_024955" FT VARIANT 1870 FT /note="L -> F (in dbSNP:rs281865053)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054746" FT VARIANT 1906 FT /note="K -> M (loss of kinase activity and ability to FT enhance NOD2 signaling; does not inhibit interaction with FT RAB29; shows a progressive increase in neurite length and FT branching; does not suppress lysosomal enlargement when FT overexpressed in LRRK2 knockout cells due to lack of FT phosphorylation activity)" FT /evidence="ECO:0000269|PubMed:17114044, FT ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:27830463, FT ECO:0000269|PubMed:30209220" FT /id="VAR_071101" FT VARIANT 1941 FT /note="R -> H (in PARK8; dbSNP:rs77428810)" FT /evidence="ECO:0000269|PubMed:16272164" FT /id="VAR_024956" FT VARIANT 2012 FT /note="I -> T (in PARK8; uncertain significance; FT dbSNP:rs34015634)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024957" FT VARIANT 2019 FT /note="G -> S (in PARK8; shows an increase in activity in FT both autophosphorylation and phosphorylation of a generic FT substrate; results in increased PRDX3 phosphorylation FT promoting dysregulation of mitochondrial function and FT oxidative damage; results in increased APP phosphorylation FT on 'T-743' promoting neurotoxicity in dopaminergic neurons; FT shows increased kinase activity in the phosphorylation of FT RAB10; does not inhibit interaction with RAB29; shows a FT progressive reduction in neurite length and branching; FT shows distinctive spheroid-like inclusions within both FT neuronal processes and at intracellular membranous FT structures; shows lysosomal swelling and reduced retrograde FT transport of selective cargo between lysosomes and the FT Golgi apparatus; shows apoptotic mechanism of cell death; FT no loss of interaction with SEC16A; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs34637584)" FT /evidence="ECO:0000269|PubMed:15680455, FT ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, FT ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, FT ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, FT ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16001413, FT ECO:0000269|PubMed:16102999, ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16157908, ECO:0000269|PubMed:16157909, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16240353, FT ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, FT ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16272164, FT ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, FT ECO:0000269|PubMed:16333314, ECO:0000269|PubMed:16533964, FT ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18213618, FT ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220, FT ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421" FT /id="VAR_024958" FT VARIANT 2020 FT /note="I -> T (in PARK8; significant increase in FT autophosphorylation of about 40% in comparison to wild-type FT protein in vitro; shows a progressive reduction in neurite FT length and branching; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; significantly FT suppresses lysosomal enlargement when overexpressed in FT LRRK2 knockout cells due to increased phosphorylation of FT Rab proteins; dbSNP:rs35870237)" FT /evidence="ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:16321986, FT ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30209220" FT /id="VAR_024959" FT VARIANT 2031 FT /note="T -> S (in PARK8; shows an increase in activity in FT phosphorylation of RAB8A and RAB10; dbSNP:rs78029637)" FT /evidence="ECO:0000269|PubMed:26824392, FT ECO:0000269|PubMed:29212815" FT /id="VAR_082047" FT VARIANT 2081 FT /note="N -> D (in dbSNP:rs33995883)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848" FT /id="VAR_024960" FT VARIANT 2119 FT /note="P -> L (in dbSNP:rs12423862)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024961" FT VARIANT 2141 FT /note="T -> M (in PARK8; dbSNP:rs111691891)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054747" FT VARIANT 2143 FT /note="R -> H (in PARK8; dbSNP:rs201271001)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054748" FT VARIANT 2175 FT /note="D -> H (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs72547981)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082048" FT VARIANT 2189 FT /note="Y -> C (in PARK8; no effect on WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs35658131)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082049" FT VARIANT 2261 FT /note="N -> I (in dbSNP:rs12581902)" FT /evidence="ECO:0000269|PubMed:16172858" FT /id="VAR_024962" FT VARIANT 2356 FT /note="T -> I (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs113511708)" FT /evidence="ECO:0000269|PubMed:16272164, FT ECO:0000269|PubMed:30635421" FT /id="VAR_024963" FT VARIANT 2385 FT /note="G -> R (in PARK8; under conditions of oxidative FT stress the variant protein is more toxic and is correlated FT with a higher rate of apoptosis; reduced binding to FT synaptic vesicles; no loss of interaction with SEC16A; FT shows an increase in activity in phosphorylation of RAB8A FT and RAB10; shows decreased WD domain homodimerization; FT reduced autophosphorylation at Ser-935; dbSNP:rs34778348)" FT /evidence="ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17019612, ECO:0000269|PubMed:21641266, FT ECO:0000269|PubMed:24687852, ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30635421" FT /id="VAR_024964" FT VARIANT 2390 FT /note="V -> M (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs79546190)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082050" FT VARIANT 2395 FT /note="E -> K (in dbSNP:rs78964014)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054749" FT VARIANT 2397 FT /note="M -> T (in dbSNP:rs3761863)" FT /evidence="ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:22415848" FT /id="VAR_024965" FT VARIANT 2439 FT /note="L -> I (in PARK8; shows decreased WD domain FT homodimerization; no effect on kinase activity; FT dbSNP:rs72547983)" FT /evidence="ECO:0000269|PubMed:30635421" FT /id="VAR_082051" FT VARIANT 2466 FT /note="L -> H (in PARK8; dbSNP:rs281865057)" FT /evidence="ECO:0000269|PubMed:18213618" FT /id="VAR_054750" FT MUTAGEN 399 FT /note="R->E: Reduces membrane localization and abolishes FT interaction with RAB29/RAB7L1. Impairs RAB29-stimulated FT kinase activity on RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 403 FT /note="L->E: Reduces membrane localization and abolishes FT interaction with RAB29/RAB7L1. Impairs RAB29-stimulated FT kinase activity on RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 727 FT /note="C->D: Decreased kinase activity. Loss of RAB29- FT mediated activation and autophosphorylation of S-910, S- FT 935, S-955, S-973 and S-1292. Decreased membrane FT association; when associated with G-1441, C-1699 and S- FT 2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 728 FT /note="L->D: Decreased kinase activity. Loss of RAB29- FT mediated activation and autophosphorylation of S-910, S- FT 935, S-955, S-973 and S-1292. Decreased membrane FT association; when associated with G-1441, C-1699 and S- FT 2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 729 FT /note="L->D: Decreased kinase activity. Loss of RAB29- FT mediated activation and autophosphorylation of S-910, S- FT 935, S-955, S-973 and S-1292. Decreased membrane FT association; when associated with G-1441, C-1699 and S- FT 2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 760 FT /note="L->D: Decreased kinase activity and loss of RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 761 FT /note="L->D: Decreased kinase activity and loss of RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 762 FT /note="L->D: Decreased kinase activity and loss of RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 789 FT /note="L->D: No effect on kinase activity and RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 790 FT /note="L->D: No effect on kinase activity and RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 791 FT /note="L->D: No effect on kinase activity and RAB29- FT mediated activation." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1343 FT /note="T->G: Decreased kinase activity; when associated FT with Q-1398." FT /evidence="ECO:0000269|PubMed:18230735" FT MUTAGEN 1347 FT /note="K->A: GTPase-dead mutant. Loss of interaction with FT SEC16A and impaired ability to recruit SEC16A to FT endoplasmic reticulum exit sites." FT /evidence="ECO:0000269|PubMed:25201882" FT MUTAGEN 1348 FT /note="T->N: Loss of GTP binding. Inhibits FT autophosphorylation and RAB10 phosphorylation; when FT associated with G-1441, C-1699, or S-2019." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1398 FT /note="R->Q: Decreased kinase activity; when associated FT with G-1343." FT /evidence="ECO:0000269|PubMed:18230735" FT MUTAGEN 1441 FT /note="R->G: Decreased membrane association when associated FT with D-727, D-728, or D-729. Inhibits autophosphorylation FT and RAB10 phosphorylation when associated with N-1348 or A- FT 2017." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1588 FT /note="P->A: Impairs RAB29-stimulated kinase activity on FT RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 1699 FT /note="Y->C: Decreased membrane association when associated FT with D-727, D-728, or D-729. Inhibits autophosphorylation FT and RAB10 phosphorylation when associated with N-1348 or A- FT 2017." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 1710 FT /note="N->A: Impairs RAB29-stimulated kinase activity on FT RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 1791 FT /note="W->A: Impairs RAB29-stimulated kinase activity on FT RAB10, RAB29 and LRRK2." FT /evidence="ECO:0000269|PubMed:38127736" FT MUTAGEN 1906 FT /note="K->A: Loss of kinase activity. Decreases proteasomal FT degradation of MAPT; when associated with N-1994 and A- FT 2017." FT /evidence="ECO:0000269|PubMed:26014385" FT MUTAGEN 1994 FT /note="D->A: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:28720718" FT MUTAGEN 1994 FT /note="D->N: Loss of kinase activity. No loss of FT interaction with SEC16A and no loss of ability to recruit FT SEC16A to endoplasmic reticulum exit sites. Decreases FT proteasomal degradation of MAPT; when associated with A- FT 1906 and A-2017." FT /evidence="ECO:0000269|PubMed:25201882, FT ECO:0000269|PubMed:26014385, ECO:0000269|PubMed:26824392" FT MUTAGEN 2017 FT /note="D->A: Loss of kinase activity. Decreases proteasomal FT degradation of MAPT; when associated with A-1906 and N- FT 1994. Loss of phosphorylation of RAB10; when associated FT with G-1441, C-1699, or S-2019." FT /evidence="ECO:0000269|PubMed:26014385, FT ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815, FT ECO:0000269|PubMed:30635421, ECO:0000269|PubMed:38127736" FT MUTAGEN 2019 FT /note="G->S: Decreased membrane association when associated FT with D-727, D-728, or D-729. Inhibits autophosphorylation FT and RAB10 phosphorylation when associated with N-1348 or A- FT 2017." FT /evidence="ECO:0000269|PubMed:29212815" FT MUTAGEN 2343 FT /note="L->D: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2344 FT /note="F->A: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2345 FT /note="S->D: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2346 FT /note="Y->A: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2391 FT /note="H->D: Increases kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2394 FT /note="R->E: Decreases WD domain homodimerization. FT Increases kinase activity and autophosphorylation at Ser- FT 1292." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2395 FT /note="E->R: Decreases WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2408 FT /note="M->A,E: No effect on WD domain homodimerization. No FT effect on kinase activity." FT /evidence="ECO:0000269|PubMed:30635421" FT MUTAGEN 2409 FT /note="S->A: Decreases WD domain homodimerization." FT /evidence="ECO:0000269|PubMed:30635421" FT CONFLICT 212 FT /note="L -> S (in Ref. 1; AAV63975)" FT /evidence="ECO:0000305" FT HELIX 560..570 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 571..574 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 585..595 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 603..606 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 607..610 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 626..637 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 638..640 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 645..656 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 660..662 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 663..666 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 667..670 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 671..678 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 689..702 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 706..714 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 715..720 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 722..730 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 740..742 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 744..750 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 755..762 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 763..765 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 768..780 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 784..787 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 788..794 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 798..801 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 802..804 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 815..818 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 819..821 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 834..852 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 913..917 FT /evidence="ECO:0007829|PDB:5MYC" FT STRAND 986..988 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 998..1000 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1001..1003 FT /evidence="ECO:0007829|PDB:7LI4" FT TURN 1005..1009 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1010..1012 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1014..1017 FT /evidence="ECO:0007829|PDB:8TZF" FT HELIX 1030..1032 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1054..1056 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1057..1059 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1087..1089 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1102..1105 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1111..1113 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1133..1135 FT /evidence="ECO:0007829|PDB:8TZF" FT TURN 1146..1149 FT /evidence="ECO:0007829|PDB:8TZF" FT STRAND 1157..1159 FT /evidence="ECO:0007829|PDB:8TZF" FT STRAND 1177..1179 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1190..1193 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1200..1202 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1214..1216 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1224..1226 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1242..1244 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1249..1251 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1262..1266 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1272..1274 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1286..1290 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1310..1312 FT /evidence="ECO:0007829|PDB:8TZF" FT HELIX 1317..1327 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1329..1332 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1336..1341 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1347..1354 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1357..1359 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1365..1368 FT /evidence="ECO:0007829|PDB:6OJE" FT STRAND 1370..1378 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1382..1384 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1388..1395 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1398..1402 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1406..1410 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1411..1420 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1421..1423 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1426..1429 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1431..1441 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1447..1452 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1454..1456 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1459..1472 FT /evidence="ECO:0007829|PDB:6OJF" FT TURN 1473..1475 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1482..1487 FT /evidence="ECO:0007829|PDB:6OJF" FT STRAND 1490..1492 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1495..1513 FT /evidence="ECO:0007829|PDB:6OJF" FT HELIX 1518..1520 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1521..1524 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 1531..1539 FT /evidence="ECO:0007829|PDB:8TZG" FT STRAND 1543..1549 FT /evidence="ECO:0007829|PDB:8TXZ" FT HELIX 1553..1557 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1564..1568 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1573..1579 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1581..1583 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1588..1590 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1591..1594 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1596..1599 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1600..1609 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1610..1612 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1628..1632 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1638..1640 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1643..1645 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1650..1655 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1661..1663 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1670..1672 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 1687..1689 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1690..1699 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1701..1703 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1704..1715 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1716..1718 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1730..1733 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1735..1743 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1746..1753 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1761..1770 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1771..1791 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1793..1796 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1800..1802 FT /evidence="ECO:0007829|PDB:8TZF" FT STRAND 1809..1814 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1816..1819 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 1823..1826 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1827..1835 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1838..1841 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1843..1845 FT /evidence="ECO:0007829|PDB:8TZB" FT STRAND 1849..1851 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1852..1854 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 1857..1863 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1866..1868 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1872..1874 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1875..1877 FT /evidence="ECO:0007829|PDB:8TYQ" FT HELIX 1881..1883 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1884..1887 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1889..1898 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1901..1908 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1910..1912 FT /evidence="ECO:0007829|PDB:8TZE" FT HELIX 1914..1924 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1935..1939 FT /evidence="ECO:0007829|PDB:8TZE" FT STRAND 1940..1942 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1946..1948 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1951..1954 FT /evidence="ECO:0007829|PDB:6VP6" FT HELIX 1955..1960 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 1963..1965 FT /evidence="ECO:0007829|PDB:8TZE" FT HELIX 1968..1987 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 1999..2003 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 2013..2015 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2018..2025 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2036..2038 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 2041..2045 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 2046..2048 FT /evidence="ECO:0007829|PDB:6VP6" FT HELIX 2054..2068 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2069..2072 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2080..2082 FT /evidence="ECO:0007829|PDB:8TZG" FT HELIX 2085..2087 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2095..2099 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2105..2107 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2108..2114 FT /evidence="ECO:0007829|PDB:8TZC" FT TURN 2119..2121 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2125..2132 FT /evidence="ECO:0007829|PDB:8TZC" FT HELIX 2135..2139 FT /evidence="ECO:0007829|PDB:8TZC" FT STRAND 2142..2145 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2152..2158 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2166..2171 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2173..2183 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2184..2186 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2189..2197 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2199..2207 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2208..2211 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2212..2219 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2224..2230 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2235..2237 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2245..2252 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2256..2258 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2262..2267 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2270..2276 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2278..2281 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2282..2284 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2288..2292 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2300..2304 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2315..2319 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2322..2330 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2335..2338 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2339..2343 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2347..2350 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2354..2367 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2371..2376 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2378..2380 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2382..2388 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2389..2393 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2397..2399 FT /evidence="ECO:0007829|PDB:7LI4" FT HELIX 2403..2406 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2414..2419 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2421..2423 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2425..2432 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2434..2437 FT /evidence="ECO:0007829|PDB:6DLO" FT TURN 2439..2441 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2444..2448 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2451..2462 FT /evidence="ECO:0007829|PDB:6DLO" FT STRAND 2468..2475 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2482..2484 FT /evidence="ECO:0007829|PDB:7LI4" FT STRAND 2491..2497 FT /evidence="ECO:0007829|PDB:6DLO" FT HELIX 2500..2521 FT /evidence="ECO:0007829|PDB:8TZC" SQ SEQUENCE 2527 AA; 286103 MW; 26142A0CECBBC3F4 CRC64; MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSER ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLIE VCPGTMQSLM GPQDVGNDWE VLGVHQLILK MLTVHNASVN LSVIGLKTLD LLLTSGKITL LILDEESDIF MLIFDAMHSF PANDEVQKLG CKALHVLFER VSEEQLTEFV ENKDYMILLS ALTNFKDEEE IVLHVLHCLH SLAIPCNNVE VLMSGNVRCY NIVVEAMKAF PMSERIQEVS CCLLHRLTLG NFFNILVLNE VHEFVVKAVQ QYPENAALQI SALSCLALLT ETIFLNQDLE EKNENQENDD EGEEDKLFWL EACYKALTWH RKNKHVQEAA CWALNNLLMY QNSLHEKIGD EDGHFPAHRE VMLSMLMHSS SKEVFQASAN ALSTLLEQNV NFRKILLSKG IHLNVLELMQ KHIHSPEVAE SGCKMLNHLF EGSNTSLDIM AAVVPKILTV MKRHETSLPV QLEALRAILH FIVPGMPEES REDTEFHHKL NMVKKQCFKN DIHKLVLAAL NRFIGNPGIQ KCGLKVISSI VHFPDALEML SLEGAMDSVL HTLQMYPDDQ EIQCLGLSLI GYLITKKNVF IGTGHLLAKI LVSSLYRFKD VAEIQTKGFQ TILAILKLSA SFSKLLVHHS FDLVIFHQMS SNIMEQKDQQ FLNLCCKCFA KVAMDDYLKN VMLERACDQN NSIMVECLLL LGADANQAKE GSSLICQVCE KESSPKLVEL LLNSGSREQD VRKALTISIG KGDSQIISLL LRRLALDVAN NSICLGGFCI GKVEPSWLGP LFPDKTSNLR KQTNIASTLA RMVIRYQMKS AVEEGTASGS DGNFSEDVLS KFDEWTFIPD SSMDSVFAQS DDLDSEGSEG SFLVKKKSNS ISVGEFYRDA VLQRCSPNLQ RHSNSLGPIF DHEDLLKRKR KILSSDDSLR SSKLQSHMRH SDSISSLASE REYITSLDLS ANELRDIDAL SQKCCISVHL EHLEKLELHQ NALTSFPQQL CETLKSLTHL DLHSNKFTSF PSYLLKMSCI ANLDVSRNDI GPSVVLDPTV KCPTLKQFNL SYNQLSFVPE NLTDVVEKLE QLILEGNKIS GICSPLRLKE LKILNLSKNH ISSLSENFLE ACPKVESFSA RMNFLAAMPF LPPSMTILKL SQNKFSCIPE AILNLPHLRS LDMSSNDIQY LPGPAHWKSL NLRELLFSHN QISILDLSEK AYLWSRVEKL HLSHNKLKEI PPEIGCLENL TSLDVSYNLE LRSFPNEMGK LSKIWDLPLD ELHLNFDFKH IGCKAKDIIR FLQQRLKKAV PYNRMKLMIV GNTGSGKTTL LQQLMKTKKS DLGMQSATVG IDVKDWPIQI RDKRKRDLVL NVWDFAGREE FYSTHPHFMT QRALYLAVYD LSKGQAEVDA MKPWLFNIKA RASSSPVILV GTHLDVSDEK QRKACMSKIT KELLNKRGFP AIRDYHFVNA TEESDALAKL RKTIINESLN FKIRDQLVVG QLIPDCYVEL EKIILSERKN VPIEFPVIDR KRLLQLVREN QLQLDENELP HAVHFLNESG VLLHFQDPAL QLSDLYFVEP KWLCKIMAQI LTVKVEGCPK HPKGIISRRD VEKFLSKKRK FPKNYMSQYF KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI ELPHCENSEI IIRLYEMPYF PMGFWSRLIN RLLEISPYML SGRERALRPN RMYWRQGIYL NWSPEAYCLV GSEVLDNHPE SFLKITVPSC RKGCILLGQV VDHIDSLMEE WFPGLLEIDI CGEGETLLKK WALYSFNDGE EHQKILLDDL MKKAEEGDLL VNPDQPRLTI PISQIAPDLI LADLPRNIML NNDELEFEQA PEFLLGDGSF GSVYRAAYEG EEVAVKIFNK HTSLRLLRQE LVVLCHLHHP SLISLLAAGI RPRMLVMELA SKGSLDRLLQ QDKASLTRTL QHRIALHVAD GLRYLHSAMI IYRDLKPHNV LLFTLYPNAA IIAKIADYGI AQYCCRMGIK TSEGTPGFRA PEVARGNVIY NQQADVYSFG LLLYDILTTG GRIVEGLKFP NEFDELEIQG KLPDPVKEYG CAPWPMVEKL IKQCLKENPQ ERPTSAQVFD ILNSAELVCL TRRILLPKNV IVECMVATHH NSRNASIWLG CGHTDRGQLS FLDLNTEGYT SEEVADSRIL CLALVHLPVE KESWIVSGTQ SGTLLVINTE DGKKRHTLEK MTDSVTCLYC NSFSKQSKQK NFLLVGTADG KLAIFEDKTV KLKGAAPLKI LNIGNVSTPL MCLSESTNST ERNVMWGGCG TKIFSFSNDF TIQKLIETRT SQLFSYAAFS DSNIITVVVD TALYIAKQNS PVVEVWDKKT EKLCGLIDCV HFLREVMVKE NKESKHKMSY SGRVKTLCLQ KNTALWIGTG GGHILLLDLS TRRLIRVIYN FCNSVRVMMT AQLGSLKNVM LVLGYNRKNT EGTQKQKEIQ SCLTVWDINL PHEVQNLEKH IEVRKELAEK MRRTSVE // 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 PINK1_HUMAN Reviewed; 581 AA. AC Q9BXM7; Q8N6T9; Q8NBU3; Q96DE4; DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 28-JAN-2026, entry version 212. DE RecName: Full=Serine/threonine-protein kinase PINK1, mitochondrial; DE EC=2.7.11.1 {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:32484300}; DE AltName: Full=BRPK; DE AltName: Full=PTEN-induced putative kinase protein 1; DE Flags: Precursor; GN Name=PINK1; 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|EMBL:AAK28062.1}; RN [1] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Endometrium {ECO:0000269|PubMed:11494141}; RX PubMed=11494141; DOI=10.1038/sj.onc.1204608; RA Unoki M., Nakamura Y.; RT "Growth-suppressive effects of BPOZ and EGR2, two genes involved in the RT PTEN signaling pathway."; RL Oncogene 20:4457-4465(2001). RN [2] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND AUTOPHOSPHORYLATION. RC TISSUE=Placenta {ECO:0000312|EMBL:AAK28062.1}; RX PubMed=14607334; DOI=10.1016/s0304-3835(03)00443-9; RA Nakajima A., Kataoka K., Hong M., Sakaguchi M., Huh N.-H.; RT "BRPK, a novel protein kinase showing increased expression in mouse cancer RT cell lines with higher metastatic potential."; RL Cancer Lett. 201:195-201(2003). RN [3] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANTS THR-340 RP AND THR-521. RC TISSUE=Placenta {ECO:0000312|EMBL:BAC11484.1}; 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=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Leukocyte {ECO:0000312|EMBL:AAH28215.1}, and RC Lung {ECO:0000312|EMBL:AAH09534.1}; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP SUBCELLULAR LOCATION. RX PubMed=16672980; DOI=10.1038/nature04788; RA Park J., Lee S.B., Lee S., Kim Y., Song S., Kim S., Bae E., Kim J., RA Shong M., Kim J.M., Chung J.; RT "Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by RT parkin."; RL Nature 441:1157-1161(2006). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, PHOSPHORYLATION, AND RP MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384. RX PubMed=18957282; DOI=10.1016/j.bbrc.2008.10.104; RA Kim Y., Park J., Kim S., Song S., Kwon S.K., Lee S.H., Kitada T., Kim J.M., RA Chung J.; RT "PINK1 controls mitochondrial localization of Parkin through direct RT phosphorylation."; RL Biochem. Biophys. Res. Commun. 377:975-980(2008). RN [8] RP FUNCTION. RX PubMed=18443288; DOI=10.1073/pnas.0711845105; RA Yang Y., Ouyang Y., Yang L., Beal M.F., McQuibban A., Vogel H., Lu B.; RT "Pink1 regulates mitochondrial dynamics through interaction with the RT fission/fusion machinery."; RL Proc. Natl. Acad. Sci. U.S.A. 105:7070-7075(2008). RN [9] RP ERRATUM OF PUBMED:18443288. RA Yang Y., Ouyang Y., Yang L., Beal M.F., McQuibban A., Vogel H., Lu B.; RT "Pink1 regulates mitochondrial dynamics through interaction with the RT fission/fusion machinery."; RL Proc. Natl. Acad. Sci. U.S.A. 105:17585-17585(2008). RN [10] RP SUBCELLULAR LOCATION, AND MEMBRANE TOPOLOGY. RX PubMed=18687899; DOI=10.1073/pnas.0802814105; RA Zhou C., Huang Y., Shao Y., May J., Prou D., Perier C., Dauer W., RA Schon E.A., Przedborski S.; RT "The kinase domain of mitochondrial PINK1 faces the cytoplasm."; RL Proc. Natl. Acad. Sci. U.S.A. 105:12022-12027(2008). RN [11] RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1, RP SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, CHARACTERIZATION OF VARIANTS RP PARK6 ASP-309 AND MET-313, AND CHARACTERIZATION OF VARIANT LEU-399. RX PubMed=19229105; DOI=10.1172/jci37617; RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W., RA Ronai Z., Zhuang X., Zhang Z.; RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting RT unfolded protein degradation."; RL J. Clin. Invest. 119:650-660(2009). RN [12] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION WITH RP PRKN, AND CHARACTERIZATION OF VARIANTS PARK6 PRO-126; ASP-309 AND PRO-347. RX PubMed=20798600; DOI=10.4161/auto.6.7.13286; RA Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S., Fiesel F.C., RA Kahle P.J., Springer W.; RT "The PINK1/Parkin-mediated mitophagy is compromised by PD-associated RT mutations."; RL Autophagy 6:871-878(2010). RN [13] RP FUNCTION, AND CHARACTERIZATION OF VARIANT PARK6 492-ARG--LYS-581 DEL. RX PubMed=20547144; DOI=10.1016/j.brainres.2010.06.005; RA Yuan X.L., Guo J.F., Shi Z.H., Xiao Z.Q., Yan X.X., Zhao B.L., Tang B.S.; RT "R492X mutation in PTEN-induced putative kinase 1 induced cellular RT mitochondrial dysfunction and oxidative stress."; RL Brain Res. 1351:229-237(2010). RN [14] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND PHOSPHORYLATION. RX PubMed=20404107; DOI=10.1083/jcb.200910140; RA Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A., RA Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M., RA Hattori N., Tanaka K.; RT "PINK1 stabilized by mitochondrial depolarization recruits Parkin to RT damaged mitochondria and activates latent Parkin for mitophagy."; RL J. Cell Biol. 189:211-221(2010). RN [15] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND INTERACTION WITH PRKN. RX PubMed=19966284; DOI=10.1073/pnas.0911187107; RA Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J., May J., RA Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J., Dawson V.L., RA Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.; RT "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy."; RL Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010). RN [16] RP INVOLVEMENT IN PARK6. RX PubMed=22043288; DOI=10.1371/journal.pone.0025622; RA Abramov A.Y., Gegg M., Grunewald A., Wood N.W., Klein C., Schapira A.H.; RT "Bioenergetic consequences of PINK1 mutations in Parkinson disease."; RL PLoS ONE 6:E25622-E25622(2011). RN [17] RP PROTEOLYTIC CLEAVAGE, AND SUBCELLULAR LOCATION. RX PubMed=22354088; DOI=10.1038/embor.2012.14; RA Greene A.W., Grenier K., Aguileta M.A., Muise S., Farazifard R., RA Haque M.E., McBride H.M., Park D.S., Fon E.A.; RT "Mitochondrial processing peptidase regulates PINK1 processing, import and RT Parkin recruitment."; RL EMBO Rep. 13:378-385(2012). RN [18] RP PHOSPHORYLATION AT SER-228 AND SER-402. RX PubMed=22910362; DOI=10.1038/ncomms2016; RA Okatsu K., Oka T., Iguchi M., Imamura K., Kosako H., Tani N., Kimura M., RA Go E., Koyano F., Funayama M., Shiba-Fukushima K., Sato S., Shimizu H., RA Fukunaga Y., Taniguchi H., Komatsu M., Hattori N., Mihara K., Tanaka K., RA Matsuda N.; RT "PINK1 autophosphorylation upon membrane potential dissipation is essential RT for Parkin recruitment to damaged mitochondria."; RL Nat. Commun. 3:1016-1016(2012). RN [19] RP FUNCTION, AND CHARACTERIZATION OF VARIANT PARK6 PRO-347. RX PubMed=22396657; DOI=10.1371/journal.pgen.1002537; RA Liu S., Sawada T., Lee S., Yu W., Silverio G., Alapatt P., Millan I., RA Shen A., Saxton W., Kanao T., Takahashi R., Hattori N., Imai Y., Lu B.; RT "Parkinson's disease-associated kinase PINK1 regulates Miro protein level RT and axonal transport of mitochondria."; RL PLoS Genet. 8:E1002537-E1002537(2012). RN [20] RP FUNCTION. RX PubMed=23754282; DOI=10.1074/jbc.m113.467530; RA Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M., RA Suzuki N., Uchiyama S., Tanaka K., Matsuda N.; RT "Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent RT phosphorylation."; RL J. Biol. Chem. 288:22019-22032(2013). RN [21] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7. RX PubMed=23933751; DOI=10.1038/nn.3489; RA Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M., RA Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H., RA Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H., RA Plun-Favreau H.; RT "The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to RT mediate mitophagy."; RL Nat. Neurosci. 16:1257-1265(2013). RN [22] RP FUNCTION IN MITOPHAGY, AND MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384. RX PubMed=23620051; DOI=10.1126/science.1231031; RA Chen Y., Dorn G.W. II; RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged RT mitochondria."; RL Science 340:471-475(2013). RN [23] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=24660806; DOI=10.1042/bj20140334; RA Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S., RA Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.; RT "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at RT Ser65."; RL Biochem. J. 460:127-139(2014). RN [24] RP FUNCTION. RX PubMed=24898855; DOI=10.7554/elife.01958; RA Yun J., Puri R., Yang H., Lizzio M.A., Wu C., Sheng Z.H., Guo M.; RT "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin RT and compensates for loss of PINK1/parkin."; RL Elife 3:E01958-E01958(2014). RN [25] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=24751536; DOI=10.1083/jcb.201402104; RA Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A., RA Banerjee S., Youle R.J.; RT "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase RT activity."; RL J. Cell Biol. 205:143-153(2014). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANTS PARK6 RP PRO-168 AND ALA-386. RX PubMed=24784582; DOI=10.1038/nature13392; RA Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y., RA Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F., RA Saeki Y., Tanaka K., Matsuda N.; RT "Ubiquitin is phosphorylated by PINK1 to activate parkin."; RL Nature 510:162-166(2014). RN [27] RP FUNCTION. RX PubMed=24896179; DOI=10.1038/nature13418; RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q., RA Foreman O., Kirkpatrick D.S., Sheng M.; RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated RT mitophagy."; RL Nature 510:370-375(2014). RN [28] RP FUNCTION. RX PubMed=25474007; DOI=10.1371/journal.pgen.1004861; RA Shiba-Fukushima K., Arano T., Matsumoto G., Inoshita T., Yoshida S., RA Ishihama Y., Ryu K.Y., Nukina N., Hattori N., Imai Y.; RT "Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin RT mitochondrial tethering."; RL PLoS Genet. 10:e1004861-e1004861(2014). RN [29] RP VARIANTS PARK6 GLY-170 AND 456-GLN--LEU-581 DEL. RX PubMed=24652937; DOI=10.1126/science.1249161; RA Morais V.A., Haddad D., Craessaerts K., De Bock P.J., Swerts J., Vilain S., RA Aerts L., Overbergh L., Gruenewald A., Seibler P., Klein C., Gevaert K., RA Verstreken P., De Strooper B.; RT "PINK1 loss-of-function mutations affect mitochondrial complex I activity RT via NdufA10 ubiquinone uncoupling."; RL Science 344:203-207(2014). RN [30] RP FUNCTION. RX PubMed=25527291; DOI=10.15252/embj.201489847; RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N., RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.; RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain RT assembly and hydrolysis."; RL EMBO J. 34:307-325(2015). RN [31] RP PROTEOLYTIC CLEAVAGE, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 112-GLU--GLU-117. RX PubMed=30733118; DOI=10.1016/j.molcel.2019.01.002; RA Sekine S., Wang C., Sideris D.P., Bunker E., Zhang Z., Youle R.J.; RT "Reciprocal roles of Tom7 and OMA1 during mitochondrial import and RT activation of PINK1."; RL Mol. Cell 73:1028-1043(2019). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH NENF, AND SUBCELLULAR RP LOCATION. RX PubMed=31536960; DOI=10.1016/j.isci.2019.08.057; RA Moutaoufik M.T., Malty R., Amin S., Zhang Q., Phanse S., Gagarinova A., RA Zilocchi M., Hoell L., Minic Z., Gagarinova M., Aoki H., Stockwell J., RA Jessulat M., Goebels F., Broderick K., Scott N.E., Vlasblom J., Musso G., RA Prasad B., Lamantea E., Garavaglia B., Rajput A., Murayama K., Okazaki Y., RA Foster L.J., Bader G.D., Cayabyab F.S., Babu M.; RT "Rewiring of the Human Mitochondrial Interactome during Neuronal RT Reprogramming Reveals Regulators of the Respirasome and Neurogenesis."; RL IScience 19:1114-1132(2019). RN [33] RP FUNCTION, AND MUTAGENESIS OF LYS-219; ASP-362 AND ASP-384. RX PubMed=32047033; DOI=10.1073/pnas.1909814117; RA Ham S.J., Lee D., Yoo H., Jun K., Shin H., Chung J.; RT "Decision between mitophagy and apoptosis by Parkin via VDAC1 RT ubiquitination."; RL Proc. Natl. Acad. Sci. U.S.A. 117:4281-4291(2020). RN [34] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLY-309 AND ASP-384, AND RP CHARACTERIZATION OF VARIANTS ASP-309; MET-313 AND 492-ARG--LYS-581 DEL. RX PubMed=32484300; DOI=10.15252/embr.201948686; RA Han H., Tan J., Wang R., Wan H., He Y., Yan X., Guo J., Gao Q., Li J., RA Shang S., Chen F., Tian R., Liu W., Liao L., Tang B., Zhang Z.; RT "PINK1 phosphorylates Drp1S616 to regulate mitophagy-independent RT mitochondrial dynamics."; RL EMBO Rep. 21:48686-48686(2020). RN [35] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=29123128; DOI=10.1038/s41467-017-01435-1; RA Huang E., Qu D., Huang T., Rizzi N., Boonying W., Krolak D., Ciana P., RA Woulfe J., Klein C., Slack R.S., Figeys D., Park D.S.; RT "PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium RT transport and protects neurons against mitochondrial stress."; RL Nat. Commun. 8:1399-1399(2017). RN [36] RP INTERACTION WITH TOMM70. RX PubMed=35391620; DOI=10.1007/s00109-022-02191-6; RA Maruszczak K.K., Jung M., Rasool S., Trempe J.F., Rapaport D.; RT "The role of the individual TOM subunits in the association of PINK1 with RT depolarized mitochondria."; RL J. Mol. Med. 100:747-762(2022). RN [37] RP INTERACTION WITH TIMM23, AND CHARACTERIZATION OF VARIANTS LEU-52; PHE-67; RP PRO-68; VAL-78; PHE-92; TRP-98; SER-111; LEU-115; VAL-124; GLY-125; RP PRO-126; MET-145; HIS-147; TRP-148; PRO-168; LYS-240; GLN-271; ASP-309; RP PRO-347; ALA-386; VAL-409; GLY-417 AND GLN-534 INS. RX PubMed=37160114; DOI=10.1016/j.celrep.2023.112454; RA Akabane S., Watanabe K., Kosako H., Yamashita S.I., Nishino K., Kato M., RA Sekine S., Kanki T., Matsuda N., Endo T., Oka T.; RT "TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated RT degradation in damaged mitochondria."; RL Cell Rep. 42:112454-112454(2023). RN [38] RP INTERACTION WITH TOM AND TIM23 COMPLEXES, INTERACTION WITH TOMM20, RP MUTAGENESIS OF ILE-131; ALA-536; LEU-540 AND ARG-543, AND CHARACTERIZATION RP OF VARIANTS SER-111; LEU-115; GLY-125 AND PRO-126. RX PubMed=38416681; DOI=10.1073/pnas.2313540121; RA Eldeeb M.A., Bayne A.N., Fallahi A., Goiran T., MacDougall E.J., RA Soumbasis A., Zorca C.E., Tabah J.J., Thomas R.A., Karpilovsky N., RA Mathur M., Durcan T.M., Trempe J.F., Fon E.A.; RT "Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 RT translocases upon mitochondrial stress."; RL Proc. Natl. Acad. Sci. U.S.A. 121:e2313540121-e2313540121(2024). RN [39] RP INTERACTION WITH TOMM20, MUTAGENESIS OF LEU-532; LEU-539 AND LEU-540, AND RP CHARACTERIZATION OF VARIANTS PRO-126; LYS-240; ASP-309 AND GLN-534 INS. RX PubMed=38848361; DOI=10.1126/sciadv.adn7191; RA Raimi O.G., Ojha H., Ehses K., Dederer V., Lange S.M., Rivera C.P., RA Deegan T.D., Chen Y., Wightman M., Toth R., Labib K.P.M., Mathea S., RA Ranson N., Fernandez-Busnadiego R., Muqit M.M.K.; RT "Mechanism of human PINK1 activation at the TOM complex in a reconstituted RT system."; RL Sci. Adv. 10:Eadn7191-Eadn7191(2024). RN [40] {ECO:0007744|PDB:9EIH, ECO:0007744|PDB:9EII, ECO:0007744|PDB:9EIJ} RP STRUCTURE BY ELECTRON MICROSCOPY (2.75 ANGSTROMS) IN COMPLEX WITH VDAC2 AND RP THE TOM COMPLEX, FUNCTION, INTERACTION WITH VDAC2 AND THE TOM COMPLEX, AND RP SUBCELLULAR LOCATION. RX PubMed=40080546; DOI=10.1126/science.adu6445; RA Callegari S., Kirk N.S., Gan Z.Y., Dite T., Cobbold S.A., Leis A., RA Dagley L.F., Glukhova A., Komander D.; RT "Structure of human PINK1 at a mitochondrial TOM-VDAC array."; RL Science 0:0-0(2025). RN [41] RP VARIANTS PARK6 PHE-92; PRO-168 AND HIS-464, AND VARIANTS LEU-296; THR-340; RP THR-442; LYS-476; THR-521 AND ASN-525. RX PubMed=15349860; DOI=10.1002/ana.20256; RA Valente E.M., Salvi S., Ialongo T., Marongiu R., Elia A.E., Caputo V., RA Romito L., Albanese A., Dallapiccola B., Bentivoglio A.R.; RT "PINK1 mutations are associated with sporadic early-onset parkinsonism."; RL Ann. Neurol. 56:336-341(2004). RN [42] RP VARIANTS PARK6 GLN-271; PRO-347 AND GLY-417. RX PubMed=15349870; DOI=10.1002/ana.20251; RA Hatano Y., Li Y., Sato K., Asakawa S., Yamamura Y., Tomiyama H., RA Yoshino H., Asahina M., Kobayashi S., Hassin-Baer S., Lu C.-S., Ng A.R., RA Rosales R.L., Shimizu N., Toda T., Mizuno Y., Hattori N.; RT "Novel PINK1 mutations in early-onset parkinsonism."; RL Ann. Neurol. 56:424-427(2004). RN [43] RP ERRATUM OF PUBMED:15349870. RA Hatano Y., Li Y., Sato K., Asakawa S., Yamamura Y., Tomiyama H., RA Yoshino H., Asahina M., Kobayashi S., Hassin-Baer S., Lu C.-S., Ng A.R., RA Rosales R.L., Shimizu N., Toda T., Mizuno Y., Hattori N.; RL Ann. Neurol. 56:603-603(2004). RN [44] RP VARIANTS PARK6 LYS-240; PRO-347 AND PRO-489, AND VARIANTS GLY-231; ILE-235; RP GLY-263; LEU-318; THR-339; THR-340; HIS-362; SER-425; LYS-476 AND THR-521. RX PubMed=15596610; DOI=10.1001/archneur.61.12.1898; RA Rogaeva E., Johnson J., Lang A.E., Gulick C., Gwinn-Hardy K., Kawarai T., RA Sato C., Morgan A., Werner J., Nussbaum R., Petit A., Okun M.S., RA McInerney A., Mandel R., Groen J.L., Fernandez H.H., Postuma R., RA Foote K.D., Salehi-Rad S., Liang Y., Reimsnider S., Tandon A., Hardy J., RA St George-Hyslop P., Singleton A.B.; RT "Analysis of the PINK1 gene in a large cohort of cases with Parkinson RT disease."; RL Arch. Neurol. 61:1898-1904(2004). RN [45] RP VARIANT PARK6 HIS-147. RX PubMed=15505171; DOI=10.1212/01.wnl.0000142089.38301.8e; RA Healy D.G., Abou-Sleiman P.M., Gibson J.M., Ross O.A., Jain S., Gandhi S., RA Gosal D., Muqit M.M.K., Wood N.W., Lynch T.; RT "PINK1 (PARK6) associated Parkinson disease in Ireland."; RL Neurology 63:1486-1488(2004). RN [46] RP VARIANT PARK6 ASP-309, CHARACTERIZATION OF VARIANT PARK6 ASP-309, FUNCTION, RP AND SUBCELLULAR LOCATION. RX PubMed=15087508; DOI=10.1126/science.1096284; RA Valente E.M., Abou-Sleiman P.M., Caputo V., Muqit M.M.K., Harvey K., RA Gispert S., Ali Z., Del Turco D., Bentivoglio A.R., Healy D.G., RA Albanese A., Nussbaum R., Gonzalez-Maldonado R., Deller T., Salvi S., RA Cortelli P., Gilks W.P., Latchman D.S., Harvey R.J., Dallapiccola B., RA Auburger G., Wood N.W.; RT "Hereditary early-onset Parkinson's disease caused by mutations in PINK1."; RL Science 304:1158-1160(2004). RN [47] RP VARIANT PARK6 VAL-268. RX PubMed=16207217; DOI=10.1111/j.1399-0004.2005.00500.x; RA Tan E.K., Yew K., Chua E., Shen H., Jamora R.D., Lee E., Puong K.Y., RA Zhao Y., Pavanni R., Wong M.C., Puvan K., Yih Y., Tan L.C.S.; RT "Analysis of PINK1 in Asian patients with familial parkinsonism."; RL Clin. Genet. 68:468-470(2005). RN [48] RP VARIANTS PARK6 HIS-279 AND GLN-534 INS, AND VARIANT LEU-115. RX PubMed=15970950; DOI=10.1038/sj.ejhg.5201455; RA Klein C., Djarmati A., Hedrich K., Schaefer N., Scaglione C., Marchese R., RA Kock N., Schuele B., Hiller A., Lohnau T., Winkler S., Wiegers K., RA Hering R., Bauer P., Riess O., Abbruzzese G., Martinelli P., RA Pramstaller P.P.; RT "PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset RT parkinsonism."; RL Eur. J. Hum. Genet. 13:1086-1093(2005). RN [49] RP CHARACTERIZATION OF VARIANTS PARK6 PRO-168 AND ASP-309. RX PubMed=16207731; DOI=10.1093/hmg/ddi377; RA Silvestri L., Caputo V., Bellacchio E., Atorino L., Dallapiccola B., RA Valente E.M., Casari G.; RT "Mitochondrial import and enzymatic activity of PINK1 mutants associated to RT recessive parkinsonism."; RL Hum. Mol. Genet. 14:3477-3492(2005). RN [50] RP VARIANT PARK6 ARG-388. RX PubMed=15955953; DOI=10.1212/01.wnl.0000164009.36740.4e; RA Li Y., Tomiyama H., Sato K., Hatano Y., Yoshino H., Atsumi M., RA Kitaguchi M., Sasaki S., Kawaguchi S., Miyajima H., Toda T., Mizuno Y., RA Hattori N.; RT "Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset RT parkinsonism."; RL Neurology 64:1955-1957(2005). RN [51] RP VARIANTS PARK6 PRO-168 AND LEU-196, AND VARIANTS LEU-115; THR-340; LYS-476 RP AND THR-521. RX PubMed=16009891; DOI=10.1212/01.wnl.0000167546.39375.82; RG The Italian Parkinson genetics network; RA Bonifati V., Rohe C.F., Breedveld G.J., Fabrizio E., De Mari M., RA Tassorelli C., Tavella A., Marconi R., Nicholl D.J., Chien H.F., RA Fincati E., Abbruzzese G., Marini P., De Gaetano A., Horstink M.W., RA Maat-Kievit J.A., Sampaio C., Antonini A., Stocchi F., Montagna P., RA Toni V., Guidi M., Dalla Libera A., Tinazzi M., De Pandis F., Fabbrini G., RA Goldwurm S., de Klein A., Barbosa E., Lopiano L., Martignoni E., RA Lamberti P., Vanacore N., Meco G., Oostra B.A.; RT "Early-onset parkinsonism associated with PINK1 mutations: frequency, RT genotypes, and phenotypes."; RL Neurology 65:87-95(2005). RN [52] RP VARIANTS ILE-317; THR-339; THR-383; SER-411; HIS-431; SER-451; SER-461; RP LYS-476; PRO-501 AND ARG-575, AND CHARACTERIZATION OF VARIANTS HIS-431; RP SER-451; LYS-476; PRO-501 AND ARG-575. RX PubMed=16969854; DOI=10.1002/ana.20960; RA Abou-Sleiman P.M., Muqit M.M.K., McDonald N.Q., Yang Y.X., Gandhi S., RA Healy D.G., Harvey K., Harvey R.J., Deas E., Bhatia K., Quinn N., Lees A., RA Latchman D.S., Wood N.W.; RT "A heterozygous effect for PINK1 mutations in Parkinson's disease?"; RL Ann. Neurol. 60:414-419(2006). RN [53] RP VARIANT PARK6 ASP-217. RX PubMed=16966503; DOI=10.1001/archneur.63.9.1257; RA Leutenegger A.-L., Salih M.A.M., Ibanez P., Mukhtar M.M., Lesage S., RA Arabi A., Lohmann E., Duerr A., Ahmed A.E.M., Brice A.; RT "Juvenile-onset Parkinsonism as a result of the first mutation in the RT adenosine triphosphate orientation domain of PINK1."; RL Arch. Neurol. 63:1257-1261(2006). RN [54] RP VARIANT PARK6 MET-313. RX PubMed=17030667; DOI=10.1001/archneur.63.10.1483; RA Chishti M.A., Bohlega S., Ahmed M., Loualich A., Carroll P., Sato C., RA St George-Hyslop P., Westaway D., Rogaeva E.; RT "T313M PINK1 mutation in an extended highly consanguineous Saudi family RT with early-onset Parkinson disease."; RL Arch. Neurol. 63:1483-1485(2006). RN [55] RP VARIANTS PARK6 GLY-125; LYS-240; PRO-369; ALA-386 AND VAL-409. RX PubMed=16401616; DOI=10.1093/brain/awl005; RG The French Parkinson's disease genetics study group; RA Ibanez P., Lesage S., Lohmann E., Thobois S., De Michele G., Borg M., RA Agid Y., Durr A., Brice A.; RT "Mutational analysis of the PINK1 gene in early-onset parkinsonism in RT Europe and North Africa."; RL Brain 129:686-694(2006). RN [56] RP VARIANT LEU-399. RX PubMed=16632486; DOI=10.1093/hmg/ddl104; RA Tang B., Xiong H., Sun P., Zhang Y., Wang D., Hu Z., Zhu Z., Ma H., Pan Q., RA Xia J.-H., Xia K., Zhang Z.; RT "Association of PINK1 and DJ-1 confers digenic inheritance of early-onset RT Parkinson's disease."; RL Hum. Mol. Genet. 15:1816-1825(2006). RN [57] RP VARIANT PARK6 THR-280, AND VARIANTS THR-340 AND THR-521. RX PubMed=16482571; DOI=10.1002/mds.20810; RA Tan E.-K., Yew K., Chua E., Puvan K., Shen H., Lee E., Puong K.-Y., RA Zhao Y., Pavanni R., Wong M.-C., Jamora D., de Silva D., Moe K.-T., RA Woon F.-P., Yuen Y., Tan L.; RT "PINK1 mutations in sporadic early-onset Parkinson's disease."; RL Mov. Disord. 21:789-793(2006). RN [58] RP VARIANT PARK6 GLN-407, AND VARIANTS THR-340 AND THR-521. RX PubMed=16257123; DOI=10.1016/j.neulet.2005.10.005; RA Fung H.-C., Chen C.-M., Hardy J., Singleton A.B., Lee-Chen G.-J., Wu Y.-R.; RT "Analysis of the PINK1 gene in a cohort of patients with sporadic early- RT onset parkinsonism in Taiwan."; RL Neurosci. Lett. 394:33-36(2006). RN [59] RP VARIANTS [LARGE SCALE ANALYSIS] TRP-148; SER-196; LEU-209; LEU-215; RP THR-339; THR-340; ILE-341; PHE-377; THR-477 AND THR-521. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [60] RP VARIANTS PHE-67; PRO-68; TRP-98; SER-111; VAL-124; MET-145; ASN-186; RP ILE-257; VAL-268; GLN-276; LEU-296; ILE-317; LEU-322; THR-339; THR-383; RP VAL-395; THR-442; LYS-476; ASN-525 AND THR-537. RX PubMed=18330912; DOI=10.1002/humu.20719; RG The Italian PD study group; RA Marongiu R., Ferraris A., Ialongo T., Michiorri S., Soleti F., Ferrari F., RA Elia A.E., Ghezzi D., Albanese A., Altavista M.C., Antonini A., Barone P., RA Brusa L., Cortelli P., Martinelli P., Pellecchia M.T., Pezzoli G., RA Scaglione C., Stanzione P., Tinazzi M., Zecchinelli A., Zeviani M., RA Cassetta E., Garavaglia B., Dallapiccola B., Bentivoglio A.R., RA Valente E.M.; RT "PINK1 heterozygous rare variants: prevalence, significance and phenotypic RT spectrum."; RL Hum. Mutat. 29:565-565(2008). RN [61] RP VARIANT PARK6 PRO-126. RX PubMed=18286320; DOI=10.1007/s00415-008-0763-4; RA Prestel J., Gempel K., Hauser T.K., Schweitzer K., Prokisch H., Ahting U., RA Freudenstein D., Bueltmann E., Naegele T., Berg D., Klopstock T., RA Gasser T.; RT "Clinical and molecular characterisation of a Parkinson family with a novel RT PINK1 mutation."; RL J. Neurol. 255:643-648(2008). RN [62] RP VARIANTS PARK6 MET-313 AND 492-ARG--LYS-581 DEL. RX PubMed=18785233; DOI=10.1002/mds.22156; RA Guo J.F., Xiao B., Liao B., Zhang X.W., Nie L.L., Zhang Y.H., Shen L., RA Jiang H., Xia K., Pan Q., Yan X.X., Tang B.S.; RT "Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese RT patients with autosomal recessive early-onset Parkinsonism."; RL Mov. Disord. 23:2074-2079(2008). RN [63] RP VARIANT PARK6 LEU-52. RX PubMed=19351622; DOI=10.1136/jmg.2008.063917; RA Brooks J., Ding J., Simon-Sanchez J., Paisan-Ruiz C., Singleton A.B., RA Scholz S.W.; RT "Parkin and PINK1 mutations in early-onset Parkinson's disease: RT comprehensive screening in publicly available cases and control."; RL J. Med. Genet. 46:375-381(2009). RN [64] RP VARIANT PARK6 PRO-347. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ- RT 1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). CC -!- FUNCTION: Serine/threonine-protein kinase which acts as a sensor of CC mitochondrial damage and protects against mitochondrial dysfunction CC during cellular stress (PubMed:40080546). It phosphorylates CC mitochondrial proteins to coordinate mitochondrial quality control CC mechanisms that remove and replace dysfunctional mitochondrial CC components (PubMed:14607334, PubMed:15087508, PubMed:18443288, CC PubMed:18957282, PubMed:19229105, PubMed:19966284, PubMed:20404107, CC PubMed:20547144, PubMed:20798600, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24751536, CC PubMed:24784582, PubMed:24896179, PubMed:24898855, PubMed:25527291, CC PubMed:32484300). In healthy mitochondria, PINK1 is translocated across CC the mitochondrial outer membrane (MOM) via the translocase of the outer CC membrane (TOM) complex, and inserted into the mitochondrial inner CC membrane (MIM) via the translocase of the inner membrane (TIM23) CC complex where it is cleaved and released into the cytosol CC (PubMed:40080546). Depending on the severity of mitochondrial damage, CC activity ranges from preventing apoptosis and stimulating mitochondrial CC biogenesis to eliminating severely damaged mitochondria via PINK1-PRKN- CC dependent mitophagy (PubMed:14607334, PubMed:15087508, PubMed:18443288, CC PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:22396657, CC PubMed:23620051, PubMed:23933751, PubMed:24898855, PubMed:32047033, CC PubMed:32484300). When cellular stress results in irreversible CC mitochondrial damage, PINK1 accumulates at the outer mitochondrial CC membrane (OMM) where it phosphorylates pre-existing polyubiquitin CC chains at 'Ser-65', recruits PRKN from the cytosol to the OMM and CC activates PRKN by phosphorylation at 'Ser-65'; activated PRKN then CC ubiquitinates VDAC1 and other OMM proteins to initiate mitophagy CC (PubMed:14607334, PubMed:15087508, PubMed:19966284, PubMed:20404107, CC PubMed:20798600, PubMed:23754282, PubMed:23933751, PubMed:24660806, CC PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291, CC PubMed:32047033, PubMed:40080546). The PINK1-PRKN pathway also promotes CC fission of damaged mitochondria through phosphorylation and PRKN- CC dependent degradation of mitochondrial proteins involved in fission CC such as MFN2 (PubMed:18443288, PubMed:23620051, PubMed:24898855). This CC prevents the refusion of unhealthy mitochondria with the mitochondrial CC network or initiates mitochondrial fragmentation facilitating their CC later engulfment by autophagosomes (PubMed:18443288, PubMed:23620051). CC Also promotes mitochondrial fission independently of PRKN and ATG7- CC mediated mitophagy, via the phosphorylation and activation of DNM1L CC (PubMed:18443288, PubMed:32484300). Regulates motility of damaged CC mitochondria by promoting the ubiquitination and subsequent degradation CC of MIRO1 and MIRO2; in motor neurons, this likely inhibits CC mitochondrial intracellular anterograde transport along the axons which CC probably increases the chance of the mitochondria undergoing mitophagy CC in the soma (PubMed:22396657). Required for ubiquinone reduction by CC mitochondrial complex I by mediating phosphorylation of complex I CC subunit NDUFA10 (By similarity). Phosphorylates LETM1, positively CC regulating its mitochondrial calcium transport activity CC (PubMed:29123128). {ECO:0000250|UniProtKB:Q99MQ3, CC ECO:0000269|PubMed:14607334, ECO:0000269|PubMed:15087508, CC ECO:0000269|PubMed:18443288, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20547144, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23754282, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:24898855, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:29123128, ECO:0000269|PubMed:32047033, CC ECO:0000269|PubMed:32484300, ECO:0000269|PubMed:40080546}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:32484300}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:29123128, ECO:0000269|PubMed:32484300}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC -!- SUBUNIT: Upon mitochondrial depolarization, associates with the TOM CC complex and the VDAC2 homodimer; its import into the mitochondria is CC stalled at the TOM complex (PubMed:40080546). Upon mitochondrial CC depolarization, interacts with TIMM23 (PubMed:38416681). Forms a CC supercomplex with TOM and TIM23 complexes; PINK1-TOM-TIM23 supercomplex CC formation requires PINK1 interaction with TOMM20 and TOMM70 CC (PubMed:38416681). The interaction with TOM and TIM23 complexes is CC critical for PINK1 stabilization at the outer mitochondrial membrane, CC kinase activation and downstream mitophagy (PubMed:35391620, CC PubMed:38416681, PubMed:38848361, PubMed:40080546). Interacts with PRKN CC (PubMed:19966284, PubMed:20798600). Interacts with FBXO7 CC (PubMed:23933751). Forms a complex with PRKN and PARK7 CC (PubMed:19229105). Interacts with NENF (PubMed:31536960). CC {ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:31536960, ECO:0000269|PubMed:35391620, CC ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38416681, CC ECO:0000269|PubMed:38848361, ECO:0000269|PubMed:40080546}. CC -!- INTERACTION: CC Q9BXM7; P63010-2: AP2B1; NbExp=3; IntAct=EBI-2846068, EBI-11529439; CC Q9BXM7; P05067: APP; NbExp=3; IntAct=EBI-2846068, EBI-77613; CC Q9BXM7; O15392: BIRC5; NbExp=3; IntAct=EBI-2846068, EBI-518823; CC Q9BXM7; Q9Y3I1: FBXO7; NbExp=8; IntAct=EBI-2846068, EBI-1161222; CC Q9BXM7; Q9Y3I1-1: FBXO7; NbExp=2; IntAct=EBI-2846068, EBI-9102965; CC Q9BXM7; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-2846068, EBI-396453; CC Q9BXM7; P08238: HSP90AB1; NbExp=3; IntAct=EBI-2846068, EBI-352572; CC Q9BXM7; P42858: HTT; NbExp=9; IntAct=EBI-2846068, EBI-466029; CC Q9BXM7; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-2846068, EBI-21911304; CC Q9BXM7; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-2846068, EBI-1108377; CC Q9BXM7; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-2846068, EBI-373144; CC Q9BXM7; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-2846068, EBI-716063; CC Q9BXM7; P00491: PNP; NbExp=3; IntAct=EBI-2846068, EBI-712238; CC Q9BXM7; O60260: PRKN; NbExp=7; IntAct=EBI-2846068, EBI-716346; CC Q9BXM7; Q8IXI2: RHOT1; NbExp=3; IntAct=EBI-2846068, EBI-1396430; CC Q9BXM7; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-2846068, EBI-3942425; CC Q9BXM7; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-2846068, EBI-11959123; CC Q9BXM7; P28347-2: TEAD1; NbExp=3; IntAct=EBI-2846068, EBI-12151837; CC Q9BXM7; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-2846068, EBI-11141397; CC Q9BXM7; Q8N895: ZNF366; NbExp=3; IntAct=EBI-2846068, EBI-2813661; CC Q9BXM7-1; O60260: PRKN; NbExp=2; IntAct=EBI-15643376, EBI-716346; CC Q9BXM7-1; Q12931: TRAP1; NbExp=4; IntAct=EBI-15643376, EBI-1055869; CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane CC {ECO:0000269|PubMed:15087508, ECO:0000269|PubMed:16672980, CC ECO:0000269|PubMed:18687899, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20798600, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:31536960}. CC Mitochondrion inner membrane {ECO:0000250|UniProtKB:Q99MQ3}. Cytoplasm, CC cytosol {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22354088}. CC Note=Localizes mostly in mitochondrion and the two smaller proteolytic CC processed fragments localize mainly in cytosol (PubMed:19229105). In CC healthy mitochondria, PINK1 is translocated across the mitochondrial CC membranes (PubMed:40080546). Upon mitochondrial membrane depolarization CC following damage, PINK1 import is stalled, which induces its CC accumulation in the outer mitochondrial membrane and the activation of CC its kinase activity (PubMed:18957282, PubMed:40080546). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:40080546}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1 {ECO:0000269|PubMed:14607334}; CC IsoId=Q9BXM7-1; Sequence=Displayed; CC Name=2 {ECO:0000305}; CC IsoId=Q9BXM7-2; Sequence=VSP_050754, VSP_050755; CC -!- TISSUE SPECIFICITY: Highly expressed in heart, skeletal muscle and CC testis, and at lower levels in brain, placenta, liver, kidney, CC pancreas, prostate, ovary and small intestine. Present in the embryonic CC testis from an early stage of development. CC {ECO:0000269|PubMed:11494141}. CC -!- PTM: Proteolytically cleaved (PubMed:19229105, PubMed:22354088, CC PubMed:30733118). In healthy cells, the precursor is continuously CC imported into the inner mitochondrial membrane (IMM), where it is CC proteolytically cleaved by mitochondrial-processing peptidase (MPP) and CC then undergoes further proteolytic cleavage by PARL or AFG3L2 to give CC rise to the 52 kDa short form (PubMed:19229105, PubMed:22354088). The CC 52 kDa short form is then released into the cytosol where it rapidly CC undergoes proteasome-dependent degradation (PubMed:20404107). In CC unhealthy cells, when cellular stress conditions lead to the loss of CC mitochondrial membrane potential, mitochondrial import is impaired CC leading to the precursor accumulating on the outer mitochondrial CC membrane (OMM) (PubMed:20404107, PubMed:30733118). If accumulation at CC the OMM fails and it is imported into the depolarized mitochondria, it CC undergoes cleavage by the IMM protease OMA1, promoting its subsequent CC degradation by the proteasome (PubMed:30733118). CC {ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:30733118}. CC -!- PTM: Autophosphorylated (PubMed:18957282, PubMed:20404107, CC PubMed:22910362). Loss of mitochondrial membrane potential results in CC the precursor accumulating on the outer mitochondrial membrane (OMM) CC where it is activated by autophosphorylation (PubMed:18957282, CC PubMed:20404107, PubMed:22910362). Autophosphorylation at Ser-228 and CC Ser-402 is sufficient and essential for selective recruitment of PRKN CC to depolarized mitochondria, via PINK1-dependent phosphorylation of CC ubiquitin and maybe PRKN (PubMed:18957282, PubMed:22910362). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:22910362}. CC -!- DISEASE: Parkinson disease 6 (PARK6) [MIM:605909]: An early-onset form CC of Parkinson disease, a neurodegenerative disorder characterized by CC parkinsonian signs such as rigidity, resting tremor and bradykinesia. A CC subset of patients manifest additional symptoms including CC hyperreflexia, autonomic instability, dementia and psychiatric CC disturbances. Symptoms show diurnal fluctuation and can improve after CC sleep. PARK6 pathogenesis involves respiratory complex I deficiency CC causing mitochondrial depolarization and dysfunction. Inheritance is CC autosomal recessive. {ECO:0000269|PubMed:15087508, CC ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15349870, CC ECO:0000269|PubMed:15505171, ECO:0000269|PubMed:15596610, CC ECO:0000269|PubMed:15955953, ECO:0000269|PubMed:15970950, CC ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16207217, CC ECO:0000269|PubMed:16207731, ECO:0000269|PubMed:16257123, CC ECO:0000269|PubMed:16401616, ECO:0000269|PubMed:16482571, CC ECO:0000269|PubMed:16632486, ECO:0000269|PubMed:16966503, CC ECO:0000269|PubMed:17030667, ECO:0000269|PubMed:18286320, CC ECO:0000269|PubMed:18785233, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19351622, ECO:0000269|PubMed:20547144, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22043288, CC ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:22956510, CC ECO:0000269|PubMed:24652937, ECO:0000269|PubMed:24784582}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}. 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; AB053323; BAB55647.1; -; mRNA. DR EMBL; AF316873; AAK28062.1; -; mRNA. DR EMBL; AK075225; BAC11484.1; -; mRNA. DR EMBL; AL391357; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC009534; AAH09534.1; -; mRNA. DR EMBL; BC028215; AAH28215.1; -; mRNA. DR CCDS; CCDS211.1; -. [Q9BXM7-1] DR RefSeq; NP_115785.1; NM_032409.3. [Q9BXM7-1] DR PDB; 9EIH; EM; 3.10 A; A/B=1-581. DR PDB; 9EII; EM; 2.75 A; B=1-581. DR PDB; 9EIJ; EM; 3.30 A; B=1-581. DR PDBsum; 9EIH; -. DR PDBsum; 9EII; -. DR PDBsum; 9EIJ; -. DR AlphaFoldDB; Q9BXM7; -. DR EMDB; EMD-48083; -. DR EMDB; EMD-48084; -. DR EMDB; EMD-48085; -. DR SMR; Q9BXM7; -. DR BioGRID; 122376; 696. DR CORUM; Q9BXM7; -. DR DIP; DIP-29427N; -. DR FunCoup; Q9BXM7; 1190. DR IntAct; Q9BXM7; 177. DR MINT; Q9BXM7; -. DR STRING; 9606.ENSP00000364204; -. DR ChEMBL; CHEMBL3337330; -. DR TCDB; 8.A.104.1.16; the 5'-amp-activated protein kinase (ampk) family. DR CarbonylDB; Q9BXM7; -. DR GlyGen; Q9BXM7; 3 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q9BXM7; -. DR PhosphoSitePlus; Q9BXM7; -. DR BioMuta; PINK1; -. DR DMDM; 48428484; -. DR MassIVE; Q9BXM7; -. DR PaxDb; 9606-ENSP00000364204; -. DR PeptideAtlas; Q9BXM7; -. DR ProteomicsDB; 79455; -. [Q9BXM7-1] DR ProteomicsDB; 79456; -. [Q9BXM7-2] DR ABCD; Q9BXM7; 4 sequenced antibodies. DR Antibodypedia; 1105; 806 antibodies from 48 providers. DR DNASU; 65018; -. DR Ensembl; ENST00000321556.5; ENSP00000364204.3; ENSG00000158828.9. [Q9BXM7-1] DR GeneID; 65018; -. DR KEGG; hsa:65018; -. DR MANE-Select; ENST00000321556.5; ENSP00000364204.3; NM_032409.3; NP_115785.1. DR UCSC; uc001bdm.3; human. [Q9BXM7-1] DR AGR; HGNC:14581; -. DR ClinPGx; PA33325; -. DR CTD; 65018; -. DR DisGeNET; 65018; -. DR GeneCards; PINK1; -. DR GeneReviews; PINK1; -. DR HGNC; HGNC:14581; PINK1. DR HPA; ENSG00000158828; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; PINK1; -. DR MIM; 168600; phenotype. DR MIM; 605909; phenotype. DR MIM; 608309; gene. DR OpenTargets; ENSG00000158828; -. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000158828; -. DR eggNOG; KOG4158; Eukaryota. DR GeneTree; ENSGT00390000001206; -. DR HOGENOM; CLU_022208_1_0_1; -. DR InParanoid; Q9BXM7; -. DR OMA; TCCSLRN; -. DR OrthoDB; 1405469at2759; -. DR PAN-GO; Q9BXM7; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q9BXM7; -. DR PathwayCommons; Q9BXM7; -. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-9614657; FOXO-mediated transcription of cell death genes. DR SignaLink; Q9BXM7; -. DR SIGNOR; Q9BXM7; -. DR Agora; ENSG00000158828; -. DR BioGRID-ORCS; 65018; 17 hits in 1195 CRISPR screens. DR ChiTaRS; PINK1; human. DR GeneWiki; PINK1; -. DR GenomeRNAi; 65018; -. DR Pharos; Q9BXM7; Tbio. DR PRO; PR:Q9BXM7; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9BXM7; protein. DR Bgee; ENSG00000158828; Expressed in tendon of biceps brachii and 210 other cell types or tissues. DR GO; GO:0097449; C:astrocyte projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0030424; C:axon; IDA:ParkinsonsUK-UCL. DR GO; GO:0044297; C:cell body; IDA:ParkinsonsUK-UCL. DR GO; GO:0000785; C:chromatin; IDA:ParkinsonsUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0005856; C:cytoskeleton; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0030426; C:growth cone; IEA:Ensembl. DR GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0055131; F:C3HC4-type RING finger domain binding; IPI:BHF-UCL. DR GO; GO:0016301; F:kinase activity; IDA:MGI. DR GO; GO:0019900; F:kinase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0016504; F:peptidase activator activity; TAS:ParkinsonsUK-UCL. DR GO; GO:0002020; F:protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB. DR GO; GO:0043422; F:protein kinase B binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0106310; F:protein serine kinase activity; IMP:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IMP:ParkinsonsUK-UCL. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; IMP:UniProtKB. DR GO; GO:1904881; P:cellular response to hydrogen sulfide; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IMP:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0097237; P:cellular response to toxic substance; TAS:ParkinsonsUK-UCL. DR GO; GO:0014046; P:dopamine secretion; IEA:Ensembl. DR GO; GO:0072655; P:establishment of protein localization to mitochondrion; IMP:UniProtKB. DR GO; GO:0030097; P:hemopoiesis; IGI:ARUK-UCL. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0016236; P:macroautophagy; TAS:Reactome. DR GO; GO:0072656; P:maintenance of protein location in mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0007005; P:mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0099074; P:mitochondrion to lysosome vesicle-mediated transport; IMP:ParkinsonsUK-UCL. DR GO; GO:0000423; P:mitophagy; IDA:UniProt. DR GO; GO:1902902; P:negative regulation of autophagosome assembly; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:ParkinsonsUK-UCL. DR GO; GO:1903384; P:negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903298; P:negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; IDA:UniProtKB. DR GO; GO:1903751; P:negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide; IDA:ParkinsonsUK-UCL. DR GO; GO:0046329; P:negative regulation of JNK cascade; TAS:ParkinsonsUK-UCL. DR GO; GO:0016242; P:negative regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IMP:ParkinsonsUK-UCL. DR GO; GO:1901525; P:negative regulation of mitophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:ParkinsonsUK-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:ParkinsonsUK-UCL. DR GO; GO:1903852; P:positive regulation of cristae formation; IMP:ParkinsonsUK-UCL. DR GO; GO:0033603; P:positive regulation of dopamine secretion; IEA:Ensembl. DR GO; GO:1904544; P:positive regulation of free ubiquitin chain polymerization; ISS:ParkinsonsUK-UCL. DR GO; GO:0016239; P:positive regulation of macroautophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:1902958; P:positive regulation of mitochondrial electron transport, NADH to ubiquinone; TAS:ParkinsonsUK-UCL. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; IBA:GO_Central. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISS:ParkinsonsUK-UCL. DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IMP:BHF-UCL. DR GO; GO:0032226; P:positive regulation of synaptic transmission, dopaminergic; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0045727; P:positive regulation of translation; IEA:Ensembl. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0010310; P:regulation of hydrogen peroxide metabolic process; IEA:Ensembl. DR GO; GO:0051881; P:regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IMP:ParkinsonsUK-UCL. DR GO; GO:0002082; P:regulation of oxidative phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; NAS:ParkinsonsUK-UCL. DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0031396; P:regulation of protein ubiquitination; IDA:BHF-UCL. DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:BHF-UCL. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0022904; P:respiratory electron transport chain; IEA:Ensembl. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IGI:ParkinsonsUK-UCL. DR GO; GO:0038203; P:TORC2 signaling; IDA:ParkinsonsUK-UCL. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL. DR CDD; cd14018; STKc_PINK1; 1. DR FunFam; 1.10.510.10:FF:000418; PTEN induced kinase 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR051511; MitoQC_Scaffold_Kinases. DR InterPro; IPR040110; PINK1_STKc. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR22972; SERINE/THREONINE PROTEIN KINASE; 1. DR PANTHER; PTHR22972:SF7; SERINE_THREONINE-PROTEIN KINASE PINK1, MITOCHONDRIAL; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Autophagy; Cytoplasm; KW Disease variant; Kinase; Magnesium; Membrane; Metal-binding; Mitochondrion; KW Mitochondrion inner membrane; Mitochondrion outer membrane; KW Neurodegeneration; Nucleotide-binding; Parkinson disease; Parkinsonism; KW Phosphoprotein; Primary mitochondrial disease; Proteomics identification; KW Reference proteome; Serine/threonine-protein kinase; Transferase; KW Transit peptide. FT TRANSIT 1..77 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 78..581 FT /note="Serine/threonine-protein kinase PINK1, FT mitochondrial" FT /id="PRO_0000024369" FT DOMAIN 156..511 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000305" FT REGION 111..117 FT /note="Required for outer membrane localization; this FT region is trapped in the TOM complex upon mitochondrial FT depolarization" FT /evidence="ECO:0000269|PubMed:30733118, FT ECO:0000269|PubMed:40080546" FT REGION 189..208 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 362 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 162..170 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q02750, FT ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 186 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 228 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:22910362" FT MOD_RES 402 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:22910362" FT VAR_SEQ 1..307 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050754" FT VAR_SEQ 308..320 FT /note="LGHGRTLFLVMKN -> MCGSQRPSPLSTS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050755" FT VARIANT 52 FT /note="P -> L (in PARK6; uncertain significance; no effect FT on interaction with TIMM23; dbSNP:rs776293086)" FT /evidence="ECO:0000269|PubMed:19351622, FT ECO:0000269|PubMed:37160114" FT /id="VAR_089730" FT VARIANT 67 FT /note="L -> F (no effect on interaction with TIMM23; FT dbSNP:rs763142730)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046566" FT VARIANT 68 FT /note="R -> P (no effect on interaction with TIMM23; FT dbSNP:rs1385309950)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046567" FT VARIANT 78 FT /note="A -> V (severely decreased interaction with TIMM23; FT dbSNP:rs1409111496)" FT /evidence="ECO:0000269|PubMed:37160114" FT /id="VAR_089731" FT VARIANT 92 FT /note="C -> F (in PARK6; uncertain significance; no effect FT on interaction with TIMM23; dbSNP:rs1553145550)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046568" FT VARIANT 98 FT /note="R -> W (severely decreased interaction with TIMM23; FT dbSNP:rs575668171)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046569" FT VARIANT 111 FT /note="I -> S (found in a patient with Parkinson disease; FT uncertain significance; under depolarizing conditions, it FT fails to support PINK1-TOM-TIM23 complex assembly and FT mitophagy activation; no effect on interaction with TIMM23; FT dbSNP:rs1553145560)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38416681" FT /id="VAR_046570" FT VARIANT 115 FT /note="Q -> L (under depolarizing conditions, does not FT affect PINK1-TOM-TIM23 complex assembly and mitophagy FT activation; no effect on interaction with TIMM23; FT dbSNP:rs148871409)" FT /evidence="ECO:0000269|PubMed:15970950, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:37160114, FT ECO:0000269|PubMed:38416681" FT /id="VAR_046571" FT VARIANT 124 FT /note="A -> V (no effect on interaction with TIMM23; FT dbSNP:rs1274588239)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046572" FT VARIANT 125 FT /note="C -> G (in PARK6; under depolarizing conditions, it FT fails to support PINK1-TOM-TIM23 complex assembly and FT mitophagy activation; no effect on interaction with FT TIMM23)" FT /evidence="ECO:0000269|PubMed:16401616, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38416681" FT /id="VAR_062773" FT VARIANT 126 FT /note="Q -> P (in PARK6; strongly reduces interaction with FT PRKN; under depolarizing conditions, it fails to support FT PINK1-TOM-TIM23 complex assembly and mitophagy activation; FT loss of autophosphorylation on S-228 and kinase activation; FT no effect on interaction with TIMM23; dbSNP:rs775809722)" FT /evidence="ECO:0000269|PubMed:18286320, FT ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:37160114, FT ECO:0000269|PubMed:38416681, ECO:0000269|PubMed:38848361" FT /id="VAR_064344" FT VARIANT 145 FT /note="T -> M (no effect on interaction with TIMM23; FT dbSNP:rs45604240)" FT /evidence="ECO:0000269|PubMed:18330912, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046573" FT VARIANT 147 FT /note="R -> H (in PARK6; uncertain significance; no effect FT on interaction with TIMM23; dbSNP:rs138050841)" FT /evidence="ECO:0000269|PubMed:15505171, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046574" FT VARIANT 148 FT /note="L -> W (no effect on interaction with TIMM23; FT dbSNP:rs56297806)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:37160114" FT /id="VAR_041010" FT VARIANT 168 FT /note="A -> P (in PARK6; no effect on autophosphorylation; FT localizes to the mitochondria and immunogold experiments FT reveal that both wild-type and mutant proteins face the FT mitochondrial intermembrane space; no effect on interaction FT with TIMM23; dbSNP:rs768091663)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16207731, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:37160114" FT /id="VAR_046575" FT VARIANT 170 FT /note="V -> G (in PARK6; dbSNP:rs1553145929)" FT /evidence="ECO:0000269|PubMed:24652937" FT /id="VAR_078934" FT VARIANT 186 FT /note="K -> N (in dbSNP:rs143204084)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046576" FT VARIANT 196 FT /note="P -> L (in PARK6; dbSNP:rs138302371)" FT /evidence="ECO:0000269|PubMed:16009891" FT /id="VAR_046577" FT VARIANT 196 FT /note="P -> S (in dbSNP:rs35802484)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041011" FT VARIANT 209 FT /note="P -> L (in dbSNP:rs34677717)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041012" FT VARIANT 215 FT /note="P -> L (in a glioblastoma multiforme sample; somatic FT mutation; dbSNP:rs371854396)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041013" FT VARIANT 217 FT /note="A -> D (in PARK6; dbSNP:rs74315360)" FT /evidence="ECO:0000269|PubMed:16966503" FT /id="VAR_046578" FT VARIANT 231 FT /note="E -> G (in dbSNP:rs1303935100)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046579" FT VARIANT 235 FT /note="N -> I (in dbSNP:rs1557562082)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046580" FT VARIANT 240 FT /note="E -> K (in PARK6; loss of autophosphorylation on S- FT 228 and kinase activation; no effect on interaction with FT TIMM23; dbSNP:rs573931674)" FT /evidence="ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16401616, ECO:0000269|PubMed:37160114, FT ECO:0000269|PubMed:38848361" FT /id="VAR_046581" FT VARIANT 257 FT /note="T -> I (in dbSNP:rs370906995)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046582" FT VARIANT 263 FT /note="R -> G (in dbSNP:rs1553146419)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046583" FT VARIANT 268 FT /note="L -> V (in PARK6; dbSNP:rs372280083)" FT /evidence="ECO:0000269|PubMed:16207217, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046584" FT VARIANT 271 FT /note="H -> Q (in PARK6; no effect on interaction with FT TIMM23; dbSNP:rs28940284)" FT /evidence="ECO:0000269|PubMed:15349870, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046585" FT VARIANT 276 FT /note="R -> Q (in dbSNP:rs548506734)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046586" FT VARIANT 279 FT /note="R -> H (in PARK6; dbSNP:rs74315358)" FT /evidence="ECO:0000269|PubMed:15970950" FT /id="VAR_046587" FT VARIANT 280 FT /note="A -> T (in PARK6; dbSNP:rs772510148)" FT /evidence="ECO:0000269|PubMed:16482571" FT /id="VAR_062774" FT VARIANT 296 FT /note="P -> L (in dbSNP:rs779060308)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046588" FT VARIANT 305 FT /note="P -> L (in dbSNP:rs7349186)" FT /id="VAR_018993" FT VARIANT 309 FT /note="G -> D (in PARK6; affects cellular response to FT stress resulting in increased mitochondrial depolarization FT under stress conditions compared to wild type; has no FT effect on autophosphorylation; strongly reduces interaction FT with PRKN; decreases PRKN and SNCAIP ubiquitination and FT degradation; decreases Drp1 phosphorylation; loss of FT ubiquitin phosphorylation; no effect on interaction with FT TIMM23; dbSNP:rs74315355)" FT /evidence="ECO:0000269|PubMed:15087508, FT ECO:0000269|PubMed:16207731, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:32484300, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38848361" FT /id="VAR_018994" FT VARIANT 313 FT /note="T -> M (in PARK6; decreases PRKN and SNCAIP FT ubiquitination and degradation; slightly decreases Drp1 FT phosphorylation; dbSNP:rs74315359)" FT /evidence="ECO:0000269|PubMed:17030667, FT ECO:0000269|PubMed:18785233, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:32484300" FT /id="VAR_046589" FT VARIANT 317 FT /note="V -> I (in dbSNP:rs200949139)" FT /evidence="ECO:0000269|PubMed:16969854, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046590" FT VARIANT 318 FT /note="M -> L (in dbSNP:rs139226733)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046591" FT VARIANT 322 FT /note="P -> L (in dbSNP:rs768019187)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046592" FT VARIANT 339 FT /note="A -> T (in dbSNP:rs55831733)" FT /evidence="ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16969854, ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:18330912" FT /id="VAR_041014" FT VARIANT 340 FT /note="A -> T (in dbSNP:rs3738136)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16257123, FT ECO:0000269|PubMed:16482571, ECO:0000269|PubMed:17344846" FT /id="VAR_018995" FT VARIANT 341 FT /note="M -> I (in dbSNP:rs35813094)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041015" FT VARIANT 347 FT /note="L -> P (in PARK6; strongly reduces interaction with FT PRKN; reduced ubiquitination of MIRO1; severely decreased FT interaction with TIMM23; dbSNP:rs28940285)" FT /evidence="ECO:0000269|PubMed:15349870, FT ECO:0000269|PubMed:15596610, ECO:0000269|PubMed:20798600, FT ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046593" FT VARIANT 362 FT /note="D -> H" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046594" FT VARIANT 369 FT /note="L -> P (in PARK6; dbSNP:rs1195888869)" FT /evidence="ECO:0000269|PubMed:16401616" FT /id="VAR_062775" FT VARIANT 377 FT /note="C -> F (in dbSNP:rs34203620)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041016" FT VARIANT 383 FT /note="A -> T (in dbSNP:rs45515602)" FT /evidence="ECO:0000269|PubMed:16969854, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046595" FT VARIANT 386 FT /note="G -> A (in PARK6; abolishes kinase activity; no FT effect on interaction with TIMM23)" FT /evidence="ECO:0000269|PubMed:16401616, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:37160114" FT /id="VAR_062776" FT VARIANT 388 FT /note="C -> R (in PARK6; dbSNP:rs1553146806)" FT /evidence="ECO:0000269|PubMed:15955953" FT /id="VAR_046596" FT VARIANT 395 FT /note="G -> V (in dbSNP:rs1035071310)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046597" FT VARIANT 399 FT /note="P -> L (found in early-onset Parkinson disease with FT digenic inheritance; likely pathogenic; the patient also FT has mutation S-39 in PARK7; decreases PRKN and SNCAIP FT ubiquitination and degradation; dbSNP:rs119451946)" FT /evidence="ECO:0000269|PubMed:16632486, FT ECO:0000269|PubMed:19229105" FT /id="VAR_062777" FT VARIANT 407 FT /note="R -> Q (in PARK6; early-onset; dbSNP:rs556540177)" FT /evidence="ECO:0000269|PubMed:16257123" FT /id="VAR_062778" FT VARIANT 409 FT /note="G -> V (in PARK6; no effect on interaction with FT TIMM23; dbSNP:rs1553146818)" FT /evidence="ECO:0000269|PubMed:16401616, FT ECO:0000269|PubMed:37160114" FT /id="VAR_062779" FT VARIANT 411 FT /note="G -> S (in dbSNP:rs45478900)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046598" FT VARIANT 417 FT /note="E -> G (in PARK6; no effect on interaction with FT TIMM23; dbSNP:rs1553146822)" FT /evidence="ECO:0000269|PubMed:15349870, FT ECO:0000269|PubMed:37160114" FT /id="VAR_046599" FT VARIANT 425 FT /note="P -> S (in dbSNP:rs554114655)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046600" FT VARIANT 431 FT /note="Y -> H (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs74315361)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046601" FT VARIANT 442 FT /note="I -> T (in dbSNP:rs1553146877)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046602" FT VARIANT 451 FT /note="N -> S (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs747400197)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046603" FT VARIANT 456..581 FT /note="Missing (in PARK6)" FT /evidence="ECO:0000269|PubMed:24652937" FT /id="VAR_078935" FT VARIANT 461 FT /note="L -> S" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046604" FT VARIANT 464 FT /note="R -> H (in PARK6; dbSNP:rs764328076)" FT /evidence="ECO:0000269|PubMed:15349860" FT /id="VAR_046605" FT VARIANT 476 FT /note="E -> K (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs115477764)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:15596610, ECO:0000269|PubMed:16009891, FT ECO:0000269|PubMed:16969854, ECO:0000269|PubMed:18330912" FT /id="VAR_046606" FT VARIANT 477 FT /note="S -> T (in dbSNP:rs34416410)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041017" FT VARIANT 489 FT /note="L -> P (in PARK6; dbSNP:rs1553146903)" FT /evidence="ECO:0000269|PubMed:15596610" FT /id="VAR_046607" FT VARIANT 492..581 FT /note="Missing (in PARK6; mitochondria are deformed and FT dysfunctional with decreased mitochondrial membrane FT potential; shows increased apoptosis; increased oxidative FT stress; decreased phosphorylation of DNM1L and Drp1; FT dbSNP:rs34208370)" FT /evidence="ECO:0000269|PubMed:18785233, FT ECO:0000269|PubMed:20547144, ECO:0000269|PubMed:32484300" FT /id="VAR_084338" FT VARIANT 501 FT /note="R -> P (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs61744200)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046608" FT VARIANT 521 FT /note="N -> T (in dbSNP:rs1043424)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15596610, FT ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16257123, FT ECO:0000269|PubMed:16482571, ECO:0000269|PubMed:17344846" FT /id="VAR_018996" FT VARIANT 525 FT /note="D -> N (in dbSNP:rs531477772)" FT /evidence="ECO:0000269|PubMed:15349860, FT ECO:0000269|PubMed:18330912" FT /id="VAR_046609" FT VARIANT 534 FT /note="Q -> QQ (in PARK6; loss of autophosphorylation on S- FT 228 and kinase activation; no effect on interaction with FT TIMM23)" FT /evidence="ECO:0000269|PubMed:15970950, FT ECO:0000269|PubMed:37160114, ECO:0000269|PubMed:38848361" FT /id="VAR_046610" FT VARIANT 537 FT /note="A -> T (in dbSNP:rs771032673)" FT /evidence="ECO:0000269|PubMed:18330912" FT /id="VAR_046611" FT VARIANT 575 FT /note="C -> R (may predispose to Parkinson disease FT development; affects cellular response to stress resulting FT in increased mitochondrial depolarization under stress FT conditions compared to wild type; dbSNP:rs1553147052)" FT /evidence="ECO:0000269|PubMed:16969854" FT /id="VAR_046612" FT MUTAGEN 112..117 FT /note="EEKQAE->AAKQAA: In 3EA; impaired ability to localize FT to the outer mitochondrial membrane." FT /evidence="ECO:0000269|PubMed:30733118" FT MUTAGEN 131 FT /note="I->E: Under depolarizing conditions, it results in FT loss of interaction with TOMM20 and fails to support PINK1- FT TOM-TIM23 complex assembly and mitophagy activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 219 FT /note="K->A: Abolishes MFN2 phosphorylation and interaction FT with PRKN; when associated with Ala-362 and Ala-384." FT /evidence="ECO:0000269|PubMed:23620051" FT MUTAGEN 219 FT /note="K->M: Loss of enzyme activity and impaired FT localization of PRKN to mitochondria; when associated with FT A-362 and A-384." FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:32047033" FT MUTAGEN 362 FT /note="D->A: Abolishes MFN2 phosphorylation and interaction FT with PRKN; when associated with A-219 and A-384. Loss of FT enzyme activity and impaired localization of PRKN to FT mitochondria; when associated with M-219 and A-384." FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033" FT MUTAGEN 384 FT /note="D->A: Abolishes MFN2 phosphorylation and interaction FT with PRKN; when associated with A-219 and A-362. Loss of FT enzyme activity and impaired localization of PRKN to FT mitochondria; when associated with M-219 and A-362." FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033" FT MUTAGEN 384 FT /note="D->N: Loss of activity. Abolishes Drp1 FT phosphorylation. No effect on localization to FT mitochondria." FT /evidence="ECO:0000269|PubMed:32484300" FT MUTAGEN 532 FT /note="L->A: Under depolarizing conditions, it results in FT severely reduced autophosphorylation on S-228 and loss of FT kinase activation." FT /evidence="ECO:0000269|PubMed:38848361" FT MUTAGEN 536 FT /note="A->E: Under depolarizing conditions, it results in FT loss of interaction with TOMM20 and fails to support PINK1- FT TOM-TIM23 complex assembly and mitophagy activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 536 FT /note="A->S: Under depolarizing conditions, it fails to FT support PINK1-TOM-TIM23 complex assembly and mitophagy FT activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 539 FT /note="L->A: Under depolarizing conditions, it results in FT severely reduced autophosphorylation on S-228 and loss of FT kinase activation." FT /evidence="ECO:0000269|PubMed:38848361" FT MUTAGEN 540 FT /note="L->A: Under depolarizing conditions, does not affect FT autophosphorylation on S-228 and kinase activation." FT /evidence="ECO:0000269|PubMed:38848361" FT MUTAGEN 540 FT /note="L->K: Under depolarizing conditions, it results in FT loss of interaction with TOMM20 and fails to support PINK1- FT TOM-TIM23 complex assembly and mitophagy activation." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 543 FT /note="R->D: No effect on interaction with TOMM20 and FT mitophagy activation under depolarizing conditions." FT /evidence="ECO:0000269|PubMed:38416681" FT MUTAGEN 543 FT /note="R->G: Under depolarizing conditions, it fails to FT support PINK1-TOM-TIM23 complex assembly and mitophagy FT activation." FT /evidence="ECO:0000269|PubMed:38416681" FT CONFLICT 209 FT /note="P -> A (in Ref. 5; AAH28215)" FT /evidence="ECO:0000305" FT CONFLICT 419 FT /note="S -> P (in Ref. 3; BAC11484)" FT /evidence="ECO:0000305" FT HELIX 64..66 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 67..69 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 71..73 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 77..90 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 108..135 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 142..144 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 153..155 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 157..164 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 166..174 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 216..222 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 230..236 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 237..243 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 248..250 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 277..283 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 313..319 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 322..324 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 325..331 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 336..356 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 367..372 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 378..382 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 385..387 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 392..396 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 397..399 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 408..412 FT /evidence="ECO:0007829|PDB:9EIJ" FT HELIX 416..419 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 428..430 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 434..446 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 454..456 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 457..459 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 463..465 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 468..470 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 480..489 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 494..496 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 500..512 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 514..517 FT /evidence="ECO:0007829|PDB:9EII" FT STRAND 519..521 FT /evidence="ECO:0007829|PDB:9EIH" FT HELIX 524..544 FT /evidence="ECO:0007829|PDB:9EII" FT TURN 545..547 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 550..560 FT /evidence="ECO:0007829|PDB:9EII" FT HELIX 564..578 FT /evidence="ECO:0007829|PDB:9EII" SQ SEQUENCE 581 AA; 62769 MW; 721FE01F63263A64 CRC64; MAVRQALGRG LQLGRALLLR FTGKPGRAYG LGRPGPAAGC VRGERPGWAA GPGAEPRRVG LGLPNRLRFF RQSVAGLAAR LQRQFVVRAW GCAGPCGRAV FLAFGLGLGL IEEKQAESRR AVSACQEIQA IFTQKSKPGP DPLDTRRLQG FRLEEYLIGQ SIGKGCSAAV YEATMPTLPQ NLEVTKSTGL LPGRGPGTSA PGEGQERAPG APAFPLAIKM MWNISAGSSS EAILNTMSQE LVPASRVALA GEYGAVTYRK SKRGPKQLAP HPNIIRVLRA FTSSVPLLPG ALVDYPDVLP SRLHPEGLGH GRTLFLVMKN YPCTLRQYLC VNTPSPRLAA MMLLQLLEGV DHLVQQGIAH RDLKSDNILV ELDPDGCPWL VIADFGCCLA DESIGLQLPF SSWYVDRGGN GCLMAPEVST ARPGPRAVID YSKADAWAVG AIAYEIFGLV NPFYGQGKAH LESRSYQEAQ LPALPESVPP DVRQLVRALL QREASKRPSA RVAANVLHLS LWGEHILALK NLKLDKMVGW LLQQSAATLL ANRLTEKCCV ETKMKMLFLA NLECETLCQA ALLLCSWRAA L // ID PRIO_HUMAN Reviewed; 253 AA. AC P04156; O60489; P78446; Q15216; Q15221; Q27H91; Q5QPB4; Q8TBG0; Q96E70; AC Q9UP19; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1986, sequence version 1. DT 28-JAN-2026, entry version 280. DE RecName: Full=Major prion protein; DE Short=PrP; DE AltName: Full=ASCR; DE AltName: Full=PrP27-30; DE AltName: Full=PrP33-35C; DE AltName: CD_antigen=CD230; DE Flags: Precursor; GN Name=PRNP; Synonyms=ALTPRP, PRIP, PRP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3755672; DOI=10.1089/dna.1986.5.315; RA Kretzschmar H.A., Stowring L.E., Westaway D., Stubblebine W.H., RA Prusiner S.B., Dearmond S.J.; RT "Molecular cloning of a human prion protein cDNA."; RL DNA 5:315-324(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT 56-GLY--GLY-63 DEL. RC TISSUE=Brain; RX PubMed=1678248; RA Puckett C., Concannon P., Casey C., Hood L.E.; RT "Genomic structure of the human prion protein gene."; RL Am. J. Hum. Genet. 49:320-329(1991). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9799790; DOI=10.1101/gr.8.10.1022; RA Lee I.Y., Westaway D., Smit A.F.A., Wang K., Seto J., Chen L., Acharya C., RA Ankener M., Baskin D., Cooper C., Yao H., Prusiner S.B., Hood L.E.; RT "Complete genomic sequence and analysis of the prion protein gene region RT from three mammalian species."; RL Genome Res. 8:1022-1037(1998). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GSD ARG-187. RC TISSUE=Blood; RX PubMed=10581485; RX DOI=10.1002/(sici)1096-8628(19991215)88:6<653::aid-ajmg14>3.0.co;2-e; RA Cervenakova L., Buetefisch C., Lee H.S., Taller I., Stone G., RA Gibbs C.J. Jr., Brown P., Hallett M., Goldfarb L.G.; RT "Novel PRNP sequence variant associated with familial encephalopathy."; RL Am. J. Med. Genet. 88:653-656(1999). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Prostate; RA Hryb D.J., Reynolds T.A., Nakhla A.M., Kahn S.M., Khan S.M., Romas N.A., RA Rosner W.; RT "Cloning of human prostate prion protein cDNA."; RL Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Zhang J., Liu Y., Chen H., Jiang H., Lu W., Zhu X., Xie Q., Cai X., Liu X.; RT "Analysis and comparison of several mammalian prion protein genes Prnp."; RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 8-253. RX PubMed=3014653; DOI=10.1126/science.3014653; RA Liao Y.-C.J., Lebo R.V., Clawson G.A., Smuckler E.A.; RT "Human prion protein cDNA: molecular cloning, chromosomal mapping, and RT biological implications."; RL Science 233:364-367(1986). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 9-232, AND VARIANT 56-GLY--GLY-63 DEL. RC TISSUE=Brain; RX PubMed=1363802; DOI=10.1093/hmg/1.6.443; RA Diedrich J.F., Knopman D.S., List J.F., Olson K., Frey W.H., Emory C.R., RA Sung J.H., Haase A.T.; RT "Deletion in the prion protein gene in a demented patient."; RL Hum. Mol. Genet. 1:443-444(1992). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 8-253, AND VARIANT SCHIZOAFFECTIVE RP DISORDER SER-171. RX PubMed=9384372; DOI=10.1038/36757; RA Samaia H.B., Mari J.J., Vallada H.P., Moura R.P., Simpson A.J.G., RA Brentani R.R.; RT "A prion-linked psychiatric disorder."; RL Nature 390:241-241(1997). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 41-85, AND VARIANT 56-GLY--GLY-63 DEL. RX PubMed=7485229; DOI=10.1002/ajmg.1320600104; RA Perry R.T., Go R.C., Harrell L.E., Acton R.T.; RT "SSCP analysis and sequencing of the human prion protein gene (PRNP) RT detects two different 24 bp deletions in an atypical Alzheimer's disease RT family."; RL Am. J. Med. Genet. 60:12-18(1995). RN [13] RP PROTEIN SEQUENCE OF 58-85 AND 111-150. RX PubMed=1672107; DOI=10.1002/j.1460-2075.1991.tb07977.x; RA Tagliavini F., Prelli F., Ghiso J., Bugiani O., Serban D., Prusiner S.B., RA Farlow M.R., Ghetti B., Frangione B.; RT "Amyloid protein of Gerstmann-Straussler-Scheinker disease (Indiana RT kindred) is an 11 kd fragment of prion protein with an N-terminal glycine RT at codon 58."; RL EMBO J. 10:513-519(1991). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 84-91. RX PubMed=1683708; DOI=10.1073/pnas.88.23.10926; RA Goldfarb L.G., Brown P., McCombie W.R., Goldgaber D., Swergold G.D., RA Wills P.R., Cervenakova L., Baron H., Gibbs C.J. Jr., Gajdusek D.C.; RT "Transmissible familial Creutzfeldt-Jakob disease associated with five, RT seven, and eight extra octapeptide coding repeats in the PRNP gene."; RL Proc. Natl. Acad. Sci. U.S.A. 88:10926-10930(1991). RN [15] RP INVOLVEMENT IN HDL1. RX PubMed=9792871; DOI=10.1086/302093; RA Xiang F., Almqvist E.W., Huq M., Lundin A., Hayden M.R., Edstroem L., RA Anvret M., Zhang Z.; RT "A Huntington disease-like neurodegenerative disorder maps to chromosome RT 20p."; RL Am. J. Hum. Genet. 63:1431-1438(1998). RN [16] RP COPPER-BINDING, AND FUNCTION. RX PubMed=12732622; DOI=10.1074/jbc.m300394200; RA Mani K., Cheng F., Havsmark B., Jonsson M., Belting M., Fransson L.A.; RT "Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S- RT nitroso-dependent autocleavage of glypican-1 heparan sulfate."; RL J. Biol. Chem. 278:38956-38965(2003). RN [17] RP GLYCOSYLATION AT ASN-181, VARIANT SENF ALA-183, AND CHARACTERIZATION OF RP VARIANT SENF ALA-183. RX PubMed=12214108; DOI=10.3233/jad-2000-2104; RA Capellari S., Zaidi S.I., Long A.C., Kwon E.E., Petersen R.B.; RT "The Thr183Ala mutation, not the loss of the first glycosylation site, RT alters the physical properties of the prion protein."; RL J. Alzheimers Dis. 2:27-35(2000). RN [18] RP COPPER-BINDING. RX PubMed=16144413; DOI=10.1021/ja053254z; RA Chattopadhyay M., Walter E.D., Newell D.J., Jackson P.J., RA Aronoff-Spencer E., Peisach J., Gerfen G.J., Bennett B., Antholine W.E., RA Millhauser G.L.; RT "The octarepeat domain of the prion protein binds Cu(II) with three RT distinct coordination modes at pH 7.4."; RL J. Am. Chem. Soc. 127:12647-12656(2005). RN [19] RP COPPER-BINDING, AND ZINC-BINDING. RX PubMed=18034490; DOI=10.1021/ja077146j; RA Walter E.D., Stevens D.J., Visconte M.P., Millhauser G.L.; RT "The prion protein is a combined zinc and copper binding protein: Zn2+ RT alters the distribution of Cu2+ coordination modes."; RL J. Am. Chem. Soc. 129:15440-15441(2007). RN [20] RP RETRACTED PAPER. RX PubMed=19059915; DOI=10.1074/jbc.m804051200; RA Juanes M.E., Elvira G., Garcia-Grande A., Calero M., Gasset M.; RT "Biosynthesis of prion protein nucleocytoplasmic isoforms by alternative RT initiation of translation."; RL J. Biol. Chem. 284:2787-2794(2009). RN [21] RP RETRACTION NOTICE OF PUBMED:19059915. RX PubMed=29222195; DOI=10.1074/jbc.w117.000658; RA Juanes M.E., Elvira G., Garcia-Grande A., Calero M., Gasset M.; RT "Biosynthesis of prion protein nucleocytoplasmic isoforms by alternative RT initiation of translation."; RL J. Biol. Chem. 292:20044-20044(2017). RN [22] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-197. 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 [23] RP FUNCTION, SUBCELLULAR LOCATION, AND DISEASE ASSOCIATION. RX PubMed=19936054; DOI=10.1371/journal.ppat.1000666; RA Taylor D.R., Whitehouse I.J., Hooper N.M.; RT "Glypican-1 mediates both prion protein lipid raft association and disease RT isoform formation."; RL PLoS Pathog. 5:E1000666-E1000666(2009). RN [24] RP COPPER-BINDING. RX PubMed=19381258; DOI=10.1371/journal.ppat.1000390; RA Stevens D.J., Walter E.D., Rodriguez A., Draper D., Davies P., Brown D.R., RA Millhauser G.L.; RT "Early onset prion disease from octarepeat expansion correlates with copper RT or zinc binding properties."; RL PLoS Pathog. 5:E1000390-E1000390(2009). RN [25] RP SUBUNIT, AND DOMAIN. RX PubMed=20375014; DOI=10.1074/jbc.m110.111815; RA Adrover M., Pauwels K., Prigent S., de Chiara C., Xu Z., Chapuis C., RA Pastore A., Rezaei H.; RT "Prion fibrillization is mediated by a native structural element that RT comprises helices H2 and H3."; RL J. Biol. Chem. 285:21004-21012(2010). RN [26] RP COPPER-BINDING, CIRCULAR DICHROISM, DOMAIN, FUNCTION, AND SUBUNIT. RX PubMed=20564047; DOI=10.1002/jcb.22743; RA Wu D., Zhang W., Luo Q., Luo K., Huang L., Wang W., Huang T., Chen R., RA Lin Y., Pang D., Xiao G.; RT "Copper (II) promotes the formation of soluble neurotoxic PrP oligomers in RT acidic environment."; RL J. Cell. Biochem. 111:627-633(2010). RN [27] RP BICISTRONIC GENE. RX PubMed=21478263; DOI=10.1096/fj.10-173815; RA Vanderperre B., Staskevicius A.B., Tremblay G., McCoy M., O'Neill M.A., RA Cashman N.R., Roucou X.; RT "An overlapping reading frame in the PRNP gene encodes a novel polypeptide RT distinct from the prion protein."; RL FASEB J. 25:2373-2386(2011). RN [28] RP INTERACTION WITH KIAA1191. RX PubMed=21153684; DOI=10.1007/s11010-010-0690-4; RA Mishra M., Inoue N., Heese K.; RT "Characterizing the novel protein p33MONOX."; RL Mol. Cell. Biochem. 350:127-134(2011). RN [29] RP STRUCTURE BY NMR OF 90-231 OF MUTANT LYS-200. RX PubMed=10954699; DOI=10.1074/jbc.c000483200; RA Zhang Y., Swietnicki W., Zagorski M.G., Surewicz W.K., Soennichsen F.D.; RT "Solution structure of the E200K variant of human prion protein. RT Implications for the mechanism of pathogenesis in familial prion RT diseases."; RL J. Biol. Chem. 275:33650-33654(2000). RN [30] RP STRUCTURE BY NMR OF 23-230. RX PubMed=10618385; DOI=10.1073/pnas.97.1.145; RA Zahn R., Liu A., Luhrs T., Riek R., von Schroetter C., Lopez Garcia F., RA Billeter M., Calzolai L., Wider G., Wuethrich K.; RT "NMR solution structure of the human prion protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:145-150(2000). RN [31] RP STRUCTURE BY NMR OF 118-221. RX PubMed=10900000; DOI=10.1073/pnas.97.15.8340; RA Calzolai L., Lysek D.A., Guntert P., von Schroetter C., Riek R., Zahn R., RA Wuethrich K.; RT "NMR structures of three single-residue variants of the human prion RT protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:8340-8345(2000). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 119-226, DOMAIN, AND SUBUNIT. RX PubMed=11524679; DOI=10.1038/nsb0901-770; RA Knaus K.J., Morillas M., Swietnicki W., Malone M., Surewicz W.K., Yee V.C.; RT "Crystal structure of the human prion protein reveals a mechanism for RT oligomerization."; RL Nat. Struct. Biol. 8:770-774(2001). RN [33] RP X-RAY CRYSTALLOGRAPHY (0.75 ANGSTROMS) OF 61-65 IN COMPLEX WITH COPPER ION, RP DOMAIN, AND SUBUNIT. RX PubMed=11900542; DOI=10.1021/bi011922x; RA Burns C.S., Aronoff-Spencer E., Dunham C.M., Lario P., Avdievich N.I., RA Antholine W.E., Olmstead M.M., Vrielink A., Gerfen G.J., Peisach J., RA Scott W.G., Millhauser G.L.; RT "Molecular features of the copper binding sites in the octarepeat domain of RT the prion protein."; RL Biochemistry 41:3991-4001(2002). RN [34] RP STRUCTURE BY NMR OF 61-68, DISULFIDE BOND, AND SUBUNIT. RX PubMed=14623188; DOI=10.1016/j.jmb.2003.09.048; RA Zahn R.; RT "The octapeptide repeats in mammalian prion protein constitute a pH- RT dependent folding and aggregation site."; RL J. Mol. Biol. 334:477-488(2003). RN [35] RP REVIEW ON VARIANTS. RX PubMed=8364585; DOI=10.1002/humu.1380020303; RA Palmer M.S., Collinge J.; RT "Mutations and polymorphisms in the prion protein gene."; RL Hum. Mutat. 2:168-173(1993). RN [36] RP REVIEW ON VARIANTS, AND INVOLVEMENT IN PRION DISEASES. RX PubMed=8105771; DOI=10.1001/archneur.1993.00540110011002; RA Prusiner S.B.; RT "Genetic and infectious prion diseases."; RL Arch. Neurol. 50:1129-1153(1993). RN [37] RP X-RAY CRYSTALLOGRAPHY (0.85 ANGSTROMS) OF 170-175, SUBUNIT, AND DOMAIN. RX PubMed=17468747; DOI=10.1038/nature05695; RA Sawaya M.R., Sambashivan S., Nelson R., Ivanova M.I., Sievers S.A., RA Apostol M.I., Thompson M.J., Balbirnie M., Wiltzius J.J., McFarlane H.T., RA Madsen A.O., Riekel C., Eisenberg D.; RT "Atomic structures of amyloid cross-beta spines reveal varied steric RT zippers."; RL Nature 447:453-457(2007). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 119-231 IN COMPLEX WITH FAB RP FRAGMENT OF MONOCLONAL ANTIBODY ICSM 18, AND SUBUNIT. RX PubMed=19204296; DOI=10.1073/pnas.0809170106; RA Antonyuk S.V., Trevitt C.R., Strange R.W., Jackson G.S., Sangar D., RA Batchelor M., Cooper S., Fraser C., Jones S., Georgiou T., RA Khalili-Shirazi A., Clarke A.R., Hasnain S.S., Collinge J.; RT "Crystal structure of human prion protein bound to a therapeutic RT antibody."; RL Proc. Natl. Acad. Sci. U.S.A. 106:2554-2558(2009). RN [39] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 125-227 OF VARIANT VAL-129, RP VARIANT VAL-129, VARIANT CJD ASN-178, VARIANT FFI ASN-178, VARIANT GSD RP SER-198, SUBUNIT, AND DOMAIN. RX PubMed=19927125; DOI=10.1038/emboj.2009.333; RA Lee S., Antony L., Hartmann R., Knaus K.J., Surewicz K., Surewicz W.K., RA Yee V.C.; RT "Conformational diversity in prion protein variants influences RT intermolecular beta-sheet formation."; RL EMBO J. 29:251-262(2010). RN [40] RP VARIANT GSD LEU-102. RX PubMed=2564168; DOI=10.1038/338342a0; RA Hsiao K., Baker H.F., Crow T.J., Poulter M., Owen F., Terwilliger J.D., RA Westaway D., Ott J., Pursiner S.B.; RT "Linkage of a prion protein missense variant to Gerstmann-Straussler RT syndrome."; RL Nature 338:342-345(1989). RN [41] RP VARIANTS LEU-102; VAL-117 AND VAL-129. RX PubMed=2783132; DOI=10.1016/0006-291x(89)92317-6; RA Doh-Ura K., Tateishi J., Sasaki H., Kitamoto T., Sakaki Y.; RT "Pro-->Leu change at position 102 of prion protein is the most common but RT not the sole mutation related to Gerstmann-Straussler syndrome."; RL Biochem. Biophys. Res. Commun. 163:974-979(1989). RN [42] RP VARIANT FFI ASN-178. RX PubMed=1347910; DOI=10.1212/wnl.42.3.669; RA Medori R., Montagna P., Tritschler H.J., Leblanc A., Cortelli P., RA Tinuper P., Lugaresi E., Gambetti P.; RT "Fatal familial insomnia: a second kindred with mutation of prion protein RT gene at codon 178."; RL Neurology 42:669-670(1992). RN [43] RP VARIANT CJD ASN-178. RX PubMed=1671440; DOI=10.1016/0140-6736(91)91198-4; RA Goldfarb L.G., Haltia M., Brown P., Nieto A., Kovanen J., McCombie W.R., RA Trapp S., Gajdusek D.C.; RT "New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish RT Creutzfeldt-Jakob kindred."; RL Lancet 337:425-425(1991). RN [44] RP VARIANT CJD LYS-200. RX PubMed=1975028; DOI=10.1016/0140-6736(90)92073-q; RA Goldfarb L., Mitrova E., Brown P., Toh B.K., Gajdusek D.C.; RT "Mutation in codon 200 of scrapie amyloid protein gene in two clusters of RT Creutzfeldt-Jakob disease in Slovakia."; RL Lancet 336:514-515(1990). RN [45] RP VARIANT GSD ARG-217. RX PubMed=1363810; DOI=10.1038/ng0492-68; RA Hsiao K., Dlouhy S.R., Farlow M.R., Cass C., da Costa M., Conneally P.M., RA Hodes M.E., Ghetti B., Prusiner S.B.; RT "Mutant prion proteins in Gerstmann-Straussler-Scheinker disease with RT neurofibrillary tangles."; RL Nat. Genet. 1:68-71(1992). RN [46] RP VARIANT VAL-129, VARIANT CJD ASN-178, VARIANT FFI ASN-178, CHARACTERIZATION RP OF VARIANT VAL-129, CHARACTERIZATION OF VARIANT CJD ASN-178, RP CHARACTERIZATION OF VARIANT FFI ASN-178, AND POLYMORPHISM. RX PubMed=1439789; DOI=10.1126/science.1439789; RA Goldfarb L.G., Petersen R.B., Tabaton M., Brown P., LeBlanc A.C., RA Montagna P., Cortelli P., Julien J., Vital C., Pendelbury W.W.; RT "Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease RT phenotype determined by a DNA polymorphism."; RL Science 258:806-808(1992). RN [47] RP VARIANTS CJD ILE-180 AND ARG-232. RX PubMed=8461023; DOI=10.1006/bbrc.1993.1275; RA Kitamoto T., Ohta M., Doh-Ura K., Hitoshi S., Terao Y., Tateishi J.; RT "Novel missense variants of prion protein in Creutzfeldt-Jakob disease or RT Gerstmann-Straussler syndrome."; RL Biochem. Biophys. Res. Commun. 191:709-714(1993). RN [48] RP VARIANT CJD ILE-210. RX PubMed=7902693; DOI=10.1002/ana.410340608; RA Pocchiari M., Salvatore M., Cutruzzola F., Genuardi M., Allcatelli C.T., RA Masullo C., Macchi G., Alema G., Galgani S., Xi Y.G., Petraroli R., RA Silvestrini M.C., Brunori M.; RT "A new point mutation of the prion protein gene in Creutzfeldt-Jakob RT disease."; RL Ann. Neurol. 34:802-807(1993). RN [49] RP VARIANT GSD LEU-105. RX PubMed=7902972; DOI=10.1212/wnl.43.12.2723-a; RA Yamada M., Itoh Y., Fujigasaki H., Naruse S., Kaneko K., Kitamoto T., RA Tateishi J., Otomo E., Hayakawa M., Tanaka J., Matsushita M., Miyatake T.; RT "A missense mutation at codon 105 with codon 129 polymorphism of the prion RT protein gene in a new variant of Gerstmann-Straussler-Scheinker disease."; RL Neurology 43:2723-2724(1993). RN [50] RP VARIANT GSD LEU-105. RX PubMed=7699395; DOI=10.1016/0022-510x(94)90138-4; RA Itoh Y., Yamada M., Hayakawa M., Shozawa T., Tanaka J., Matsushita M., RA Kitamoto T., Tateishi J., Otomo E.; RT "A variant of Gerstmann-Straussler-Scheinker disease carrying codon 105 RT mutation with codon 129 polymorphism of the prion protein gene: a RT clinicopathological study."; RL J. Neurol. Sci. 127:77-86(1994). RN [51] RP VARIANT CJD LYS-200. RX PubMed=7906019; DOI=10.1212/wnl.44.2.299; RA Inoue I., Kitamoto T., Doh-Ura K., Shii H., Goto I., Tateishi J.; RT "Japanese family with Creutzfeldt-Jakob disease with codon 200 point RT mutation of the prion protein gene."; RL Neurology 44:299-301(1994). RN [52] RP VARIANT CJD LYS-200. RX PubMed=7913755; DOI=10.1098/rstb.1994.0033; RA Gabizon R., Rosenman H., Meiner Z., Kahana I., Kahana E., Shugart Y., RA Ott J., Prusiner S.B.; RT "Mutation in codon 200 and polymorphism in codon 129 of the prion protein RT gene in Libyan Jews with Creutzfeldt-Jakob disease."; RL Philos. Trans. R. Soc. Lond., B, Biol. Sci. 343:385-390(1994). RN [53] RP VARIANT GSD LEU-102. RX PubMed=7783876; DOI=10.1212/wnl.45.6.1127; RA Young K., Jones C.K., Piccardo P., Lazzarini A., Golbe L.I., RA Zimmerman T.R., Dickson D.W., McLachlan D.C., St George-Hyslop P.H., RA Lennox A.; RT "Gerstmann-Straussler-Scheinker disease with mutation at codon 102 and RT methionine at codon 129 of PRNP in previously unreported patients."; RL Neurology 45:1127-1134(1995). RN [54] RP VARIANT GSD LEU-102, AND VARIANT LYS-219. RX PubMed=8797472; DOI=10.1212/wnl.47.3.734; RA Barbanti P., Fabbrini G., Salvatore M., Petraroli R., Cardone F., Maras B., RA Equestre M., Macchi G., Lenzi G.L., Pocchiari M.; RT "Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity RT in a previously unreported family with Gerstmann-Straussler-Scheinker RT disease (PrP-P102L mutation)."; RL Neurology 47:734-741(1996). RN [55] RP VARIANT CJD HIS-208. RX PubMed=8909447; DOI=10.1212/wnl.47.5.1305; RA Mastrianni J.A., Iannicola C., Myers R.M., Dearmond S., Prusiner S.B.; RT "Mutation of the prion protein gene at codon 208 in familial Creutzfeldt- RT Jakob disease."; RL Neurology 47:1305-1312(1996). RN [56] RP VARIANT SENF ALA-183. RX PubMed=9266722; DOI=10.1002/ana.410420203; RA Nitrini R., Rosemberg S., Passos-Bueno M.R., da Silva L.S., Iughetti P., RA Papadopoulos M., Carrilho P.M., Caramelli P., Albrecht S., Zatz M., RA Leblanc A.; RT "Familial spongiform encephalopathy associated with a novel prion protein RT gene mutation."; RL Ann. Neurol. 42:138-146(1997). RN [57] RP VARIANTS GSD ASN-202 AND PRO-212. RX PubMed=9786248; DOI=10.1097/00005072-199810000-00010; RA Piccardo P., Dlouhy S.R., Lievens P.M., Young K., Bird T.D., Nochlin D., RA Dickson D.W., Vinters H.V., Zimmerman T.R., Mackenzie I.R., Kish S.J., RA Ang L.C., De Carli C., Pocchiari M., Brown P., Gibbs C.J. Jr., RA Gajdusek D.C., Bugiani O., Ironside J., Tagliavini F., Ghetti B.; RT "Phenotypic variability of Gerstmann-Straussler-Scheinker disease is RT associated with prion protein heterogeneity."; RL J. Neuropathol. Exp. Neurol. 57:979-988(1998). RN [58] RP VARIANT LYS-219, CHARACTERIZATION OF VARIANT LYS-219, AND POLYMORPHISM. RX PubMed=9482303; DOI=10.1016/s0140-6736(05)78358-6; RA Shibuya S., Higuchi J., Shin R.W., Tateishi J., Kitamoto T.; RT "Protective prion protein polymorphisms against sporadic Creutzfeldt-Jakob RT disease."; RL Lancet 351:419-419(1998). RN [59] RP VARIANTS ARG-188 AND SER-238. RX PubMed=10987652; DOI=10.1007/s004399900124; RA Windl O., Giese A., Schulz-Schaeffer W., Zerr I., Skworc K., Arendt S., RA Oberdieck C., Bodemer M., Poser S., Kretzschmar H.A.; RT "Molecular genetics of human prion diseases in Germany."; RL Hum. Genet. 105:244-252(1999). RN [60] RP VARIANTS EARLY-ONSET DEMENTIA LEU-102; ALA-183 AND LYS-188. 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 [61] RP VARIANTS CJD LYS-196; ILE-203 AND GLN-211. RX PubMed=10790216; RX DOI=10.1002/(sici)1098-1004(200005)15:5<482::aid-humu16>3.0.co;2-1; RA Peoc'h K., Manivet P., Beaudry P., Attane F., Besson G., Didier H., RA Delasnerie-Laupretre N., Laplanche J.-L.; RT "Identification of three novel mutations (E196K, V203I, E211Q) in the prion RT protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob RT disease phenotype."; RL Hum. Mutat. 15:482-482(2000). RN [62] RP VARIANT GSD VAL-131. RX PubMed=11709001; DOI=10.1001/archneur.58.11.1899; RA Panegyres P.K., Toufexis K., Kakulas B.A., Cernevakova L., Brown P., RA Ghetti B., Piccardo P., Dlouhy S.R.; RT "A new PRNP mutation (G131V) associated with Gerstmann-Straussler-Scheinker RT disease."; RL Arch. Neurol. 58:1899-1902(2001). RN [63] RP VARIANT VAL-129, AND CHARACTERIZATION OF VARIANT VAL-129. RX PubMed=12690204; DOI=10.1126/science.1083320; RA Mead S., Stumpf M.P., Whitfield J., Beck J.A., Poulter M., Campbell T., RA Uphill J.B., Goldstein D., Alpers M., Fisher E.M., Collinge J.; RT "Balancing selection at the prion protein gene consistent with prehistoric RT kurulike epidemics."; RL Science 300:640-643(2003). RN [64] RP VARIANT VAL-127, AND INVOLVEMENT IN KURU. RX PubMed=19923577; DOI=10.1056/nejmoa0809716; RA Mead S., Whitfield J., Poulter M., Shah P., Uphill J., Campbell T., RA Al-Dujaily H., Hummerich H., Beck J., Mein C.A., Verzilli C., Whittaker J., RA Alpers M.P., Collinge J.; RT "A novel protective prion protein variant that colocalizes with kuru RT exposure."; RL N. Engl. J. Med. 361:2056-2065(2009). RN [65] RP VARIANT VAL-127, CHARACTERIZATION OF VARIANT VAL-127, INVOLVEMENT IN KURU, RP AND POLYMORPHISM. RX PubMed=26061765; DOI=10.1038/nature14510; RA Asante E.A., Smidak M., Grimshaw A., Houghton R., Tomlinson A., Jeelani A., RA Jakubcova T., Hamdan S., Richard-Londt A., Linehan J.M., Brandner S., RA Alpers M., Whitfield J., Mead S., Wadsworth J.D., Collinge J.; RT "A naturally occurring variant of the human prion protein completely RT prevents prion disease."; RL Nature 522:478-481(2015). CC -!- FUNCTION: Its primary physiological function is unclear. May play a CC role in neuronal development and synaptic plasticity. May be required CC for neuronal myelin sheath maintenance. May promote myelin homeostasis CC through acting as an agonist for ADGRG6 receptor. May play a role in CC iron uptake and iron homeostasis. Soluble oligomers are toxic to CC cultured neuroblastoma cells and induce apoptosis (in vitro) (By CC similarity). Association with GPC1 (via its heparan sulfate chains) CC targets PRNP to lipid rafts. Also provides Cu(2+) or Zn(2+) for the CC ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate CC side chains (By similarity). {ECO:0000250|UniProtKB:P04925, CC ECO:0000269|PubMed:12732622, ECO:0000269|PubMed:19936054, CC ECO:0000269|PubMed:20564047, ECO:0000305}. CC -!- SUBUNIT: Monomer and homodimer. Has a tendency to aggregate into CC amyloid fibrils containing a cross-beta spine, formed by a steric CC zipper of superposed beta-strands. Soluble oligomers may represent an CC intermediate stage on the path to fibril formation. Copper binding may CC promote oligomerization (PubMed:11524679, PubMed:11900542, CC PubMed:14623188, PubMed:17468747, PubMed:19204296, PubMed:19927125, CC PubMed:20375014, PubMed:20564047). Interacts with GRB2, APP, CC ERI3/PRNPIP and SYN1. Mislocalized cytosolically exposed PrP interacts CC with MGRN1; this interaction alters MGRN1 subcellular location and CC causes lysosomal enlargement (By similarity). Interacts with KIAA1191 CC (PubMed:21153684). Interacts with ADGRG6 (By similarity). CC {ECO:0000250|UniProtKB:P04925, ECO:0000269|PubMed:11524679, CC ECO:0000269|PubMed:11900542, ECO:0000269|PubMed:14623188, CC ECO:0000269|PubMed:17468747, ECO:0000269|PubMed:19204296, CC ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:20375014, CC ECO:0000269|PubMed:20564047, ECO:0000269|PubMed:21153684}. CC -!- INTERACTION: CC P04156; Q9UL18: AGO1; NbExp=2; IntAct=EBI-977302, EBI-527363; CC P04156; Q9UKV8: AGO2; NbExp=4; IntAct=EBI-977302, EBI-528269; CC P04156; P05067: APP; NbExp=6; IntAct=EBI-977302, EBI-77613; CC P04156; P05067-4: APP; NbExp=2; IntAct=EBI-977302, EBI-302641; CC P04156; PRO_0000000092 [P05067]: APP; NbExp=3; IntAct=EBI-977302, EBI-821758; CC P04156; Q8WXF7: ATL1; NbExp=3; IntAct=EBI-977302, EBI-2410266; CC P04156; P25311: AZGP1; NbExp=4; IntAct=EBI-977302, EBI-2513837; CC P04156; P55085: F2RL1; NbExp=3; IntAct=EBI-977302, EBI-4303189; CC P04156; Q13642: FHL1; NbExp=3; IntAct=EBI-977302, EBI-912547; CC P04156; O75084: FZD7; NbExp=3; IntAct=EBI-977302, EBI-746917; CC P04156; P49639: HOXA1; NbExp=4; IntAct=EBI-977302, EBI-740785; CC P04156; P42858: HTT; NbExp=13; IntAct=EBI-977302, EBI-466029; CC P04156; P10636: MAPT; NbExp=2; IntAct=EBI-977302, EBI-366182; CC P04156; P29372: MPG; NbExp=4; IntAct=EBI-977302, EBI-1043398; CC P04156; Q9BSJ6: PIMREG; NbExp=5; IntAct=EBI-977302, EBI-2568609; CC P04156; Q9H4B4: PLK3; NbExp=4; IntAct=EBI-977302, EBI-751877; CC P04156; Q06830: PRDX1; NbExp=4; IntAct=EBI-977302, EBI-353193; CC P04156; P04156: PRNP; NbExp=33; IntAct=EBI-977302, EBI-977302; CC P04156; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-977302, EBI-11528848; CC P04156; Q8CJG0: Ago2; Xeno; NbExp=2; IntAct=EBI-977302, EBI-528299; CC P04156; P04925: Prnp; Xeno; NbExp=3; IntAct=EBI-977302, EBI-768613; CC P04156; P10279: PRNP; Xeno; NbExp=5; IntAct=EBI-977302, EBI-7430632; CC P04156; P23907: PRNP; Xeno; NbExp=3; IntAct=EBI-977302, EBI-7670302; CC PRO_0000025675; P31424-2: Grm5; Xeno; NbExp=4; IntAct=EBI-8830282, EBI-8830305; CC PRO_0000025675; P52480: Pkm; Xeno; NbExp=5; IntAct=EBI-8830282, EBI-647785; CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor CC {ECO:0000269|PubMed:19936054}. Golgi apparatus CC {ECO:0000250|UniProtKB:P04925}. Note=Targeted to lipid rafts via CC association with the heparan sulfate chains of GPC1. Colocates, in the CC presence of Cu(2+), to vesicles in para- and perinuclear regions, where CC both proteins undergo internalization. Heparin displaces PRNP from CC lipid rafts and promotes endocytosis. {ECO:0000269|PubMed:19936054}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=2; CC Name=1; Synonyms=PrP; CC IsoId=P04156-1; Sequence=Displayed; CC Name=3; Synonyms=AltPrP; CC IsoId=F7VJQ1-1; Sequence=External; CC -!- DOMAIN: The normal, monomeric form, PRPN(C), has a mainly alpha-helical CC structure. Misfolding of this form produces a disease-associated, CC protease-resistant form, PRPN (Sc), accompanied by a large increase of CC the beta-sheet content and formation of amyloid fibrils. These fibrils CC consist of a cross-beta spine, formed by a steric zipper of superposed CC beta-strands. Disease mutations may favor intermolecular contacts via CC short beta strands, and may thereby trigger oligomerization. In CC addition, the heparan-sulfate proteoglycan, GPC1, promotes the CC association of PRPN (C) to lipid rafts and appears to facilitate the CC conversion to PRPN (Sc). {ECO:0000269|PubMed:17468747, CC ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:20564047}. CC -!- DOMAIN: Contains an N-terminal region composed of octamer repeats. At CC low copper concentrations, the sidechains of His residues from three or CC four repeats contribute to the binding of a single copper ion. CC Alternatively, a copper ion can be bound by interaction with the CC sidechain and backbone amide nitrogen of a single His residue. The CC observed copper binding stoichiometry suggests that two repeat regions CC cooperate to stabilize the binding of a single copper ion. At higher CC copper concentrations, each octamer can bind one copper ion by CC interactions with the His sidechain and Gly backbone atoms. A mixture CC of binding types may occur, especially in the case of octamer repeat CC expansion. Copper binding may stabilize the conformation of this region CC and may promote oligomerization. {ECO:0000269|PubMed:11524679, CC ECO:0000269|PubMed:11900542, ECO:0000269|PubMed:20375014}. CC -!- PTM: The glycosylation pattern (the amount of mono-, di- and non- CC glycosylated forms or glycoforms) seems to differ in normal and CJD CC prion. {ECO:0000269|PubMed:12214108}. CC -!- POLYMORPHISM: The five tandem octapeptide repeats region is highly CC unstable. Insertions or deletions of octapeptide repeat units are CC associated to prion disease. {ECO:0000269|PubMed:1683708}. CC -!- POLYMORPHISM: A number of polymorphisms confer resistance to prion CC diseases (PubMed:1439789, PubMed:19923577, PubMed:26061765, CC PubMed:9482303). Val-127 has been selected for in response to the Kuru CC epidemic and confers resistance to prion disease by acting as a CC 'dominant negative' inhibitor of prion conversion (PubMed:26061765). CC Val-127 is not only itself resistant to conformational conversion, but CC also inhibits conversion of wild-type proteins. Confers protection CC against classical Creutzfeldt-Jakob disease (CJD) and Kuru in the CC heterozygous state, but can be infected with variant CJD prions, CC resulting from exposure to bovine spongiform encephalopathy prions. CC Confers complete resistance to all prion strains when homozygous CC (PubMed:26061765). Always associated with M-129 variant CC (PubMed:26061765). Val-129 confers relative protection against CC acquired, sporadic and some inherited prion diseases in the CC heterozygous state, possibly by preventing homodimerization CC (PubMed:1439789). Lys-219 confers relative protection against sporadic CC Creutzfeldt-Jakob disease (CJD) in the heterozygous state CC (PubMed:9482303). {ECO:0000269|PubMed:1439789, CC ECO:0000269|PubMed:26061765, ECO:0000269|PubMed:9482303}. CC -!- DISEASE: Note=PrP is found in high quantity in the brain of humans and CC animals infected with neurodegenerative diseases known as transmissible CC spongiform encephalopathies or prion diseases, like: Creutzfeldt-Jakob CC disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler CC disease (GSD), Huntington disease-like type 1 (HDL1) and kuru in CC humans; scrapie in sheep and goat; bovine spongiform encephalopathy CC (BSE) in cattle; transmissible mink encephalopathy (TME); chronic CC wasting disease (CWD) of mule deer and elk; feline spongiform CC encephalopathy (FSE) in cats and exotic ungulate encephalopathy (EUE) CC in nyala and greater kudu. The prion diseases illustrate three CC manifestations of CNS degeneration: (1) infectious (2) sporadic and (3) CC dominantly inherited forms. TME, CWD, BSE, FSE, EUE are all thought to CC occur after consumption of prion-infected foodstuffs. CC {ECO:0000269|PubMed:8105771}. CC -!- DISEASE: Creutzfeldt-Jakob disease (CJD) [MIM:123400]: Occurs primarily CC as a sporadic disorder (1 per million), while 10-15% are familial. CC Accidental transmission of CJD to humans appears to be iatrogenic CC (contaminated human growth hormone (HGH), corneal transplantation, CC electroencephalographic electrode implantation, etc.). Epidemiologic CC studies have failed to implicate the ingestion of infected animal meat CC in the pathogenesis of CJD in human. The triad of microscopic features CC that characterize the prion diseases consists of (1) spongiform CC degeneration of neurons, (2) severe astrocytic gliosis that often CC appears to be out of proportion to the degree of nerve cell loss, and CC (3) amyloid plaque formation. CJD is characterized by progressive CC dementia and myoclonic seizures, affecting adults in mid-life. Some CC patients present sleep disorders, abnormalities of high cortical CC function, cerebellar and corticospinal disturbances. The disease ends CC in death after a 3-12 months illness. {ECO:0000269|PubMed:10790216, CC ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:1671440, CC ECO:0000269|PubMed:1975028, ECO:0000269|PubMed:19927125, CC ECO:0000269|PubMed:7902693, ECO:0000269|PubMed:7906019, CC ECO:0000269|PubMed:7913755, ECO:0000269|PubMed:8461023, CC ECO:0000269|PubMed:8909447}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Fatal familial insomnia (FFI) [MIM:600072]: Autosomal dominant CC disorder and is characterized by neuronal degeneration limited to CC selected thalamic nuclei and progressive insomnia. CC {ECO:0000269|PubMed:1347910, ECO:0000269|PubMed:1439789, CC ECO:0000269|PubMed:19927125}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gerstmann-Straussler disease (GSD) [MIM:137440]: A rare CC inherited prion disease characterized by adult onset of memory loss, CC dementia, ataxia, and pathologic deposition of amyloid-like plaques in CC the brain. GSD presents with progressive limb and truncal ataxia, CC dysarthria, and cognitive decline in the thirties and forties, and the CC average disease duration is 7 years. {ECO:0000269|PubMed:10581485, CC ECO:0000269|PubMed:11709001, ECO:0000269|PubMed:1363810, CC ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:19927125, CC ECO:0000269|PubMed:2564168, ECO:0000269|PubMed:7699395, CC ECO:0000269|PubMed:7783876, ECO:0000269|PubMed:7902972, CC ECO:0000269|PubMed:8797472, ECO:0000269|PubMed:9786248}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Huntington disease-like 1 (HDL1) [MIM:603218]: Autosomal CC dominant, early-onset neurodegenerative disorder with prominent CC psychiatric features. {ECO:0000269|PubMed:9792871}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Kuru (KURU) [MIM:245300]: Kuru is transmitted during CC ritualistic cannibalism, among natives of the New Guinea highlands. CC Patients exhibit various movement disorders like cerebellar CC abnormalities, rigidity of the limbs, and clonus. Emotional lability is CC present, and dementia is conspicuously absent. Death usually occurs CC from 3 to 12 month after onset. {ECO:0000269|PubMed:19923577, CC ECO:0000269|PubMed:26061765}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spongiform encephalopathy with neuropsychiatric features CC (SENF) [MIM:606688]: Autosomal dominant presenile dementia with a CC rapidly progressive and protracted clinical course. The dementia was CC characterized clinically by frontotemporal features, including early CC personality changes. Some patients had memory loss, several showed CC aggressiveness, hyperorality and verbal stereotypy, others had CC parkinsonian symptoms. {ECO:0000269|PubMed:12214108, CC ECO:0000269|PubMed:9266722}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: This protein is produced by a bicistronic gene which CC also produces the alternative prion protein/AltPrP (AC F7VJQ1) from an CC overlapping reading frame. {ECO:0000305|PubMed:21478263}. CC -!- MISCELLANEOUS: The alternative prion protein/AltPrP (AC F7VJQ1) and CC PRNP have no apparent direct functional relation since a mutation that CC removes the start codon of the AltPrP has no apparent effect on the CC biology of PRNP. In mouse and hamster, the alternative initiation AUG CC codon is absent and is replaced by a GUG codon. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the prion family. {ECO:0000305}. CC -!- CAUTION: An isoform was shown to be localized to both the cytoplasm and CC the nucleus and to be sumoylated with SUMO1 (PubMed:19059915). The CC article has later been withdrawn by the authors. CC {ECO:0000269|PubMed:19059915, ECO:0000305|PubMed:29222195}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=PRNP entry; CC URL="https://en.wikipedia.org/wiki/PRNP"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The shape of harm - Issue CC 179 of May 2016; CC URL="https://www.proteinspotlight.org/back_issues/179/"; 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; M13899; AAA60182.1; -; mRNA. DR EMBL; X83416; CAA58442.1; -; Genomic_DNA. DR EMBL; U29185; AAC78725.1; -; Genomic_DNA. DR EMBL; AF076976; AAD46098.1; -; Genomic_DNA. DR EMBL; AY008282; AAG21693.1; -; mRNA. DR EMBL; DQ408531; ABD63004.1; -; Genomic_DNA. DR EMBL; AL133396; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC012844; AAH12844.1; -; mRNA. DR EMBL; BC022532; AAH22532.1; -; mRNA. DR EMBL; D00015; BAA00011.1; -; mRNA. DR EMBL; M13667; AAA19664.1; -; mRNA. DR EMBL; M81929; AAB59442.1; -; Genomic_DNA. DR EMBL; M81930; AAB59443.1; -; Genomic_DNA. DR EMBL; AF030575; AAC05365.1; -; Genomic_DNA. DR EMBL; S80732; AAB50648.2; -; Genomic_DNA. DR EMBL; S80743; AAB50649.2; -; Genomic_DNA. DR EMBL; S71208; AAB20521.1; -; Genomic_DNA. DR EMBL; S71210; AAB20522.1; -; Genomic_DNA. DR EMBL; S71212; AAB20523.1; -; Genomic_DNA. DR CCDS; CCDS13080.1; -. [P04156-1] DR PIR; A24173; UJHU. DR RefSeq; NP_000302.1; NM_000311.5. [P04156-1] DR RefSeq; NP_001073590.1; NM_001080121.3. [P04156-1] DR RefSeq; NP_001073591.1; NM_001080122.3. [P04156-1] DR RefSeq; NP_001073592.1; NM_001080123.3. [P04156-1] DR RefSeq; NP_001258490.1; NM_001271561.2. DR RefSeq; NP_898902.1; NM_183079.4. [P04156-1] DR PDB; 1E1G; NMR; -; A=125-228. DR PDB; 1E1J; NMR; -; A=125-228. DR PDB; 1E1P; NMR; -; A=125-228. DR PDB; 1E1S; NMR; -; A=125-228. DR PDB; 1E1U; NMR; -; A=125-228. DR PDB; 1E1W; NMR; -; A=125-228. DR PDB; 1FKC; NMR; -; A=90-231. DR PDB; 1FO7; NMR; -; A=90-231. DR PDB; 1H0L; NMR; -; A=121-230. DR PDB; 1HJM; NMR; -; A=125-228. DR PDB; 1HJN; NMR; -; A=125-228. DR PDB; 1I4M; X-ray; 2.00 A; A=119-226. DR PDB; 1OEH; NMR; -; A=77-84. DR PDB; 1OEI; NMR; -; A=61-84. DR PDB; 1QLX; NMR; -; A=23-230. DR PDB; 1QLZ; NMR; -; A=23-230. DR PDB; 1QM0; NMR; -; A=90-230. DR PDB; 1QM1; NMR; -; A=90-230. DR PDB; 1QM2; NMR; -; A=121-230. DR PDB; 1QM3; NMR; -; A=121-230. DR PDB; 2IV4; NMR; -; A=180-195. DR PDB; 2IV5; NMR; -; A=173-195. DR PDB; 2IV6; NMR; -; A=173-195. DR PDB; 2K1D; NMR; -; A=90-231. DR PDB; 2KUN; NMR; -; A=90-231. DR PDB; 2LBG; NMR; -; A=110-136. DR PDB; 2LEJ; NMR; -; A=90-231. DR PDB; 2LFT; NMR; -; A=90-231. DR PDB; 2LSB; NMR; -; A=90-231. DR PDB; 2LV1; NMR; -; A=90-231. DR PDB; 2M8T; NMR; -; A=90-231. DR PDB; 2OL9; X-ray; 0.85 A; A=170-175. DR PDB; 2W9E; X-ray; 2.90 A; A=119-231. DR PDB; 3HAF; X-ray; 2.26 A; A=90-231. DR PDB; 3HAK; X-ray; 1.80 A; A=125-227. DR PDB; 3HEQ; X-ray; 1.80 A; A/B=90-231. DR PDB; 3HER; X-ray; 1.85 A; A/B=90-231. DR PDB; 3HES; X-ray; 2.00 A; A/B=90-231. DR PDB; 3HJ5; X-ray; 3.10 A; A/B=90-231. DR PDB; 3HJX; X-ray; 2.00 A; A=126-231. DR PDB; 3MD4; X-ray; 1.15 A; A/B=127-132. DR PDB; 3MD5; X-ray; 1.40 A; A/B=127-132. DR PDB; 3NHC; X-ray; 1.57 A; A/B=127-132. DR PDB; 3NHD; X-ray; 1.92 A; A/B=127-132. DR PDB; 3NVF; X-ray; 1.80 A; A=138-143. DR PDB; 4DGI; X-ray; 2.40 A; A=120-230. DR PDB; 4E1H; X-ray; 1.40 A; A/C/E/G/I/K=177-182, B/D/F/H/J/L=211-216. DR PDB; 4E1I; X-ray; 2.03 A; A/C/E/G/I/K=177-182, B/D/F/H/J/L=211-216. DR PDB; 4KML; X-ray; 1.50 A; A=24-231. DR PDB; 4N9O; X-ray; 1.50 A; A=90-231. DR PDB; 5L6R; NMR; -; A=90-226. DR PDB; 5YJ4; NMR; -; A=91-231. DR PDB; 5YJ5; NMR; -; A=91-231. DR PDB; 6DU9; X-ray; 2.33 A; A=90-230. DR PDB; 6LNI; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=23-231. DR PDB; 6PQ5; X-ray; 1.50 A; A/B=113-118. DR PDB; 6PQA; X-ray; 1.46 A; A=119-124. DR PDB; 6SUZ; X-ray; 2.50 A; A=125-223. DR PDB; 6SV2; X-ray; 2.30 A; A=119-231. DR PDB; 6UUR; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=94-178. DR PDB; 7DWV; EM; 3.07 A; A/B/C/D/E/F=23-231. DR PDB; 7FHQ; NMR; -; A=91-231. DR PDB; 7RL4; EM; 2.86 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=23-144. DR PDB; 7RVC; EM; 1.00 A; A=168-176. DR PDB; 7RVE; EM; 0.85 A; A=168-176. DR PDB; 7RVJ; EM; 1.00 A; A/B=169-175. DR PDB; 7RVK; EM; 1.00 A; A=169-175. DR PDB; 7RVL; EM; 1.00 A; A=168-176. DR PDB; 7UMQ; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J=80-141. DR PDB; 7UN5; EM; 3.13 A; A/B/C/D/E/F/G/H/I/J=80-141. DR PDBsum; 1E1G; -. DR PDBsum; 1E1J; -. DR PDBsum; 1E1P; -. DR PDBsum; 1E1S; -. DR PDBsum; 1E1U; -. DR PDBsum; 1E1W; -. DR PDBsum; 1FKC; -. DR PDBsum; 1FO7; -. DR PDBsum; 1H0L; -. DR PDBsum; 1HJM; -. DR PDBsum; 1HJN; -. DR PDBsum; 1I4M; -. DR PDBsum; 1OEH; -. DR PDBsum; 1OEI; -. DR PDBsum; 1QLX; -. DR PDBsum; 1QLZ; -. DR PDBsum; 1QM0; -. DR PDBsum; 1QM1; -. DR PDBsum; 1QM2; -. DR PDBsum; 1QM3; -. DR PDBsum; 2IV4; -. DR PDBsum; 2IV5; -. DR PDBsum; 2IV6; -. DR PDBsum; 2K1D; -. DR PDBsum; 2KUN; -. DR PDBsum; 2LBG; -. DR PDBsum; 2LEJ; -. DR PDBsum; 2LFT; -. DR PDBsum; 2LSB; -. DR PDBsum; 2LV1; -. DR PDBsum; 2M8T; -. DR PDBsum; 2OL9; -. DR PDBsum; 2W9E; -. DR PDBsum; 3HAF; -. DR PDBsum; 3HAK; -. DR PDBsum; 3HEQ; -. DR PDBsum; 3HER; -. DR PDBsum; 3HES; -. DR PDBsum; 3HJ5; -. DR PDBsum; 3HJX; -. DR PDBsum; 3MD4; -. DR PDBsum; 3MD5; -. DR PDBsum; 3NHC; -. DR PDBsum; 3NHD; -. DR PDBsum; 3NVF; -. DR PDBsum; 4DGI; -. DR PDBsum; 4E1H; -. DR PDBsum; 4E1I; -. DR PDBsum; 4KML; -. DR PDBsum; 4N9O; -. DR PDBsum; 5L6R; -. DR PDBsum; 5YJ4; -. DR PDBsum; 5YJ5; -. DR PDBsum; 6DU9; -. DR PDBsum; 6LNI; -. DR PDBsum; 6PQ5; -. DR PDBsum; 6PQA; -. DR PDBsum; 6SUZ; -. DR PDBsum; 6SV2; -. DR PDBsum; 6UUR; -. DR PDBsum; 7DWV; -. DR PDBsum; 7FHQ; -. DR PDBsum; 7RL4; -. DR PDBsum; 7RVC; -. DR PDBsum; 7RVE; -. DR PDBsum; 7RVJ; -. DR PDBsum; 7RVK; -. DR PDBsum; 7RVL; -. DR PDBsum; 7UMQ; -. DR PDBsum; 7UN5; -. DR AlphaFoldDB; P04156; -. DR BMRB; P04156; -. DR EMDB; EMD-0931; -. DR EMDB; EMD-20900; -. DR EMDB; EMD-24514; -. DR EMDB; EMD-26607; -. DR EMDB; EMD-26613; -. DR EMDB; EMD-30887; -. DR SASBDB; P04156; -. DR SMR; P04156; -. DR BioGRID; 111606; 2255. DR CORUM; P04156; -. DR DIP; DIP-29933N; -. DR ELM; P04156; -. DR FunCoup; P04156; 501. DR IntAct; P04156; 454. DR MINT; P04156; -. DR STRING; 9606.ENSP00000399376; -. DR BindingDB; P04156; -. DR ChEMBL; CHEMBL4869; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB00759; Tetracycline. DR DrugCentral; P04156; -. DR MoonDB; P04156; Predicted. DR TCDB; 1.C.48.1.2; the prion peptide (prp) family. DR GlyConnect; 2056; 3 N-Linked glycans (1 site). DR GlyCosmos; P04156; 2 sites, 6 glycans. DR GlyGen; P04156; 4 sites, 12 N-linked glycans (2 sites), 2 O-linked glycans (2 sites). DR iPTMnet; P04156; -. DR MetOSite; P04156; -. DR PhosphoSitePlus; P04156; -. DR SwissPalm; P04156; -. DR BioMuta; PRNP; -. DR DMDM; 130912; -. DR jPOST; P04156; -. DR MassIVE; P04156; -. DR PaxDb; 9606-ENSP00000368752; -. DR PeptideAtlas; P04156; -. DR ProteomicsDB; 51667; -. [P04156-1] DR Pumba; P04156; -. DR ABCD; P04156; 3 sequenced antibodies. DR Antibodypedia; 3351; 881 antibodies from 47 providers. DR DNASU; 5621; -. DR Ensembl; ENST00000379440.9; ENSP00000368752.4; ENSG00000171867.19. DR Ensembl; ENST00000424424.2; ENSP00000411599.2; ENSG00000171867.19. DR Ensembl; ENST00000430350.2; ENSP00000399376.2; ENSG00000171867.19. DR Ensembl; ENST00000457586.2; ENSP00000415284.2; ENSG00000171867.19. DR GeneID; 5621; -. DR KEGG; hsa:5621; -. DR MANE-Select; ENST00000379440.9; ENSP00000368752.4; NM_000311.5; NP_000302.1. DR AGR; HGNC:9449; -. DR ClinPGx; PA33796; -. DR CTD; 5621; -. DR DisGeNET; 5621; -. DR GeneCards; PRNP; -. DR GeneReviews; PRNP; -. DR HGNC; HGNC:9449; PRNP. DR HPA; ENSG00000171867; Tissue enhanced (choroid). DR MalaCards; PRNP; -. DR MIM; 123400; phenotype. DR MIM; 137440; phenotype. DR MIM; 176640; gene. DR MIM; 245300; phenotype. DR MIM; 600072; phenotype. DR MIM; 603218; phenotype. DR MIM; 606688; phenotype. DR OpenTargets; ENSG00000171867; -. DR Orphanet; 280397; Familial Alzheimer-like prion disease. DR Orphanet; 466; Fatal familial insomnia. DR Orphanet; 356; Gerstmann-Straussler-Scheinker syndrome. DR Orphanet; 157941; Huntington disease-like 1. DR Orphanet; 282166; Inherited Creutzfeldt-Jakob disease. DR Orphanet; 454745; Kuru. DR Orphanet; 397606; PrP systemic amyloidosis. DR VEuPathDB; HostDB:ENSG00000171867; -. DR eggNOG; ENOG502S2A8; Eukaryota. DR GeneTree; ENSGT00510000049083; -. DR InParanoid; P04156; -. DR OMA; QMCTTQY; -. DR OrthoDB; 9048788at2759; -. DR PAN-GO; P04156; 3 GO annotations based on evolutionary models. DR PhylomeDB; P04156; -. DR PathwayCommons; P04156; -. DR Reactome; R-HSA-419037; NCAM1 interactions. DR Reactome; R-HSA-9609523; Insertion of tail-anchored proteins into the endoplasmic reticulum membrane. DR SignaLink; P04156; -. DR Agora; ENSG00000171867; -. DR BioGRID-ORCS; 5621; 10 hits in 1169 CRISPR screens. DR CD-CODE; 7A2E2A6F; Synthetic Condensate 000125. DR CD-CODE; 8188F968; Tau-Prion Multiphasic condensate. DR CD-CODE; 9F779CC8; Nuclear body. DR ChiTaRS; PRNP; human. DR EvolutionaryTrace; P04156; -. DR GenomeRNAi; 5621; -. DR Pharos; P04156; Tchem. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; P04156; protein. DR Bgee; ENSG00000171867; Expressed in Brodmann (1909) area 23 and 209 other cell types or tissues. DR ExpressionAtlas; P04156; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; TAS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0009897; C:external side of plasma membrane; NAS:ARUK-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0019898; C:extrinsic component of membrane; TAS:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0016234; C:inclusion body; IMP:CAFA. DR GO; GO:0045121; C:membrane raft; IDA:MGI. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; TAS:ARUK-UCL. DR GO; GO:0014069; C:postsynaptic density; ISS:ARUK-UCL. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0001540; F:amyloid-beta binding; IDA:ARUK-UCL. DR GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; ISS:ARUK-UCL. DR GO; GO:0043008; F:ATP-dependent protein binding; IEA:Ensembl. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903135; F:cupric ion binding; IEA:Ensembl. DR GO; GO:1903136; F:cuprous ion binding; IMP:CAFA. DR GO; GO:0005539; F:glycosaminoglycan binding; ISS:ARUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0005521; F:lamin binding; IEA:Ensembl. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0060090; F:molecular adaptor activity; IDA:DisProt. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:DisProt. DR GO; GO:0140677; F:molecular function activator activity; IEA:Ensembl. DR GO; GO:0002020; F:protease binding; ISS:ARUK-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IEA:Ensembl. DR GO; GO:0038023; F:signaling receptor activity; ISS:ARUK-UCL. DR GO; GO:0044325; F:transmembrane transporter binding; IEA:Ensembl. DR GO; GO:0015631; F:tubulin binding; IDA:UniProtKB. DR GO; GO:0031802; F:type 5 metabotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0071280; P:cellular response to copper ion; IDA:MGI. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0097062; P:dendritic spine maintenance; TAS:ARUK-UCL. DR GO; GO:0006878; P:intracellular copper ion homeostasis; NAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ARUK-UCL. DR GO; GO:0007611; P:learning or memory; ISS:ARUK-UCL. DR GO; GO:0007616; P:long-term memory; TAS:ARUK-UCL. DR GO; GO:0046007; P:negative regulation of activated T cell proliferation; ISS:BHF-UCL. DR GO; GO:1902992; P:negative regulation of amyloid precursor protein catabolic process; ISS:ARUK-UCL. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; ISS:ARUK-UCL. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; ISS:BHF-UCL. DR GO; GO:1902951; P:negative regulation of dendritic spine maintenance; ISS:ARUK-UCL. DR GO; GO:0032700; P:negative regulation of interleukin-17 production; ISS:BHF-UCL. DR GO; GO:0032703; P:negative regulation of interleukin-2 production; ISS:BHF-UCL. DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0010955; P:negative regulation of protein processing; TAS:ARUK-UCL. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0032689; P:negative regulation of type II interferon production; ISS:BHF-UCL. DR GO; GO:1990535; P:neuron projection maintenance; ISS:ARUK-UCL. DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IGI:ARUK-UCL. DR GO; GO:1900451; P:positive regulation of glutamate receptor signaling pathway; IGI:ARUK-UCL. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:CAFA. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IEA:Ensembl. DR GO; GO:0090314; P:positive regulation of protein targeting to membrane; ISS:ARUK-UCL. DR GO; GO:0031648; P:protein destabilization; IMP:CAFA. DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro. DR GO; GO:1905664; P:regulation of calcium ion import across plasma membrane; ISS:ARUK-UCL. DR GO; GO:0051726; P:regulation of cell cycle; IEA:UniProtKB-KW. DR GO; GO:1900449; P:regulation of glutamate receptor signaling pathway; ISS:ARUK-UCL. DR GO; GO:1901379; P:regulation of potassium ion transmembrane transport; IEA:Ensembl. DR GO; GO:1904645; P:response to amyloid-beta; ISS:ARUK-UCL. DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:UniProtKB. DR DisProt; DP00466; -. DR FunFam; 1.10.790.10:FF:000001; Major prion protein; 1. DR Gene3D; 1.10.790.10; Prion/Doppel protein, beta-ribbon domain; 1. DR InterPro; IPR000817; Prion. DR InterPro; IPR036924; Prion/Doppel_b-ribbon_dom_sf. DR InterPro; IPR022416; Prion/Doppel_prot_b-ribbon_dom. DR InterPro; IPR020949; Prion_copper_b_octapeptide. DR InterPro; IPR025860; Prion_N. DR PANTHER; PTHR15506; DOPPEL PRION; 1. DR PANTHER; PTHR15506:SF2; MAJOR PRION PROTEIN; 1. DR Pfam; PF00377; Prion; 1. DR Pfam; PF11587; Prion_bPrPp; 1. DR Pfam; PF03991; Prion_octapep; 1. DR PRINTS; PR00341; PRION. DR SMART; SM00157; PRP; 1. DR SUPFAM; SSF54098; Prion-like; 1. DR PROSITE; PS00291; PRION_1; 1. DR PROSITE; PS00706; PRION_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Amyloid; Amyloidosis; Cell cycle; KW Cell membrane; Copper; Direct protein sequencing; Disease variant; KW Disulfide bond; Glycoprotein; Golgi apparatus; GPI-anchor; Growth arrest; KW Lipoprotein; Membrane; Metal-binding; Prion; Proteomics identification; KW Reference proteome; Repeat; Signal; Zinc. FT SIGNAL 1..22 FT /evidence="ECO:0000250|UniProtKB:P04925" FT CHAIN 23..230 FT /note="Major prion protein" FT /id="PRO_0000025675" FT PROPEP 231..253 FT /note="Removed in mature form" FT /evidence="ECO:0000250|UniProtKB:P04273" FT /id="PRO_0000025676" FT REPEAT 51..59 FT /note="1" FT REPEAT 60..67 FT /note="2" FT REPEAT 68..75 FT /note="3" FT REPEAT 76..83 FT /note="4" FT REPEAT 84..91 FT /note="5" FT REGION 23..230 FT /note="Interaction with GRB2, ERI3 and SYN1" FT /evidence="ECO:0000250|UniProtKB:P04925" FT REGION 23..38 FT /note="Interaction with ADGRG6" FT /evidence="ECO:0000250|UniProtKB:P04925" FT REGION 26..108 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 51..91 FT /note="5 X 8 AA tandem repeats of P-H-G-G-G-W-G-Q" FT COMPBIAS 52..95 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 61 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 62 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 63 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 69 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 70 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 71 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 77 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 78 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 79 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 85 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 86 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 87 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT LIPID 230 FT /note="GPI-anchor amidated serine" FT /evidence="ECO:0000250|UniProtKB:P04273" FT CARBOHYD 181 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12214108" FT CARBOHYD 197 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT DISULFID 179..214 FT /evidence="ECO:0000269|PubMed:14623188" FT VARIANT 56..63 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:1363802, FT ECO:0000269|PubMed:1678248, ECO:0000269|PubMed:7485229" FT /id="VAR_013763" FT VARIANT 102 FT /note="P -> L (in GSD and early-onset dementia; FT dbSNP:rs74315401)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:2564168, ECO:0000269|PubMed:2783132, FT ECO:0000269|PubMed:7783876, ECO:0000269|PubMed:8797472" FT /id="VAR_006464" FT VARIANT 105 FT /note="P -> L (in GSD; dbSNP:rs11538758)" FT /evidence="ECO:0000269|PubMed:7699395, FT ECO:0000269|PubMed:7902972" FT /id="VAR_006465" FT VARIANT 117 FT /note="A -> V (linked to development of dementing FT Gerstmann-Straussler disease; dbSNP:rs74315402)" FT /evidence="ECO:0000269|PubMed:2783132" FT /id="VAR_006466" FT VARIANT 127 FT /note="G -> V (protective factor against Kuru; protective FT factor against prion disease; confers protection against FT classical Creutzfeldt-Jakob disease (CJD) and Kuru in the FT heterozygous state but can be infected with variant CJD FT prions resulting from exposure to bovine spongiform FT encephalopathy prions; confers complete resistance to all FT prion strains when homozygous; acts as a 'dominant FT negative' inhibitor of prion conversion; is not only itself FT resistant to conformational conversion, but also inhibits FT conversion of wild-type proteins; dbSNP:rs267606980)" FT /evidence="ECO:0000269|PubMed:19923577, FT ECO:0000269|PubMed:26061765" FT /id="VAR_073722" FT VARIANT 129 FT /note="M -> V (protective factor against acquired, sporadic FT and some inherited prion diseases in the heterozygous FT state, possibly by preventing homodimerization; determines FT the disease phenotype in patients who have a PrP mutation FT at position 178; patients with M-129 develop FFI, those FT with V-129 develop CJD; dbSNP:rs1799990)" FT /evidence="ECO:0000269|PubMed:12690204, FT ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:19927125, FT ECO:0000269|PubMed:2783132" FT /id="VAR_006467" FT VARIANT 131 FT /note="G -> V (in GSD; dbSNP:rs74315410)" FT /evidence="ECO:0000269|PubMed:11709001" FT /id="VAR_014264" FT VARIANT 171 FT /note="N -> S (in schizoaffective disorder; FT dbSNP:rs16990018)" FT /evidence="ECO:0000269|PubMed:9384372" FT /id="VAR_006468" FT VARIANT 178 FT /note="D -> N (in FFI and CJD; dbSNP:rs74315403)" FT /evidence="ECO:0000269|PubMed:1347910, FT ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:1671440, FT ECO:0000269|PubMed:19927125" FT /id="VAR_006469" FT VARIANT 180 FT /note="V -> I (in CJD; dbSNP:rs74315408)" FT /evidence="ECO:0000269|PubMed:1439789, FT ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:8461023" FT /id="VAR_006470" FT VARIANT 183 FT /note="T -> A (in SENF and early-onset dementia; induces FT loss of glycosylation at N-181; dbSNP:rs74315411)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:12214108, ECO:0000269|PubMed:9266722" FT /id="VAR_006471" FT VARIANT 187 FT /note="H -> R (in GSD; dbSNP:rs74315413)" FT /evidence="ECO:0000269|PubMed:10581485" FT /id="VAR_008746" FT VARIANT 188 FT /note="T -> K (in early-onset dementia and dementia due to FT prion diseases)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_008748" FT VARIANT 188 FT /note="T -> R (in dbSNP:rs372878791)" FT /evidence="ECO:0000269|PubMed:10987652" FT /id="VAR_008747" FT VARIANT 196 FT /note="E -> K (in CJD)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008749" FT VARIANT 198 FT /note="F -> S (in GSD; atypical form with neurofibrillary FT tangles; dbSNP:rs74315405)" FT /evidence="ECO:0000269|PubMed:19927125" FT /id="VAR_006472" FT VARIANT 200 FT /note="E -> K (in CJD; dbSNP:rs28933385)" FT /evidence="ECO:0000269|PubMed:1975028, FT ECO:0000269|PubMed:7906019, ECO:0000269|PubMed:7913755" FT /id="VAR_006473" FT VARIANT 202 FT /note="D -> N (in GSD; dbSNP:rs761807915)" FT /evidence="ECO:0000269|PubMed:9786248" FT /id="VAR_008750" FT VARIANT 203 FT /note="V -> I (in CJD; uncertain significance; FT dbSNP:rs776593792)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008751" FT VARIANT 208 FT /note="R -> H (in CJD; dbSNP:rs74315412)" FT /evidence="ECO:0000269|PubMed:8909447" FT /id="VAR_006474" FT VARIANT 210 FT /note="V -> I (in CJD; dbSNP:rs74315407)" FT /evidence="ECO:0000269|PubMed:7902693" FT /id="VAR_006475" FT VARIANT 211 FT /note="E -> Q (in CJD; dbSNP:rs398122370)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008752" FT VARIANT 212 FT /note="Q -> P (in GSD; dbSNP:rs751882709)" FT /evidence="ECO:0000269|PubMed:9786248" FT /id="VAR_008753" FT VARIANT 217 FT /note="Q -> R (in GSD; with neurofibrillary tangles; FT dbSNP:rs74315406)" FT /evidence="ECO:0000269|PubMed:1363810" FT /id="VAR_006476" FT VARIANT 219 FT /note="E -> K (confers relative protection against sporadic FT Creutzfeldt-Jakob disease (CJD) in the heterozygous state; FT dbSNP:rs1800014)" FT /evidence="ECO:0000269|PubMed:8797472, FT ECO:0000269|PubMed:9482303" FT /id="VAR_006477" FT VARIANT 232 FT /note="M -> R (in CJD; dbSNP:rs74315409)" FT /evidence="ECO:0000269|PubMed:8461023" FT /id="VAR_006478" FT VARIANT 238 FT /note="P -> S" FT /evidence="ECO:0000269|PubMed:10987652" FT /id="VAR_008754" FT CONFLICT 118 FT /note="Missing (in Ref. 9; AAA19664/BAA00011)" FT /evidence="ECO:0000305" FT CONFLICT 169 FT /note="Y -> H (in Ref. 6; ABD63004)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="Q -> K (in Ref. 8; AAH22532)" FT /evidence="ECO:0000305" FT STRAND 63..67 FT /evidence="ECO:0007829|PDB:1OEI" FT STRAND 70..73 FT /evidence="ECO:0007829|PDB:1OEI" FT TURN 74..76 FT /evidence="ECO:0007829|PDB:1OEI" FT STRAND 79..82 FT /evidence="ECO:0007829|PDB:1OEH" FT STRAND 92..95 FT /evidence="ECO:0007829|PDB:5YJ4" FT STRAND 99..101 FT /evidence="ECO:0007829|PDB:5L6R" FT STRAND 109..112 FT /evidence="ECO:0007829|PDB:7RL4" FT TURN 114..117 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 118..122 FT /evidence="ECO:0007829|PDB:4KML" FT STRAND 125..127 FT /evidence="ECO:0007829|PDB:1H0L" FT STRAND 128..131 FT /evidence="ECO:0007829|PDB:3MD4" FT STRAND 133..135 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 138..140 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 141..143 FT /evidence="ECO:0007829|PDB:1E1S" FT HELIX 144..153 FT /evidence="ECO:0007829|PDB:4KML" FT HELIX 154..156 FT /evidence="ECO:0007829|PDB:4KML" FT STRAND 159..163 FT /evidence="ECO:0007829|PDB:1E1U" FT HELIX 166..168 FT /evidence="ECO:0007829|PDB:4KML" FT TURN 171..173 FT /evidence="ECO:0007829|PDB:1QM0" FT STRAND 178..181 FT /evidence="ECO:0007829|PDB:4E1H" FT STRAND 182..185 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 189..192 FT /evidence="ECO:0007829|PDB:6LNI" FT TURN 193..195 FT /evidence="ECO:0007829|PDB:3HAK" FT STRAND 196..202 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 205..210 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 212..215 FT /evidence="ECO:0007829|PDB:4E1H" FT TURN 223..225 FT /evidence="ECO:0007829|PDB:3HER" FT TURN 228..230 FT /evidence="ECO:0007829|PDB:2LFT" SQ SEQUENCE 253 AA; 27661 MW; 43DB596BAAA66484 CRC64; MANLGCWMLV LFVATWSDLG LCKKRPKPGG WNTGGSRYPG QGSPGGNRYP PQGGGGWGQP HGGGWGQPHG GGWGQPHGGG WGQPHGGGWG QGGGTHSQWN KPSKPKTNMK HMAGAAAAGA VVGGLGGYML GSAMSRPIIH FGSDYEDRYY RENMHRYPNQ VYYRPMDEYS NQNNFVHDCV NITIKQHTVT TTTKGENFTE TDVKMMERVV EQMCITQYER ESQAYYQRGS SMVLFSSPPV ILLISFLIFL IVG // ID PRKN_HUMAN Reviewed; 465 AA. AC O60260; A3FG77; A8K975; D3JZW7; D3K2X0; Q5TFV8; Q5VVX4; Q6Q2I6; Q8NI41; AC Q8NI43; Q8NI44; Q8WW07; DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 28-JAN-2026, entry version 236. DE RecName: Full=E3 ubiquitin-protein ligase parkin {ECO:0000305}; DE Short=Parkin; DE EC=2.3.2.31 {ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:32047033}; DE AltName: Full=Parkin RBR E3 ubiquitin-protein ligase {ECO:0000312|HGNC:HGNC:8607}; DE AltName: Full=Parkinson juvenile disease protein 2; DE Short=Parkinson disease protein 2; GN Name=PRKN {ECO:0000312|HGNC:HGNC:8607}; Synonyms=PARK2; 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] (ISOFORMS 1 AND 2), INVOLVEMENT IN PARK2, AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain, and Skeletal muscle; RX PubMed=9560156; DOI=10.1038/33416; RA Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., RA Yokochi M., Mizuno Y., Shimizu N.; RT "Mutations in the parkin gene cause autosomal recessive juvenile RT parkinsonism."; RL Nature 392:605-608(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP VARIANTS ARG-311 AND THR-371, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=19501131; DOI=10.1016/j.neulet.2009.05.079; RA Kasap M., Akpinar G., Sazci A., Idrisoglu H.A., Vahaboglu H.; RT "Evidence for the presence of full-length PARK2 mRNA and Parkin protein in RT human blood."; RL Neurosci. Lett. 460:196-200(2009). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4). RA D'Agata V., Scapagnini G., Cavallaro S.; RT "Functional and molecular diversity of parkin."; RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 7 AND 8). RC TISSUE=Retina; RA Campello L., Esteve-Rudd J., Cuenca N., Martin-Nieto J.; RT "Homo sapiens PARK2 transcript variants."; RL Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=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 [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 5). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 312-361. RA Zou H.Q., Chan P.; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [10] RP SUBCELLULAR LOCATION. RX PubMed=10319893; RX DOI=10.1002/1531-8249(199905)45:5<668::aid-ana19>3.0.co;2-z; RA Shimura H., Hattori N., Kubo S., Yoshikawa M., Kitada T., Matsumine H., RA Asakawa S., Minoshima S., Yamamura Y., Shimizu N., Mizuno Y.; RT "Immunohistochemical and subcellular localization of Parkin protein: RT absence of protein in autosomal recessive juvenile parkinsonism patients."; RL Ann. Neurol. 45:668-672(1999). RN [11] RP FUNCTION IN UBIQUITINATION. RX PubMed=10973942; DOI=10.1074/jbc.c000447200; RA Imai Y., Soda M., Takahashi R.; RT "Parkin suppresses unfolded protein stress-induced cell death through its RT E3 ubiquitin-protein ligase activity."; RL J. Biol. Chem. 275:35661-35664(2000). RN [12] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND ARG-240. RX PubMed=10888878; DOI=10.1038/77060; RA Shimura H., Hattori N., Kubo S., Mizuno Y., Asakawa S., Minoshima S., RA Shimizu N., Iwai K., Chiba T., Tanaka K., Suzuki T.; RT "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein RT ligase."; RL Nat. Genet. 25:302-305(2000). RN [13] RP INTERACTION WITH UBE2L6 AND SEPTIN5, AND UBIQUITINATION OF SEPTIN5. RX PubMed=11078524; DOI=10.1073/pnas.240347797; RA Zhang Y., Gao J., Chung K.K.K., Huang H., Dawson V.L., Dawson T.M.; RT "Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes RT the degradation of the synaptic vesicle-associated protein, CDCrel-1."; RL Proc. Natl. Acad. Sci. U.S.A. 97:13354-13359(2000). RN [14] RP UBIQUITINATION OF GPR37. RX PubMed=11439185; DOI=10.1016/s0092-8674(01)00407-x; RA Imai Y., Soda M., Inoue H., Hattori N., Mizuno Y., Takahashi R.; RT "An unfolded putative transmembrane polypeptide, which can lead to RT endoplasmic reticulum stress, is a substrate of Parkin."; RL Cell 105:891-902(2001). RN [15] RP FUNCTION, INTERACTION WITH SNCAIP, CHARACTERIZATION OF VARIANTS PARK2 RP ARG-240; CYS-256; TRP-275 AND ASN-415, AND MUTAGENESIS OF CYS-337; CYS-421 RP AND CYS-431. RX PubMed=11590439; DOI=10.1038/nm1001-1144; RA Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: RT implications for Lewy-body formation in Parkinson disease."; RL Nat. Med. 7:1144-1150(2001). RN [16] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK2 RP PRO-42 AND ARG-240. RX PubMed=11431533; DOI=10.1126/science.1060627; RA Shimura H., Schlossmacher M.G., Hattori N., Frosch M.P., Trockenbacher A., RA Schneider R., Mizuno Y., Kosik K.S., Selkoe D.J.; RT "Ubiquitination of a new form of alpha-synuclein by parkin from human RT brain: implications for Parkinson's disease."; RL Science 293:263-269(2001). RN [17] RP PRESENCE OF ATYPICAL RING FINGER DOMAINS. RX PubMed=12446796; DOI=10.1093/oxfordjournals.molbev.a004029; RA Marin I., Ferrus A.; RT "Comparative genomics of the RBR family, including the Parkinson's disease- RT related gene parkin and the genes of the ariadne subfamily."; RL Mol. Biol. Evol. 19:2039-2050(2002). RN [18] RP FUNCTION, INTERACTION WITH STUB1; HSP70 AND GPR37, AND UBIQUITINATION OF RP STUB1. RX PubMed=12150907; DOI=10.1016/s1097-2765(02)00583-x; RA Imai Y., Soda M., Hatakeyama S., Akagi T., Hashikawa T., Nakayama K., RA Takahashi R.; RT "CHIP is associated with Parkin, a gene responsible for familial RT Parkinson's disease, and enhances its ubiquitin ligase activity."; RL Mol. Cell 10:55-67(2002). RN [19] RP INTERACTION WITH SYT11, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF RP VARIANTS PARK2 GLY-289 AND ARG-418. RX PubMed=12925569; DOI=10.1093/hmg/ddg269; RA Huynh D.P., Scoles D.R., Nguyen D., Pulst S.M.; RT "The autosomal recessive juvenile Parkinson disease gene product, parkin, RT interacts with and ubiquitinates synaptotagmin XI."; RL Hum. Mol. Genet. 12:2587-2597(2003). RN [20] RP INTERACTION WITH PACRG. RX PubMed=14532270; DOI=10.1074/jbc.m309655200; RA Imai Y., Soda M., Murakami T., Shoji M., Abe K., Takahashi R.; RT "A product of the human gene adjacent to parkin is a component of Lewy RT bodies and suppresses Pael receptor-induced cell death."; RL J. Biol. Chem. 278:51901-51910(2003). RN [21] RP FUNCTION, INTERACTION WITH FBXW7 AND CUL1, TISSUE SPECIFICITY, AND RP UBIQUITINATION OF CYCLIN E. RX PubMed=12628165; DOI=10.1016/s0896-6273(03)00084-9; RA Staropoli J.F., McDermott C., Martinat C., Schulman B., Demireva E., RA Abeliovich A.; RT "Parkin is a component of an SCF-like ubiquitin ligase complex and protects RT postmitotic neurons from kainate excitotoxicity."; RL Neuron 37:735-749(2003). RN [22] RP INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=14614460; DOI=10.1038/sj.onc.1207072; RA Denison S.R., Wang F., Becker N.A., Schuele B., Kock N., Phillips L.A., RA Klein C., Smith D.I.; RT "Alterations in the common fragile site gene Parkin in ovarian and other RT cancers."; RL Oncogene 22:8370-8378(2003). RN [23] RP FUNCTION, INVOLVEMENT IN CANCER, AND TISSUE SPECIFICITY. RX PubMed=12719539; DOI=10.1073/pnas.0931262100; RA Cesari R., Martin E.S., Calin G.A., Pentimalli F., Bichi R., McAdams H., RA Trapasso F., Drusco A., Shimizu M., Masciullo V., D'Andrilli G., RA Scambia G., Picchio M.C., Alder H., Godwin A.K., Croce C.M.; RT "Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is RT a candidate tumor suppressor gene on chromosome 6q25-q27."; RL Proc. Natl. Acad. Sci. U.S.A. 100:5956-5961(2003). RN [24] RP REVIEW. RX PubMed=15229644; DOI=10.1038/sj.embor.7400188; RA Kahle P.J., Haass C.; RT "How does parkin ligate ubiquitin to Parkinson's disease?"; RL EMBO Rep. 5:681-685(2004). RN [25] RP FUNCTION, UBIQUITINATION, AND S-NITROSYLATION. RX PubMed=15105460; DOI=10.1126/science.1093891; RA Chung K.K.K., Thomas B., Li X., Pletnikova O., Troncoso J.C., Marsh L., RA Dawson V.L., Dawson T.M.; RT "S-nitrosylation of parkin regulates ubiquitination and compromises RT parkin's protective function."; RL Science 304:1328-1331(2004). RN [26] RP INTERACTION WITH PSMA7. RX PubMed=15987638; DOI=10.1016/j.febslet.2005.06.003; RA Dachsel J.C., Lucking C.B., Deeg S., Schultz E., Lalowski M., RA Casademunt E., Corti O., Hampe C., Patenge N., Vaupel K., Yamamoto A., RA Dichgans M., Brice A., Wanker E.E., Kahle P.J., Gasser T.; RT "Parkin interacts with the proteasome subunit alpha4."; RL FEBS Lett. 579:3913-3919(2005). RN [27] RP FUNCTION, AND INTERACTION WITH SNCAIP. RX PubMed=15728840; DOI=10.1523/jneurosci.4474-04.2005; RA Lim K.L., Chew K.C., Tan J.M., Wang C., Chung K.K., Zhang Y., Tanaka Y., RA Smith W., Engelender S., Ross C.A., Dawson V.L., Dawson T.M.; RT "Parkin mediates nonclassical, proteasomal-independent ubiquitination of RT synphilin-1: implications for Lewy body formation."; RL J. Neurosci. 25:2002-2009(2005). RN [28] RP FUNCTION, AND INTERACTION WITH AIMP2. RX PubMed=16135753; DOI=10.1523/jneurosci.2172-05.2005; RA Ko H.S., von Coelln R., Sriram S.R., Kim S.W., Chung K.K.K., Pletnikova O., RA Troncoso J., Johnson B., Saffary R., Goh E.L., Song H., Park B.-J., RA Kim M.J., Kim S., Dawson V.L., Dawson T.M.; RT "Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase RT cofactor, p38/JTV-1, leads to catecholaminergic cell death."; RL J. Neurosci. 25:7968-7978(2005). RN [29] RP INTERACTION WITH LRRK2. RX PubMed=16352719; DOI=10.1073/pnas.0508052102; RA Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B., Dawson V.L., RA Dawson T.M., Ross C.A.; RT "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant RT LRRK2 induces neuronal degeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 102:18676-18681(2005). RN [30] RP INTERACTION WITH RANBP2. RX PubMed=16332688; DOI=10.1074/jbc.m504994200; RA Um J.W., Min D.S., Rhim H., Kim J., Paik S.R., Chung K.C.; RT "Parkin ubiquitinates and promotes the degradation of RanBP2."; RL J. Biol. Chem. 281:3595-3603(2006). RN [31] RP INTERACTION WITH SUMO1, AND SUBCELLULAR LOCATION. RX PubMed=16955485; DOI=10.1002/jnr.21041; RA Um J.W., Chung K.C.; RT "Functional modulation of parkin through physical interaction with SUMO- RT 1."; RL J. Neurosci. Res. 84:1543-1554(2006). RN [32] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=17846173; DOI=10.1083/jcb.200611128; RA Olzmann J.A., Li L., Chudaev M.V., Chen J., Perez F.A., Palmiter R.D., RA Chin L.S.; RT "Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to RT aggresomes via binding to HDAC6."; RL J. Cell Biol. 178:1025-1038(2007). RN [33] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-175 AND THR-217, AND RP MUTAGENESIS OF THR-175; THR-217 AND CYS-238. RX PubMed=18957282; DOI=10.1016/j.bbrc.2008.10.104; RA Kim Y., Park J., Kim S., Song S., Kwon S.K., Lee S.H., Kitada T., Kim J.M., RA Chung J.; RT "PINK1 controls mitochondrial localization of Parkin through direct RT phosphorylation."; RL Biochem. Biophys. Res. Commun. 377:975-980(2008). RN [34] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, AND SUBCELLULAR LOCATION. RX PubMed=19029340; DOI=10.1083/jcb.200809125; RA Narendra D., Tanaka A., Suen D.F., Youle R.J.; RT "Parkin is recruited selectively to impaired mitochondria and promotes RT their autophagy."; RL J. Cell Biol. 183:795-803(2008). RN [35] RP INTERACTION WITH RNF41, UBIQUITINATION, MUTAGENESIS OF CYS-421, AND RP FUNCTION. RX PubMed=18541373; DOI=10.1016/j.neulet.2008.05.052; RA Yu F., Zhou J.; RT "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative RT stress."; RL Neurosci. Lett. 440:4-8(2008). RN [36] RP FUNCTION, COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1, RP SUBCELLULAR LOCATION, UBIQUITINATION, AND CHARACTERIZATION OF VARIANT PARK2 RP PRO-42. RX PubMed=19229105; DOI=10.1172/jci37617; RA Xiong H., Wang D., Chen L., Choo Y.S., Ma H., Tang C., Xia K., Jiang W., RA Ronai Z., Zhuang X., Zhang Z.; RT "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting RT unfolded protein degradation."; RL J. Clin. Invest. 119:650-660(2009). RN [37] RP FUNCTION IN PROTECTION OF APOPTOSIS, CHARACTERIZATION OF VARIANTS PARK2 RP ASN-161; CYS-256; TRP-275; ARG-418 AND ARG-441, AND DOMAIN. RX PubMed=19801972; DOI=10.1038/ncb1981; RA da Costa C.A., Sunyach C., Giaime E., West A., Corti O., Brice A., Safe S., RA Abou-Sleiman P.M., Wood N.W., Takahashi H., Goldberg M.S., Shen J., RA Checler F.; RT "Transcriptional repression of p53 by parkin and impairment by mutations RT associated with autosomal recessive juvenile Parkinson's disease."; RL Nat. Cell Biol. 11:1370-1375(2009). RN [38] RP INTERACTION WITH PINK1. RX PubMed=20798600; DOI=10.4161/auto.6.7.13286; RA Geisler S., Holmstrom K.M., Treis A., Skujat D., Weber S.S., Fiesel F.C., RA Kahle P.J., Springer W.; RT "The PINK1/Parkin-mediated mitophagy is compromised by PD-associated RT mutations."; RL Autophagy 6:871-878(2010). RN [39] RP FUNCTION, INTERACTION WITH BCL2, SUBCELLULAR LOCATION, AND CHARACTERIZATION RP OF VARIANTS PARK2 ASN-161; ARG-240; PHE-431 AND LEU-437. RX PubMed=20889974; DOI=10.1074/jbc.m110.101469; RA Chen D., Gao F., Li B., Wang H., Xu Y., Zhu C., Wang G.; RT "Parkin mono-ubiquitinates Bcl-2 and regulates autophagy."; RL J. Biol. Chem. 285:38214-38223(2010). RN [40] RP FUNCTION IN MITOCHONDRIAL AUTOPHAGY, SUBCELLULAR LOCATION, INTERACTION WITH RP PINK1, AND CHARACTERIZATION OF VARIANTS PARK ASN-415 AND ASP-430. RX PubMed=19966284; DOI=10.1073/pnas.0911187107; RA Vives-Bauza C., Zhou C., Huang Y., Cui M., de Vries R.L., Kim J., May J., RA Tocilescu M.A., Liu W., Ko H.S., Magrane J., Moore D.J., Dawson V.L., RA Grailhe R., Dawson T.M., Li C., Tieu K., Przedborski S.; RT "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy."; RL Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010). RN [41] RP FUNCTION, INTERACTION WITH ZNF746, AND CHARACTERIZATION OF VARIANTS PARK2 RP TRP-275; ASP-430 AND PHE-431. RX PubMed=21376232; DOI=10.1016/j.cell.2011.02.010; RA Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O., RA Troconso J.C., Dawson V.L., Dawson T.M.; RT "PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration RT in Parkinson's disease."; RL Cell 144:689-702(2011). RN [42] RP CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND GLY-289. RX PubMed=20889486; DOI=10.1093/hmg/ddq428; RA Rose J.M., Novoselov S.S., Robinson P.A., Cheetham M.E.; RT "Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain RT mutant."; RL Hum. Mol. Genet. 20:16-27(2011). RN [43] RP FUNCTION. RX PubMed=21753002; DOI=10.1523/jneurosci.1917-11.2011; RA Van Humbeeck C., Cornelissen T., Hofkens H., Mandemakers W., Gevaert K., RA De Strooper B., Vandenberghe W.; RT "Parkin interacts with Ambra1 to induce mitophagy."; RL J. Neurosci. 31:10249-10261(2011). RN [44] RP FUNCTION, REACTION MECHANISM, AND INTERACTION WITH UBE2L3. RX PubMed=21532592; DOI=10.1038/nature09966; RA Wenzel D.M., Lissounov A., Brzovic P.S., Klevit R.E.; RT "UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT RT hybrids."; RL Nature 474:105-108(2011). RN [45] RP FUNCTION, INTERACTION WITH CHPF, AND SUBCELLULAR LOCATION. RX PubMed=22082830; DOI=10.1093/hmg/ddr530; RA Kuroda Y., Sako W., Goto S., Sawada T., Uchida D., Izumi Y., Takahashi T., RA Kagawa N., Matsumoto M., Matsumoto M., Takahashi R., Kaji R., Mitsui T.; RT "Parkin interacts with Klokin1 for mitochondrial import and maintenance of RT membrane potential."; RL Hum. Mol. Genet. 21:991-1003(2012). RN [46] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS PARK2 ASN-211 AND ASN-415. RX PubMed=22396657; DOI=10.1371/journal.pgen.1002537; RA Liu S., Sawada T., Lee S., Yu W., Silverio G., Alapatt P., Millan I., RA Shen A., Saxton W., Kanao T., Takahashi R., Hattori N., Imai Y., Lu B.; RT "Parkinson's disease-associated kinase PINK1 regulates Miro protein level RT and axonal transport of mitochondria."; RL PLoS Genet. 8:E1002537-E1002537(2012). RN [47] RP PHOSPHORYLATION AT SER-65, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23754282; DOI=10.1074/jbc.m113.467530; RA Iguchi M., Kujuro Y., Okatsu K., Koyano F., Kosako H., Kimura M., RA Suzuki N., Uchiyama S., Tanaka K., Matsuda N.; RT "Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent RT phosphorylation."; RL J. Biol. Chem. 288:22019-22032(2013). RN [48] RP FUNCTION. RX PubMed=23685073; DOI=10.1016/j.molcel.2013.04.012; RA Haddad D.M., Vilain S., Vos M., Esposito G., Matta S., Kalscheuer V.M., RA Craessaerts K., Leyssen M., Nascimento R.M., Vianna-Morgante A.M., RA De Strooper B., Van Esch H., Morais V.A., Verstreken P.; RT "Mutations in the intellectual disability gene Ube2a cause neuronal RT dysfunction and impair parkin-dependent mitophagy."; RL Mol. Cell 50:831-843(2013). RN [49] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FBXO7. RX PubMed=23933751; DOI=10.1038/nn.3489; RA Burchell V.S., Nelson D.E., Sanchez-Martinez A., Delgado-Camprubi M., RA Ivatt R.M., Pogson J.H., Randle S.J., Wray S., Lewis P.A., Houlden H., RA Abramov A.Y., Hardy J., Wood N.W., Whitworth A.J., Laman H., RA Plun-Favreau H.; RT "The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to RT mediate mitophagy."; RL Nat. Neurosci. 16:1257-1265(2013). RN [50] RP INTERACTION WITH BAG4; BAG5; HSPA1L; HSPA1A AND HSPA8. RX PubMed=24270810; DOI=10.1038/nature12748; RA Hasson S.A., Kane L.A., Yamano K., Huang C.H., Sliter D.A., Buehler E., RA Wang C., Heman-Ackah S.M., Hessa T., Guha R., Martin S.E., Youle R.J.; RT "High-content genome-wide RNAi screens identify regulators of parkin RT upstream of mitophagy."; RL Nature 504:291-295(2013). RN [51] RP UBIQUITINATION, MUTAGENESIS OF GLY-429, AND CHARACTERIZATION OF VARIANTS RP PARK2 ASN-415 AND ASP-430. RX PubMed=23770917; DOI=10.1038/ncomms2983; RA Spratt D.E., Martinez-Torres R.J., Noh Y.J., Mercier P., Manczyk N., RA Barber K.R., Aguirre J.D., Burchell L., Purkiss A., Walden H., Shaw G.S.; RT "A molecular explanation for the recessive nature of parkin-linked RT Parkinson's disease."; RL Nat. Commun. 4:1983-1983(2013). RN [52] RP FUNCTION IN MITOPHAGY, INTERACTION WITH MFN2, AND SUBCELLULAR LOCATION. RX PubMed=23620051; DOI=10.1126/science.1231031; RA Chen Y., Dorn G.W. II; RT "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged RT mitochondria."; RL Science 340:471-475(2013). RN [53] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65. RX PubMed=24660806; DOI=10.1042/bj20140334; RA Kazlauskaite A., Kondapalli C., Gourlay R., Campbell D.G., Ritorto M.S., RA Hofmann K., Alessi D.R., Knebel A., Trost M., Muqit M.M.; RT "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at RT Ser65."; RL Biochem. J. 460:127-139(2014). RN [54] RP SUBCELLULAR LOCATION. RX PubMed=24898855; DOI=10.7554/elife.01958; RA Yun J., Puri R., Yang H., Lizzio M.A., Wu C., Sheng Z.H., Guo M.; RT "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin RT and compensates for loss of PINK1/parkin."; RL Elife 3:E01958-E01958(2014). RN [55] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND CYS-431. RX PubMed=25474007; DOI=10.1371/journal.pgen.1004861; RA Shiba-Fukushima K., Arano T., Matsumoto G., Inoshita T., Yoshida S., RA Ishihama Y., Ryu K.Y., Nukina N., Hattori N., Imai Y.; RT "Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin RT mitochondrial tethering."; RL PLoS Genet. 10:e1004861-e1004861(2014). RN [56] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=24751536; DOI=10.1083/jcb.201402104; RA Kane L.A., Lazarou M., Fogel A.I., Li Y., Yamano K., Sarraf S.A., RA Banerjee S., Youle R.J.; RT "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase RT activity."; RL J. Cell Biol. 205:143-153(2014). RN [57] RP FUNCTION, PHOSPHORYLATION AT SER-65, UBIQUITIN-BINDING, ACTIVITY RP REGULATION, AND MUTAGENESIS OF SER-65 AND TRP-403. RX PubMed=24784582; DOI=10.1038/nature13392; RA Koyano F., Okatsu K., Kosako H., Tamura Y., Go E., Kimura M., Kimura Y., RA Tsuchiya H., Yoshihara H., Hirokawa T., Endo T., Fon E.A., Trempe J.F., RA Saeki Y., Tanaka K., Matsuda N.; RT "Ubiquitin is phosphorylated by PINK1 to activate parkin."; RL Nature 510:162-166(2014). RN [58] RP FUNCTION. RX PubMed=24896179; DOI=10.1038/nature13418; RA Bingol B., Tea J.S., Phu L., Reichelt M., Bakalarski C.E., Song Q., RA Foreman O., Kirkpatrick D.S., Sheng M.; RT "The mitochondrial deubiquitinase USP30 opposes parkin-mediated RT mitophagy."; RL Nature 510:370-375(2014). RN [59] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=25527291; DOI=10.15252/embj.201489847; RA Wauer T., Swatek K.N., Wagstaff J.L., Gladkova C., Pruneda J.N., RA Michel M.A., Gersch M., Johnson C.M., Freund S.M., Komander D.; RT "Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain RT assembly and hydrolysis."; RL EMBO J. 34:307-325(2015). RN [60] RP FUNCTION. RX PubMed=25621951; DOI=10.1038/ncb3097; RA Cunningham C.N., Baughman J.M., Phu L., Tea J.S., Yu C., Coons M., RA Kirkpatrick D.S., Bingol B., Corn J.E.; RT "USP30 and parkin homeostatically regulate atypical ubiquitin chains on RT mitochondria."; RL Nat. Cell Biol. 17:160-169(2015). RN [61] RP FUNCTION, ISGYLATION OF LYS-349 AND LYS-369, AND ACTIVITY REGULATION. RX PubMed=27534820; DOI=10.1098/rsob.160193; RA Im E., Yoo L., Hyun M., Shin W.H., Chung K.C.; RT "Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase RT activity of parkin."; RL Open Biol. 6:0-0(2016). RN [62] RP FUNCTION, MUTAGENESIS OF CYS-431, AND CHARACTERIZATION OF VARIANT PARK2 RP ASN-415. RX PubMed=32047033; DOI=10.1073/pnas.1909814117; RA Ham S.J., Lee D., Yoo H., Jun K., Shin H., Chung J.; RT "Decision between mitophagy and apoptosis by Parkin via VDAC1 RT ubiquitination."; RL Proc. Natl. Acad. Sci. U.S.A. 117:4281-4291(2020). RN [63] RP FUNCTION. RX PubMed=33499712; DOI=10.1080/15548627.2021.1874133; RA Kojima W., Yamano K., Kosako H., Imai K., Kikuchi R., Tanaka K., RA Matsuda N.; RT "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site RT in response to selective and non-selective autophagy."; RL Autophagy 1:1-26(2021). RN [64] RP STRUCTURE BY NMR OF 1-76, AND INTERACTION WITH PSMD4. RX PubMed=12634850; DOI=10.1038/sj.embor.embor764; RA Sakata E., Yamaguchi Y., Kurimoto E., Kikuchi J., Yokoyama S., Yamada S., RA Kawahara H., Yokosawa H., Hattori N., Mizuno Y., Tanaka K., Kato K.; RT "Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin- RT like domain."; RL EMBO Rep. 4:301-306(2003). RN [65] RP STRUCTURE BY NMR OF 307-384 IN COMPLEX WITH ZINC IONS, CHARACTERIZATION OF RP VARIANT PARK2 PRO-351, MUTAGENESIS OF CYS-332 AND CYS-365, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17360614; DOI=10.1073/pnas.0610548104; RA Beasley S.A., Hristova V.A., Shaw G.S.; RT "Structure of the Parkin in-between-ring domain provides insights for E3- RT ligase dysfunction in autosomal recessive Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 104:3095-3100(2007). RN [66] RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 137-465, ACTIVITY REGULATION, AND RP MUTAGENESIS OF CYS-431; HIS-433 AND GLU-444. RX PubMed=23727886; DOI=10.1038/emboj.2013.125; RA Wauer T., Komander D.; RT "Structure of the human Parkin ligase domain in an autoinhibited state."; RL EMBO J. 32:2099-2112(2013). RN [67] RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 137-465, ACTIVE SITE, CATALYTIC RP ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-431; HIS-433 AND RP GLU-444. RX PubMed=23770887; DOI=10.1038/ncomms2982; RA Riley B.E., Lougheed J.C., Callaway K., Velasquez M., Brecht E., Nguyen L., RA Shaler T., Walker D., Yang Y., Regnstrom K., Diep L., Zhang Z., Chiou S., RA Bova M., Artis D.R., Yao N., Baker J., Yednock T., Johnston J.A.; RT "Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RT RING and HECT ligases."; RL Nat. Commun. 4:1982-1982(2013). RN [68] RP REVIEW ON VARIANTS. RX PubMed=14976155; DOI=10.1093/hmg/ddh089; RA Mata I.F., Lockhart P.J., Farrer M.J.; RT "Parkin genetics: one model for Parkinson's disease."; RL Hum. Mol. Genet. 13:R127-R133(2004). RN [69] RP VARIANT PARK2 ARG-240. RX PubMed=9731209; DOI=10.1006/bbrc.1998.9134; RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RT "Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene."; RL Biochem. Biophys. Res. Commun. 249:754-758(1998). RN [70] RP ERRATUM OF PUBMED:9731209. RA Hattori N., Matsumine H., Asakawa S., Kitada T., Yoshino H., Elibol B., RA Brookes A.J., Yamamura Y., Kobayashi T., Wang M., Yoritaka A., RA Minoshima S., Shimizu N., Mizuno Y.; RL Biochem. Biophys. Res. Commun. 251:666-666(1998). RN [71] RP VARIANTS PARK2 ASN-161; CYS-256; TRP-275 AND ASN-415, AND VARIANTS ASN-167; RP LEU-380 AND ASN-394. RX PubMed=10072423; DOI=10.1093/hmg/8.4.567; RA Abbas N., Luecking C.B., Ricard S., Duerr A., Bonifati V., De Michele G., RA Bouley S., Vaughan J.R., Gasser T., Marconi R., Broussolle E., RA Brefel-Courbon C., Harhangi B.S., Oostra B.A., Fabrizio E., Bohme G.A., RA Pradier L., Wood N.W., Filla A., Meco G., Denefle P., Agid Y., Brice A.; RT "A wide variety of mutations in the parkin gene are responsible for RT autosomal recessive parkinsonism in Europe."; RL Hum. Mol. Genet. 8:567-574(1999). RN [72] RP VARIANT ASN-167. RX PubMed=10511432; DOI=10.1097/00001756-199909090-00008; RA Satoh J., Kuroda Y.; RT "Association of codon 167 Ser/Asn heterozygosity in the parkin gene with RT sporadic Parkinson's disease."; RL NeuroReport 10:2735-2739(1999). RN [73] RP VARIANT PARK2 PHE-431. RX PubMed=10939576; RX DOI=10.1002/1531-8249(200008)48:2<245::aid-ana15>3.3.co;2-u; RA Maruyama M., Ikeuchi T., Saito M., Ishikawa A., Yuasa T., Tanaka H., RA Hayashi S., Wakabayashi K., Takahashi H., Tsuji S.; RT "Novel mutations, pseudo-dominant inheritance, and possible familial RT affects in patients with autosomal recessive juvenile parkinsonism."; RL Ann. Neurol. 48:245-250(2000). RN [74] RP VARIANTS ASN-167; TRP-366 AND LEU-380. RX PubMed=10965160; DOI=10.1159/000008203; RA Hu C.-J., Sung S.-M., Liu H.-C., Lee C.-C., Tsai C.-H., Chang J.-G.; RT "Polymorphisms of the parkin gene in sporadic Parkinson's disease among RT Chinese in Taiwan."; RL Eur. Neurol. 44:90-93(2000). RN [75] RP VARIANTS PARK2 ASN-161; ASN-211; CYS-256; TRP-275; ASN-280; GLY-289; RP GLU-328; ASN-415 AND ASP-430, AND VARIANT CYS-334. RX PubMed=10824074; DOI=10.1056/nejm200005253422103; RA Luecking C.B., Duerr A., Bonifati V., Vaughan J.R., De Michele G., RA Gasser T., Harhangi B.S., Meco G., Denefle P., Wood N.W., Agid Y., RA Brice A.; RT "Association between early-onset Parkinson's disease and mutations in the RT parkin gene."; RL N. Engl. J. Med. 342:1560-1567(2000). RN [76] RP VARIANTS PARK2 ASN-211; TRP-275 AND ASP-430. RX PubMed=11179010; DOI=10.1086/318791; RA Periquet M., Luecking C.B., Vaughan J.R., Bonifati V., Duerr A., RA De Michele G., Horstink M., Farrer M., Illarioshkin S.N., Pollak P., RA Borg M., Brefel-Courbon C., Denefle P., Meco G., Gasser T., Breteler M.M., RA Wood N.W., Agid Y., Brice A.; RT "Origin of the mutations in the parkin gene in Europe: exon rearrangements RT are independent recurrent events, whereas point mutations may result from RT founder effects."; RL Am. J. Hum. Genet. 68:617-626(2001). RN [77] RP VARIANT PARK2 GLU-82. RX PubMed=11487568; DOI=10.1093/hmg/10.16.1649; RA Hedrich K., Kann M., Lanthaler A.J., Dalski A., Eskelson C., Landt O., RA Schwinger E., Vieregge P., Lang A.E., Breakefield X.O., Ozelius L.J., RA Pramstaller P.P., Klein C.; RT "The importance of gene dosage studies: mutational analysis of the parkin RT gene in early-onset parkinsonism."; RL Hum. Mol. Genet. 10:1649-1656(2001). RN [78] RP VARIANT PARK2 TYR-212. RX PubMed=11163284; DOI=10.1016/s0304-3940(00)01733-x; RA Pineda-Trujillo N., Carvajal-Carmona L.G., Buritica O., Moreno S., RA Uribe C., Pineda D., Toro M., Garcia F., Arias W., Bedoya G., Lopera F., RA Ruiz-Linares A.; RT "A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of RT juvenile parkinsonism in a population from North West Colombia."; RL Neurosci. Lett. 298:87-90(2001). RN [79] RP VARIANTS PARK2 GLU-82; CYS-256; TRP-275; GLU-328 AND ARG-441. RX PubMed=12116199; DOI=10.1002/ajmg.10525; RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.; RT "Complex relationship between parkin mutations and Parkinson disease."; RL Am. J. Med. Genet. 114:584-591(2002). RN [80] RP ERRATUM OF PUBMED:12116199. RG French Parkinson's disease genetics study group; RG European consortium on genetic susceptibility on Parkinson's disease; RA West A., Periquet M., Lincoln S., Luecking C.B., Nicholl D., Bonifati V., RA Rawal N., Gasser T., Lohmann E., Deleuze J.-F., Maraganore D., Levey A., RA Wood N.W., Duerr A., Hardy J., Brice A., Farrer M.J.; RL Am. J. Med. Genet. 114:992-992(2002). RN [81] RP VARIANTS PARK2 LEU-37 AND PRO-351. RX PubMed=12112109; DOI=10.1002/ana.10179; RA Kann M., Jacobs H., Mohrmann K., Schumacher K., Hedrich K., Garrels J., RA Wiegers K., Schwinger E., Pramstaller P.P., Breakefield X.O., Ozelius L.J., RA Vieregge P., Klein C.; RT "Role of parkin mutations in 111 community-based patients with early-onset RT parkinsonism."; RL Ann. Neurol. 51:621-625(2002). RN [82] RP VARIANTS PARK2 GLU-56 AND TYR-212. RX PubMed=12056932; DOI=10.1001/archneur.59.6.966; RA Hoenicka J., Vidal L., Morales B., Ampuero I., Jimenez-Jimenez F.J., RA Berciano J., del Ser T., Jimenez A., Ruiz P.G., de Yebenes J.G.; RT "Molecular findings in familial Parkinson disease in Spain."; RL Arch. Neurol. 59:966-970(2002). RN [83] RP VARIANTS PARK2 ASN-211; TRP-275; ASP-430 AND LEU-437. RX PubMed=12114481; DOI=10.1136/jmg.39.7.489; RA Nichols W.C., Pankratz N., Uniacke S.K., Pauciulo M.W., Halter C., RA Rudolph A., Conneally P.M., Foroud T.; RT "Linkage stratification and mutation analysis at the parkin locus RT identifies mutation positive Parkinson's disease families."; RL J. Med. Genet. 39:489-492(2002). RN [84] RP VARIANT PARK2 MET-15, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12397156; DOI=10.1136/jnnp.73.5.582; RA Munoz E., Tolosa E., Pastor P., Marti M.J., Valldeoriola F., RA Campdelacreu J., Oliva R.; RT "Relative high frequency of the c.255delA parkin gene mutation in Spanish RT patients with autosomal recessive parkinsonism."; RL J. Neurol. Neurosurg. Psych. 73:582-584(2002). RN [85] RP VARIANTS PARK2 PRO-42; LEU-192; CYS-256; TRP-275; ASP-430 AND LEU-437. RX PubMed=11971093; DOI=10.1212/wnl.58.8.1239; RA Hedrich K., Marder K., Harris J., Kann M., Lynch T., Meija-Santana H., RA Pramstaller P.P., Schwinger E., Bressman S.B., Fahn S., Klein C.; RT "Evaluation of 50 probands with early-onset Parkinson's disease for parkin RT mutations."; RL Neurology 58:1239-1246(2002). RN [86] RP VARIANT PARK2 PRO-46. RX PubMed=12362318; RA Xu Y., Liu Z., Wang Y., Tao E., Chen G., Chen B.; RT "A new point mutation on exon 2 of parkin gene in Parkinson's disease."; RL Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19:409-411(2002). RN [87] RP VARIANTS PARK2 GLN-33; GLU-82; ASP-430 AND LEU-437, VARIANTS PARK TYR-253; RP CYS-256; TRP-275 AND ASN-280, AND VARIANTS LEU-380 AND ASN-394. RX PubMed=12730996; DOI=10.1002/ana.10524; RA Oliveira S.A., Scott W.K., Martin E.R., Nance M.A., Watts R.L., RA Hubble J.P., Koller W.C., Pahwa R., Stern M.B., Hiner B.C., Ondo W.G., RA Allen F.H. Jr., Scott B.L., Goetz C.G., Small G.W., Mastaglia F., RA Stajich J.M., Zhang F., Booze M.W., Winn M.P., Middleton L.T., Haines J.L., RA Pericak-Vance M.A., Vance J.M.; RT "Parkin mutations and susceptibility alleles in late-onset Parkinson's RT disease."; RL Ann. Neurol. 53:624-629(2003). RN [88] RP VARIANTS PARK2 VAL-192; ASN-211; MET-240 AND LEU-437, VARIANT ASN-167, AND RP INVOLVEMENT IN LATE-ONSET PARK. RX PubMed=12629236; DOI=10.1212/01.wnl.0000049470.00180.07; RA Foroud T., Uniacke S.K., Liu L., Pankratz N., Rudolph A., Halter C., RA Shults C., Marder K., Conneally P.M., Nichols W.C.; RT "Heterozygosity for a mutation in the parkin gene leads to later onset RT Parkinson disease."; RL Neurology 60:796-801(2003). RN [89] RP VARIANTS HIS-100; SER-271 AND SER-339. RX PubMed=12781599; DOI=10.1016/s1353-8020(03)00018-x; RA Chen R., Gosavi N.S., Langston J.W., Chan P.; RT "Parkin mutations are rare in patients with young-onset parkinsonism in a RT US population."; RL Parkinsonism Relat. Disord. 9:309-312(2003). RN [90] RP VARIANTS PARK2 PRO-42; CYS-402; ASN-415 AND ARG-418. RX PubMed=15584030; DOI=10.1002/mds.20343; RG Italian Parkinson Genetics Network; RA Bertoli-Avella A.M., Giroud-Benitez J.L., Akyol A., Barbosa E., Schaap O., RA van der Linde H.C., Martignoni E., Lopiano L., Lamberti P., Fincati E., RA Antonini A., Stocchi F., Montagna P., Squitieri F., Marini P., RA Abbruzzese G., Fabbrini G., Marconi R., Dalla Libera A., Trianni G., RA Guidi M., De Gaetano A., Boff Maegawa G., De Leo A., Gallai V., de Rosa G., RA Vanacore N., Meco G., van Duijn C.M., Oostra B.A., Heutink P., Bonifati V.; RT "Novel parkin mutations detected in patients with early-onset Parkinson's RT disease."; RL Mov. Disord. 20:424-431(2005). RN [91] RP CHARACTERIZATION OF VARIANTS PARK2 ASN-161; ASN-211; ARG-240; ASN-280 AND RP GLU-328. RX PubMed=20404107; DOI=10.1083/jcb.200910140; RA Matsuda N., Sato S., Shiba K., Okatsu K., Saisho K., Gautier C.A., RA Sou Y.S., Saiki S., Kawajiri S., Sato F., Kimura M., Komatsu M., RA Hattori N., Tanaka K.; RT "PINK1 stabilized by mitochondrial depolarization recruits Parkin to RT damaged mitochondria and activates latent Parkin for mitophagy."; RL J. Cell Biol. 189:211-221(2010). RN [92] RP VARIANT PARK2 TRP-275. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ- RT 1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). RN [93] RP VARIANT CYS-334. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [94] RP CHARACTERIZATION OF VARIANTS PARK PRO-42 AND TRP-275, AND FUNCTION. RX PubMed=29311685; DOI=10.1038/s41467-017-02593-y; RA Wang C., Kang X., Zhou L., Chai Z., Wu Q., Huang R., Xu H., Hu M., Sun X., RA Sun S., Li J., Jiao R., Zuo P., Zheng L., Yue Z., Zhou Z.; RT "Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and RT Parkinson's disease-like pathology."; RL Nat. Commun. 9:81-81(2018). CC -!- FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, CC catalyzing the covalent attachment of ubiquitin moieties onto substrate CC proteins (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:29311685, CC PubMed:32047033). Substrates include SYT11 and VDAC1 (PubMed:29311685, CC PubMed:32047033). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, CC MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and CC AIMP2 (PubMed:10888878, PubMed:10973942, PubMed:11431533, CC PubMed:12150907, PubMed:12628165, PubMed:15105460, PubMed:16135753, CC PubMed:21376232, PubMed:21532592, PubMed:22396657, PubMed:23620051, CC PubMed:23754282, PubMed:24660806, PubMed:24751536). Mediates CC monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and CC 'Lys-63'-linked polyubiquitination of substrates depending on the CC context (PubMed:19229105, PubMed:20889974, PubMed:25474007, CC PubMed:25621951, PubMed:32047033). Participates in the removal and/or CC detoxification of abnormally folded or damaged protein by mediating CC 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: CC 'Lys-63'-linked polyubiquitinated misfolded proteins are then CC recognized by HDAC6, leading to their recruitment to aggresomes, CC followed by degradation (PubMed:17846173, PubMed:19229105). Mediates CC 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated CC isoform of SNCAIP, possibly playing a role in Lewy-body formation CC (PubMed:11431533, PubMed:11590439, PubMed:15105460, PubMed:15728840, CC PubMed:19229105). Mediates monoubiquitination of BCL2, thereby acting CC as a positive regulator of autophagy (PubMed:20889974). Protects CC against mitochondrial dysfunction during cellular stress, by acting CC downstream of PINK1 to coordinate mitochondrial quality control CC mechanisms that remove and replace dysfunctional mitochondrial CC components (PubMed:11439185, PubMed:18957282, PubMed:19029340, CC PubMed:19966284, PubMed:21376232, PubMed:22082830, PubMed:22396657, CC PubMed:23620051, PubMed:23933751, PubMed:24660806, PubMed:24784582, CC PubMed:24896179, PubMed:25474007, PubMed:25527291, PubMed:32047033). CC Depending on the severity of mitochondrial damage and/or dysfunction, CC activity ranges from preventing apoptosis and stimulating mitochondrial CC biogenesis to regulating mitochondrial dynamics and eliminating CC severely damaged mitochondria via mitophagy (PubMed:11439185, CC PubMed:19029340, PubMed:19801972, PubMed:19966284, PubMed:21376232, CC PubMed:22082830, PubMed:22396657, PubMed:23620051, PubMed:23685073, CC PubMed:23933751, PubMed:24896179, PubMed:25527291, PubMed:32047033, CC PubMed:33499712). Activation and recruitment onto the outer membrane of CC damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated CC phosphorylation of both PRKN and ubiquitin (PubMed:24660806, CC PubMed:24784582, PubMed:25474007, PubMed:25527291). After mitochondrial CC damage, functions with PINK1 to mediate the decision between mitophagy CC or preventing apoptosis by inducing either the poly- or CC monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 CC promotes mitophagy, while monoubiquitination of VDAC1 decreases CC mitochondrial calcium influx which ultimately inhibits apoptosis CC (PubMed:27534820, PubMed:32047033). When cellular stress results in CC irreversible mitochondrial damage, promotes the autophagic degradation CC of dysfunctional depolarized mitochondria (mitophagy) by promoting the CC ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, CC MFN1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:21753002, CC PubMed:22396657, PubMed:23620051, PubMed:23685073, PubMed:23933751, CC PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, CC 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to CC mitophagy (PubMed:25621951, PubMed:32047033). The PINK1-PRKN pathway CC also promotes fission of damaged mitochondria by PINK1-mediated CC phosphorylation which promotes the PRKN-dependent degradation of CC mitochondrial proteins involved in fission such as MFN2 CC (PubMed:23620051). This prevents the refusion of unhealthy mitochondria CC with the mitochondrial network or initiates mitochondrial fragmentation CC facilitating their later engulfment by autophagosomes CC (PubMed:23620051). Regulates motility of damaged mitochondria via the CC ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor CC neurons, this likely inhibits mitochondrial intracellular anterograde CC transport along the axons which probably increases the chance of the CC mitochondria undergoing mitophagy in the soma (PubMed:22396657). CC Involved in mitochondrial biogenesis via the 'Lys-48'-linked CC polyubiquitination of transcriptional repressor ZNF746/PARIS which CC leads to its subsequent proteasomal degradation and allows activation CC of the transcription factor PPARGC1A (PubMed:21376232). Limits the CC production of reactive oxygen species (ROS) (PubMed:18541373). CC Regulates cyclin-E during neuronal apoptosis (PubMed:12628165). In CC collaboration with CHPF isoform 2, may enhance cell viability and CC protect cells from oxidative stress (PubMed:22082830). Independently of CC its ubiquitin ligase activity, protects from apoptosis by the CC transcriptional repression of p53/TP53 (PubMed:19801972). May protect CC neurons against alpha synuclein toxicity, proteasomal dysfunction, CC GPR37 accumulation, and kainate-induced excitotoxicity CC (PubMed:11439185). May play a role in controlling neurotransmitter CC trafficking at the presynaptic terminal and in calcium-dependent CC exocytosis. May represent a tumor suppressor gene (PubMed:12719539). CC {ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10973942, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11439185, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12150907, CC ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:15105460, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:18957282, CC ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:21753002, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23685073, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, CC ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:25621951, ECO:0000269|PubMed:27534820, CC ECO:0000269|PubMed:29311685, ECO:0000269|PubMed:32047033, CC ECO:0000269|PubMed:33499712}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; CC EC=2.3.2.31; Evidence={ECO:0000269|PubMed:23770887}; CC -!- ACTIVITY REGULATION: In the autoinhibited state the side chain of Phe- CC 463 inserts into a hydrophobic groove in RING-0, occluding the CC ubiquitin acceptor site Cys-431, whereas the REP repressor element CC binds RING-1 and blocks its E2-binding site (PubMed:23727886, CC PubMed:23770887). Activation of PRKN requires 2 steps: (1) CC phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated CC ubiquitin, leading to unlock repression of the catalytic Cys-431 by the CC RING-0 region via an allosteric mechanism and converting PRKN to its CC fully-active form (PubMed:24660806, PubMed:24784582, PubMed:25474007, CC PubMed:25527291). According to another report, phosphorylation at Ser- CC 65 by PINK1 is not essential for activation and only binding to CC phosphorylated ubiquitin is essential to unlock repression CC (PubMed:24751536). In addition, ISG15 conjugation positively regulates CC its ubiquitin E3 ligase activity by suppressing the intramolecular CC interaction that maintains its autoinhibited conformation CC (PubMed:27534820). {ECO:0000269|PubMed:23727886, CC ECO:0000269|PubMed:23770887, ECO:0000269|PubMed:24660806, CC ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, CC ECO:0000269|PubMed:27534820}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6 CC (PubMed:11078524, PubMed:21532592). Mediates 'Lys-63'-linked CC polyubiquitination by associating with UBE2V1. Part of a SCF-like CC complex, consisting of PRKN, CUL1 and FBXW7 (PubMed:12628165). CC Interacts with SNCAIP (PubMed:11590439, PubMed:15728840). Binds to the CC C2A and C2B domains of SYT11 (PubMed:12925569). Interacts and regulates CC the turnover of SEPTIN5 (PubMed:11078524). Part of a complex, including CC STUB1, HSP70 and GPR37 (PubMed:12150907). The amount of STUB1 in the CC complex increases during ER stress (PubMed:12150907). STUB1 promotes CC the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN- CC mediated GPR37 ubiquitination (PubMed:12150907). HSP70 transiently CC associates with unfolded GPR37 and inhibits the E3 activity of PRKN, CC whereas, STUB1 enhances the E3 activity of PRKN through promotion of CC dissociation of HSP70 from PRKN-GPR37 complexes (PubMed:12150907). CC Interacts with PSMD4 and PACRG (PubMed:12634850, PubMed:14532270). CC Interacts with LRRK2 (PubMed:16352719). Interacts with RANBP2 CC (PubMed:16332688). Interacts with SUMO1 but not SUMO2, which promotes CC nuclear localization and autoubiquitination (PubMed:16955485). CC Interacts (via first RING-type domain) with AIMP2 (via N-terminus) CC (PubMed:16135753). Interacts with PSMA7 and RNF41 (PubMed:15987638, CC PubMed:18541373). Interacts with PINK1 (PubMed:19966284, CC PubMed:20798600). Forms a complex with PINK1 and PARK7 CC (PubMed:19229105). Interacts with CHPF, the interaction with isoform 2 CC may facilitate PRKN transport into the mitochondria (PubMed:22082830). CC Interacts with MFN2 (phosphorylated), promotes PRKN localization in CC dysfunctional depolarized mitochondria (PubMed:23620051). Interacts CC with FBXO7; this promotes translocation to dysfunctional depolarized CC mitochondria (PubMed:23933751). Interacts with ZNF746 CC (PubMed:21376232). Interacts with heat shock protein 70 family members, CC including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes CC translocation to damaged mitochondria (PubMed:24270810). Interacts with CC BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits CC translocation to damaged mitochondria (PubMed:24270810). Forms a CC complex with PRKN and PARK7 (PubMed:19229105). Interacts with AMBRA1 CC (By similarity). {ECO:0000250|UniProtKB:Q9WVS6, CC ECO:0000269|PubMed:11078524, ECO:0000269|PubMed:11590439, CC ECO:0000269|PubMed:12150907, ECO:0000269|PubMed:12628165, CC ECO:0000269|PubMed:12634850, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:14532270, ECO:0000269|PubMed:15728840, CC ECO:0000269|PubMed:15987638, ECO:0000269|PubMed:16135753, CC ECO:0000269|PubMed:16332688, ECO:0000269|PubMed:16352719, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:18541373, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:21376232, CC ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830, CC ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24270810}. CC -!- INTERACTION: CC O60260; P54252-2: ATXN3; NbExp=5; IntAct=EBI-716346, EBI-9684323; CC O60260; Q8IZ52-2: CHPF; NbExp=5; IntAct=EBI-716346, EBI-9029620; CC O60260; Q9Y3I1: FBXO7; NbExp=10; IntAct=EBI-716346, EBI-1161222; CC O60260; Q9Y3I1-1: FBXO7; NbExp=2; IntAct=EBI-716346, EBI-9102965; CC O60260; Q9UBN7: HDAC6; NbExp=6; IntAct=EBI-716346, EBI-301697; CC O60260; P08238: HSP90AB1; NbExp=2; IntAct=EBI-716346, EBI-352572; CC O60260; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-716346, EBI-739832; CC O60260; Q5S007: LRRK2; NbExp=3; IntAct=EBI-716346, EBI-5323863; CC O60260; Q86UL8: MAGI2; NbExp=2; IntAct=EBI-716346, EBI-311035; CC O60260; O95140: MFN2; NbExp=4; IntAct=EBI-716346, EBI-3324756; CC O60260; Q16342: PDCD2; NbExp=5; IntAct=EBI-716346, EBI-359462; CC O60260; Q9BXM7: PINK1; NbExp=7; IntAct=EBI-716346, EBI-2846068; CC O60260; Q9BXM7-1: PINK1; NbExp=2; IntAct=EBI-716346, EBI-15643376; CC O60260; O60260: PRKN; NbExp=5; IntAct=EBI-716346, EBI-716346; CC O60260; O14818-1: PSMA7; NbExp=5; IntAct=EBI-716346, EBI-7679034; CC O60260; P49792: RANBP2; NbExp=11; IntAct=EBI-716346, EBI-973138; CC O60260; Q8IXI2: RHOT1; NbExp=3; IntAct=EBI-716346, EBI-1396430; CC O60260; Q15645: TRIP13; NbExp=4; IntAct=EBI-716346, EBI-358993; CC O60260; Q6NUN9: ZNF746; NbExp=6; IntAct=EBI-716346, EBI-3862525; CC O60260; Q9Z2Q6: Septin5; Xeno; NbExp=2; IntAct=EBI-716346, EBI-772125; CC O60260; P68510: Ywhah; Xeno; NbExp=6; IntAct=EBI-716346, EBI-444641; CC O60260; PRO_0000045592 [Q99IB8]; Xeno; NbExp=3; IntAct=EBI-716346, EBI-6858513; CC O60260-5; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-21251460, EBI-25840993; CC O60260-5; Q86WR3: ANUBL1; NbExp=3; IntAct=EBI-21251460, EBI-25880850; CC O60260-5; P63010-2: AP2B1; NbExp=6; IntAct=EBI-21251460, EBI-11529439; CC O60260-5; P05067: APP; NbExp=5; IntAct=EBI-21251460, EBI-77613; CC O60260-5; Q0P5N6: ARL16; NbExp=6; IntAct=EBI-21251460, EBI-10186132; CC O60260-5; Q86TN1: ARNT2; NbExp=3; IntAct=EBI-21251460, EBI-25844820; CC O60260-5; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-707573; CC O60260-5; Q8WXK3-2: ASB13; NbExp=3; IntAct=EBI-21251460, EBI-12015080; CC O60260-5; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-21251460, EBI-14199987; CC O60260-5; Q9H672-2: ASB7; NbExp=3; IntAct=EBI-21251460, EBI-12104328; CC O60260-5; Q96DX5: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-745641; CC O60260-5; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-21251460, EBI-25843552; CC O60260-5; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-21251460, EBI-1048913; CC O60260-5; P54253: ATXN1; NbExp=6; IntAct=EBI-21251460, EBI-930964; CC O60260-5; O14867: BACH1; NbExp=3; IntAct=EBI-21251460, EBI-1263541; CC O60260-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-21251460, EBI-10988864; CC O60260-5; A8KA13: BCL6B; NbExp=3; IntAct=EBI-21251460, EBI-10174813; CC O60260-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-21251460, EBI-2837444; CC O60260-5; P29466-3: CASP1; NbExp=6; IntAct=EBI-21251460, EBI-12248206; CC O60260-5; Q13939: CCIN; NbExp=3; IntAct=EBI-21251460, EBI-25879469; CC O60260-5; P78396-2: CCNA1; NbExp=3; IntAct=EBI-21251460, EBI-21770675; CC O60260-5; Q00535: CDK5; NbExp=3; IntAct=EBI-21251460, EBI-1041567; CC O60260-5; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-21251460, EBI-350590; CC O60260-5; Q9UBU7: DBF4; NbExp=3; IntAct=EBI-21251460, EBI-372690; CC O60260-5; Q5QP82-2: DCAF10; NbExp=3; IntAct=EBI-21251460, EBI-10983996; CC O60260-5; P61962: DCAF7; NbExp=3; IntAct=EBI-21251460, EBI-359808; CC O60260-5; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-21251460, EBI-25842815; CC O60260-5; Q9BW61: DDA1; NbExp=3; IntAct=EBI-21251460, EBI-2510241; CC O60260-5; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-21251460, EBI-25842538; CC O60260-5; P78352-2: DLG4; NbExp=6; IntAct=EBI-21251460, EBI-631152; CC O60260-5; P31689: DNAJA1; NbExp=6; IntAct=EBI-21251460, EBI-347834; CC O60260-5; O77932: DXO; NbExp=3; IntAct=EBI-21251460, EBI-372173; CC O60260-5; O75530-2: EED; NbExp=3; IntAct=EBI-21251460, EBI-11132357; CC O60260-5; Q8TC29: ENKUR; NbExp=6; IntAct=EBI-21251460, EBI-9246952; CC O60260-5; Q6P1L5: FAM117B; NbExp=3; IntAct=EBI-21251460, EBI-3893327; CC O60260-5; O00757: FBP2; NbExp=3; IntAct=EBI-21251460, EBI-719781; CC O60260-5; P57775: FBXW4; NbExp=3; IntAct=EBI-21251460, EBI-2372268; CC O60260-5; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-21251460, EBI-396453; CC O60260-5; P22607: FGFR3; NbExp=3; IntAct=EBI-21251460, EBI-348399; CC O60260-5; Q9H2C0: GAN; NbExp=3; IntAct=EBI-21251460, EBI-764342; CC O60260-5; Q9NXC2: GFOD1; NbExp=3; IntAct=EBI-21251460, EBI-8799578; CC O60260-5; Q96IK5: GMCL1; NbExp=3; IntAct=EBI-21251460, EBI-2548508; CC O60260-5; P62879: GNB2; NbExp=3; IntAct=EBI-21251460, EBI-356942; CC O60260-5; Q7Z602: GPR141; NbExp=3; IntAct=EBI-21251460, EBI-21649723; CC O60260-5; P06396: GSN; NbExp=3; IntAct=EBI-21251460, EBI-351506; CC O60260-5; P68431: H3C12; NbExp=3; IntAct=EBI-21251460, EBI-79722; CC O60260-5; Q86YM7: HOMER1; NbExp=6; IntAct=EBI-21251460, EBI-746815; CC O60260-5; P0DMV8: HSPA1A; NbExp=6; IntAct=EBI-21251460, EBI-11052499; CC O60260-5; P11142: HSPA8; NbExp=9; IntAct=EBI-21251460, EBI-351896; CC O60260-5; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-21251460, EBI-21911304; CC O60260-5; Q8NA54: IQUB; NbExp=3; IntAct=EBI-21251460, EBI-10220600; CC O60260-5; P05161: ISG15; NbExp=3; IntAct=EBI-21251460, EBI-746466; CC O60260-5; Q9UKP3-2: ITGB1BP2; NbExp=3; IntAct=EBI-21251460, EBI-25856470; CC O60260-5; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-21251460, EBI-25871195; CC O60260-5; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-21251460, EBI-2796400; CC O60260-5; Q6TDP4: KLHL17; NbExp=3; IntAct=EBI-21251460, EBI-21328926; CC O60260-5; O94889: KLHL18; NbExp=3; IntAct=EBI-21251460, EBI-2510096; CC O60260-5; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-21251460, EBI-714379; CC O60260-5; Q8WZ60: KLHL6; NbExp=3; IntAct=EBI-21251460, EBI-6426464; CC O60260-5; Q3SY46: KRTAP13-3; NbExp=3; IntAct=EBI-21251460, EBI-10241252; CC O60260-5; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-21251460, EBI-1044640; CC O60260-5; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-21251460, EBI-1108377; CC O60260-5; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-21251460, EBI-739832; CC O60260-5; O95777: LSM8; NbExp=6; IntAct=EBI-21251460, EBI-347779; CC O60260-5; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-21251460, EBI-373144; CC O60260-5; P10636-6: MAPT; NbExp=3; IntAct=EBI-21251460, EBI-7796455; CC O60260-5; P61244-4: MAX; NbExp=3; IntAct=EBI-21251460, EBI-25848049; CC O60260-5; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-21251460, EBI-4397720; CC O60260-5; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-21251460, EBI-21250407; CC O60260-5; P51948: MNAT1; NbExp=3; IntAct=EBI-21251460, EBI-716139; CC O60260-5; Q8N594: MPND; NbExp=3; IntAct=EBI-21251460, EBI-2512452; CC O60260-5; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-21251460, EBI-10698053; CC O60260-5; Q9NPC7: MYNN; NbExp=3; IntAct=EBI-21251460, EBI-3446748; CC O60260-5; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-21251460, EBI-1058491; CC O60260-5; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-21251460, EBI-25830200; CC O60260-5; P68402: PAFAH1B2; NbExp=3; IntAct=EBI-21251460, EBI-713724; CC O60260-5; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-21251460, EBI-17159452; CC O60260-5; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-21251460, EBI-11022007; CC O60260-5; Q96MG8: PCMTD1; NbExp=3; IntAct=EBI-21251460, EBI-2561395; CC O60260-5; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-21251460, EBI-6309018; CC O60260-5; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-21251460, EBI-716063; CC O60260-5; Q96LB9: PGLYRP3; NbExp=3; IntAct=EBI-21251460, EBI-12339509; CC O60260-5; Q6ZR37: PLEKHG7; NbExp=6; IntAct=EBI-21251460, EBI-12891828; CC O60260-5; P25786: PSMA1; NbExp=6; IntAct=EBI-21251460, EBI-359352; CC O60260-5; P40306: PSMB10; NbExp=3; IntAct=EBI-21251460, EBI-603329; CC O60260-5; P28070: PSMB4; NbExp=3; IntAct=EBI-21251460, EBI-603350; CC O60260-5; O60671: RAD1; NbExp=6; IntAct=EBI-21251460, EBI-721835; CC O60260-5; Q8NDN9-2: RCBTB1; NbExp=3; IntAct=EBI-21251460, EBI-25880533; CC O60260-5; P41220: RGS2; NbExp=6; IntAct=EBI-21251460, EBI-712388; CC O60260-5; A0A087WUY2: RGS3; NbExp=6; IntAct=EBI-21251460, EBI-25879714; CC O60260-5; O94844: RHOBTB1; NbExp=3; IntAct=EBI-21251460, EBI-6426999; CC O60260-5; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-21251460, EBI-714023; CC O60260-5; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-21251460, EBI-396669; CC O60260-5; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-21251460, EBI-21535400; CC O60260-5; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-21251460, EBI-25829984; CC O60260-5; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-21251460, EBI-749039; CC O60260-5; Q9UBS8: RNF14; NbExp=3; IntAct=EBI-21251460, EBI-2130308; CC O60260-5; Q96A37: RNF166; NbExp=3; IntAct=EBI-21251460, EBI-2130320; CC O60260-5; Q96D59: RNF183; NbExp=3; IntAct=EBI-21251460, EBI-743938; CC O60260-5; Q96BH1: RNF25; NbExp=3; IntAct=EBI-21251460, EBI-2129220; CC O60260-5; P08865: RPSA; NbExp=3; IntAct=EBI-21251460, EBI-354112; CC O60260-5; Q8N488: RYBP; NbExp=6; IntAct=EBI-21251460, EBI-752324; CC O60260-5; Q15393: SF3B3; NbExp=3; IntAct=EBI-21251460, EBI-346977; CC O60260-5; Q2NKQ1-4: SGSM1; NbExp=6; IntAct=EBI-21251460, EBI-10182463; CC O60260-5; Q14190-2: SIM2; NbExp=3; IntAct=EBI-21251460, EBI-21623725; CC O60260-5; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-21251460, EBI-358545; CC O60260-5; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-21251460, EBI-9845742; CC O60260-5; P37840: SNCA; NbExp=8; IntAct=EBI-21251460, EBI-985879; CC O60260-5; Q9Y6H5-5: SNCAIP; NbExp=6; IntAct=EBI-21251460, EBI-25880040; CC O60260-5; Q96DI7: SNRNP40; NbExp=3; IntAct=EBI-21251460, EBI-538492; CC O60260-5; O14544: SOCS6; NbExp=3; IntAct=EBI-21251460, EBI-3929549; CC O60260-5; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-21251460, EBI-11959123; CC O60260-5; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-21251460, EBI-2510414; CC O60260-5; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-21251460, EBI-8345366; CC O60260-5; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-21251460, EBI-5235340; CC O60260-5; Q9C004: SPRY4; NbExp=3; IntAct=EBI-21251460, EBI-354861; CC O60260-5; Q96BD6: SPSB1; NbExp=3; IntAct=EBI-21251460, EBI-2659201; CC O60260-5; Q99619: SPSB2; NbExp=3; IntAct=EBI-21251460, EBI-2323209; CC O60260-5; O75886: STAM2; NbExp=3; IntAct=EBI-21251460, EBI-373258; CC O60260-5; O95630: STAMBP; NbExp=3; IntAct=EBI-21251460, EBI-396676; CC O60260-5; Q9UNE7: STUB1; NbExp=6; IntAct=EBI-21251460, EBI-357085; CC O60260-5; Q9BT88: SYT11; NbExp=6; IntAct=EBI-21251460, EBI-751770; CC O60260-5; Q13148: TARDBP; NbExp=3; IntAct=EBI-21251460, EBI-372899; CC O60260-5; Q16650: TBR1; NbExp=6; IntAct=EBI-21251460, EBI-1047158; CC O60260-5; Q15554-4: TERF2; NbExp=6; IntAct=EBI-21251460, EBI-25840535; CC O60260-5; Q04724: TLE1; NbExp=3; IntAct=EBI-21251460, EBI-711424; CC O60260-5; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-21251460, EBI-25831574; CC O60260-5; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-21251460, EBI-74615; CC O60260-5; P19474: TRIM21; NbExp=3; IntAct=EBI-21251460, EBI-81290; CC O60260-5; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-21251460, EBI-17716262; CC O60260-5; Q8NBM4-4: UBAC2; NbExp=3; IntAct=EBI-21251460, EBI-25840976; CC O60260-5; P57075-2: UBASH3A; NbExp=6; IntAct=EBI-21251460, EBI-7353612; CC O60260-5; P0CG47: UBB; NbExp=6; IntAct=EBI-21251460, EBI-413034; CC O60260-5; O15205: UBD; NbExp=3; IntAct=EBI-21251460, EBI-6657186; CC O60260-5; Q9Y385: UBE2J1; NbExp=3; IntAct=EBI-21251460, EBI-988826; CC O60260-5; P68036: UBE2L3; NbExp=3; IntAct=EBI-21251460, EBI-711173; CC O60260-5; P61081: UBE2M; NbExp=3; IntAct=EBI-21251460, EBI-1041660; CC O60260-5; Q9C0C9: UBE2O; NbExp=3; IntAct=EBI-21251460, EBI-2339946; CC O60260-5; Q13404: UBE2V1; NbExp=3; IntAct=EBI-21251460, EBI-1050671; CC O60260-5; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-21251460, EBI-11530712; CC O60260-5; Q9Y3C8: UFC1; NbExp=3; IntAct=EBI-21251460, EBI-1045733; CC O60260-5; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-21251460, EBI-17761788; CC O60260-5; O75604-3: USP2; NbExp=3; IntAct=EBI-21251460, EBI-10696113; CC O60260-5; P18206-2: VCL; NbExp=6; IntAct=EBI-21251460, EBI-11027067; CC O60260-5; P45880: VDAC2; NbExp=6; IntAct=EBI-21251460, EBI-354022; CC O60260-5; P40337-2: VHL; NbExp=3; IntAct=EBI-21251460, EBI-12157263; CC O60260-5; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-21251460, EBI-11141397; CC O60260-5; O00308: WWP2; NbExp=3; IntAct=EBI-21251460, EBI-743923; CC O60260-5; Q04917: YWHAH; NbExp=6; IntAct=EBI-21251460, EBI-306940; CC O60260-5; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-21251460, EBI-25842419; CC O60260-5; Q15916: ZBTB6; NbExp=3; IntAct=EBI-21251460, EBI-7227791; CC O60260-5; Q9Y649; NbExp=3; IntAct=EBI-21251460, EBI-25900580; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:16955485, ECO:0000269|PubMed:17846173, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24898855}. Nucleus CC {ECO:0000269|PubMed:16955485}. Endoplasmic reticulum CC {ECO:0000269|PubMed:19501131}. Mitochondrion CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, CC ECO:0000269|PubMed:24898855}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:Q9WVS6}. Cell projection, neuron projection CC {ECO:0000269|PubMed:12925569}. Postsynaptic density CC {ECO:0000250|UniProtKB:Q9WVS6}. Presynapse CC {ECO:0000250|UniProtKB:Q9WVS6}. Note=Mainly localizes in the cytosol CC (PubMed:19029340, PubMed:19229105). Co-localizes with SYT11 in CC neutrites (PubMed:12925569). Co-localizes with SNCAIP in brainstem Lewy CC bodies (PubMed:10319893, PubMed:11431533). Translocates to CC dysfunctional mitochondria that have lost the mitochondrial membrane CC potential; recruitment to mitochondria is PINK1-dependent CC (PubMed:18957282, PubMed:19966284, PubMed:23620051, PubMed:24898855). CC Mitochondrial localization also gradually increases with cellular CC growth (PubMed:22082830). {ECO:0000269|PubMed:10319893, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:12925569, CC ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19029340, CC ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, CC ECO:0000269|PubMed:24898855}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=1; CC IsoId=O60260-1; Sequence=Displayed; CC Name=2; Synonyms=SV5DEL; CC IsoId=O60260-2; Sequence=VSP_011707; CC Name=3; CC IsoId=O60260-3; Sequence=VSP_011706, VSP_011709, VSP_011710; CC Name=4; CC IsoId=O60260-4; Sequence=VSP_011705; CC Name=5; CC IsoId=O60260-5; Sequence=VSP_011708, VSP_011711, VSP_011712; CC Name=6; CC IsoId=O60260-6; Sequence=VSP_041563; CC Name=7; Synonyms=SV5,9DEL; CC IsoId=O60260-7; Sequence=VSP_011707, VSP_053651; CC Name=8; Synonyms=SV9DEL; CC IsoId=O60260-8; Sequence=VSP_053651; CC -!- TISSUE SPECIFICITY: Highly expressed in the brain including the CC substantia nigra (PubMed:19501131, PubMed:9560156). Expressed in heart, CC testis and skeletal muscle (PubMed:9560156). Expression is down- CC regulated or absent in tumor biopsies, and absent in the brain of PARK2 CC patients (PubMed:12719539, PubMed:14614460). Overexpression protects CC dopamine neurons from kainate-mediated apoptosis (PubMed:12628165). CC Found in serum (at protein level) (PubMed:19501131). CC {ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, CC ECO:0000269|PubMed:14614460, ECO:0000269|PubMed:19501131, CC ECO:0000269|PubMed:9560156}. CC -!- DOMAIN: The ubiquitin-like domain binds the PSMD4 subunit of 26S CC proteasomes. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: The RING-type 1 zinc finger domain is required to repress CC p53/TP53 transcription. {ECO:0000269|PubMed:19801972}. CC -!- DOMAIN: Members of the RBR family are atypical E3 ligases. They CC interact with the E2 conjugating enzyme UBE2L3 and function like HECT- CC type E3 enzymes: they bind E2s via the first RING domain, but require CC an obligate trans-thiolation step during the ubiquitin transfer, CC requiring a conserved cysteine residue in the second RING domain. CC {ECO:0000269|PubMed:23770917, ECO:0000305|PubMed:21532592}. CC -!- PTM: ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN- CC beta stimulation. ISGylation positively regulates its E3 ligase CC activity. {ECO:0000269|PubMed:27534820}. CC -!- PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own CC degradation (PubMed:19229105, PubMed:23770917, PubMed:25474007). Also CC polyubiquitinated by RNF41 for proteasomal degradation CC (PubMed:19229105). {ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:23770917, ECO:0000269|PubMed:25474007}. CC -!- PTM: S-nitrosylated. The inhibition of PRKN ubiquitin E3 ligase CC activity by S-nitrosylation could contribute to the degenerative CC process in PD by impairing the ubiquitination of PRKN substrates. CC {ECO:0000269|PubMed:15105460}. CC -!- PTM: Phosphorylated (PubMed:18957282, PubMed:23754282, PubMed:24660806, CC PubMed:24784582, PubMed:25474007). Activation requires phosphorylation CC at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin CC (PubMed:18957282, PubMed:23754282, PubMed:24660806, PubMed:24784582, CC PubMed:25474007). Phosphorylation at Thr-175 by PINK1 and at Thr-217 is CC important for mitochondrial localization (PubMed:18957282). CC {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:23754282, CC ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24784582, CC ECO:0000269|PubMed:25474007}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC 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:12629236, CC ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284, CC ECO:0000269|PubMed:29311685}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC Heterozygous mutations act as susceptibility alleles for late-onset CC Parkinson disease (PubMed:12629236, PubMed:12730996). CC -!- DISEASE: Parkinson disease 2 (PARK2) [MIM:600116]: An autosomal CC recessive form of Parkinson disease, a complex neurodegenerative CC disorder characterized by bradykinesia, resting tremor, muscular CC rigidity and postural instability. PARK2 differs from classic forms of CC Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation CC of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia CC is absent. Pathologically, patients show loss of dopaminergic neurons CC in the substantia nigra, similar to that seen in classic Parkinson CC disease; however, Lewy bodies (intraneuronal accumulations of CC aggregated proteins) are absent. Disease onset is usually before age 40 CC years. {ECO:0000269|PubMed:10072423, ECO:0000269|PubMed:10824074, CC ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10939576, CC ECO:0000269|PubMed:11163284, ECO:0000269|PubMed:11179010, CC ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11487568, CC ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, CC ECO:0000269|PubMed:12056932, ECO:0000269|PubMed:12112109, CC ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, CC ECO:0000269|PubMed:12362318, ECO:0000269|PubMed:12397156, CC ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, CC ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:15584030, CC ECO:0000269|PubMed:17360614, ECO:0000269|PubMed:19229105, CC ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:20404107, CC ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:20889974, CC ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22396657, CC ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:23770917, CC ECO:0000269|PubMed:32047033, ECO:0000269|PubMed:9560156, CC ECO:0000269|PubMed:9731209}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in PRKN may be involved in the development and/or CC progression of ovarian cancer. CC -!- MISCELLANEOUS: The parkin locus (PRKN), adjacent to the 6q telomere is CC hyper-recombinable and lies within FRA6E, the third most common fragile CC site in tumor tissue. CC -!- SIMILARITY: Belongs to the RBR family. Parkin subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Life's tremors - Issue 131 CC of September 2011; CC URL="https://www.proteinspotlight.org/back_issues/131"; 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; AB009973; BAA25751.1; -; mRNA. DR EMBL; EF375726; ABN46990.1; -; mRNA. DR EMBL; AF381282; AAM21457.1; -; mRNA. DR EMBL; AF381283; AAM21458.1; -; mRNA. DR EMBL; AF381286; AAM21461.1; -; mRNA. DR EMBL; GU345839; ADB90270.1; -; mRNA. DR EMBL; GU345840; ADB90271.1; -; mRNA. DR EMBL; GU361467; ADB91979.1; -; mRNA. DR EMBL; AK292590; BAF85279.1; -; mRNA. DR EMBL; AL035697; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL132982; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL445215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000886; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000887; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001576; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001577; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001578; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP003699; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW47573.1; -; Genomic_DNA. DR EMBL; CH471051; EAW47574.1; -; Genomic_DNA. DR EMBL; BC022014; AAH22014.1; -; mRNA. DR EMBL; AY564225; AAS88422.1; -; Genomic_DNA. DR CCDS; CCDS5281.1; -. [O60260-1] DR CCDS; CCDS5282.1; -. [O60260-2] DR CCDS; CCDS5283.1; -. [O60260-6] DR RefSeq; NP_004553.2; NM_004562.3. [O60260-1] DR RefSeq; NP_054642.2; NM_013987.3. [O60260-2] DR RefSeq; NP_054643.2; NM_013988.3. [O60260-6] DR PDB; 1IYF; NMR; -; A=1-76. DR PDB; 2JMO; NMR; -; A=308-384. DR PDB; 4BM9; X-ray; 2.25 A; A=137-465. DR PDB; 4I1F; X-ray; 1.58 A; A=141-465. DR PDB; 4I1H; X-ray; 2.00 A; A=141-465. DR PDB; 5C1Z; X-ray; 1.79 A; A/B=1-465. DR PDB; 5C23; X-ray; 2.37 A; A/B=1-465. DR PDB; 5C9V; X-ray; 2.35 A; A=137-465. DR PDB; 5N2W; X-ray; 2.68 A; A=1-465. DR PDB; 5N38; X-ray; 2.60 A; A=1-465. DR PDB; 5TR5; NMR; -; A=1-76. DR PDB; 6GLC; X-ray; 1.80 A; A=1-382. DR PDB; 6HUE; X-ray; 2.85 A; A/B=1-465. DR PDB; 6N13; NMR; -; B=144-465. DR PDB; 8IK6; X-ray; 3.30 A; A/C=139-465. DR PDB; 8IKM; X-ray; 1.92 A; A=141-382, C=1-140. DR PDB; 8IKT; X-ray; 2.60 A; A=77-382, C=1-76. DR PDB; 8IKV; X-ray; 2.35 A; A/C=139-465. DR PDB; 8JWV; X-ray; 2.90 A; A=141-465. DR PDB; 8WZN; X-ray; 1.80 A; A=141-465. DR PDB; 8WZO; X-ray; 2.25 A; A=141-465. DR PDBsum; 1IYF; -. DR PDBsum; 2JMO; -. DR PDBsum; 4BM9; -. DR PDBsum; 4I1F; -. DR PDBsum; 4I1H; -. DR PDBsum; 5C1Z; -. DR PDBsum; 5C23; -. DR PDBsum; 5C9V; -. DR PDBsum; 5N2W; -. DR PDBsum; 5N38; -. DR PDBsum; 5TR5; -. DR PDBsum; 6GLC; -. DR PDBsum; 6HUE; -. DR PDBsum; 6N13; -. DR PDBsum; 8IK6; -. DR PDBsum; 8IKM; -. DR PDBsum; 8IKT; -. DR PDBsum; 8IKV; -. DR PDBsum; 8JWV; -. DR PDBsum; 8WZN; -. DR PDBsum; 8WZO; -. DR AlphaFoldDB; O60260; -. DR BMRB; O60260; -. DR SMR; O60260; -. DR BioGRID; 111105; 3437. DR CORUM; O60260; -. DR DIP; DIP-37655N; -. DR FunCoup; O60260; 952. DR IntAct; O60260; 311. DR MINT; O60260; -. DR STRING; 9606.ENSP00000355865; -. DR BindingDB; O60260; -. DR TCDB; 8.A.52.2.1; the ubiquitin-related protein degradation (upd) family. DR GlyGen; O60260; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O60260; -. DR PhosphoSitePlus; O60260; -. DR BioMuta; PRKN; -. DR MassIVE; O60260; -. DR PaxDb; 9606-ENSP00000355865; -. DR PeptideAtlas; O60260; -. DR ProteomicsDB; 49290; -. [O60260-1] DR ProteomicsDB; 49291; -. [O60260-2] DR ProteomicsDB; 49292; -. [O60260-3] DR ProteomicsDB; 49293; -. [O60260-4] DR ProteomicsDB; 49294; -. [O60260-5] DR ProteomicsDB; 49295; -. [O60260-6] DR Antibodypedia; 4264; 797 antibodies from 52 providers. DR DNASU; 5071; -. DR Ensembl; ENST00000366896.5; ENSP00000355862.1; ENSG00000185345.25. [O60260-6] DR Ensembl; ENST00000366897.5; ENSP00000355863.1; ENSG00000185345.25. [O60260-2] DR Ensembl; ENST00000366898.6; ENSP00000355865.1; ENSG00000185345.25. [O60260-1] DR Ensembl; ENST00000479615.5; ENSP00000434414.1; ENSG00000185345.25. [O60260-3] DR GeneID; 5071; -. DR KEGG; hsa:5071; -. DR MANE-Select; ENST00000366898.6; ENSP00000355865.1; NM_004562.3; NP_004553.2. DR UCSC; uc003qty.5; human. [O60260-1] DR AGR; HGNC:8607; -. DR CIViC; 5071; 2 evidence items across 2 molecular profiles. DR ClinPGx; PA32942; -. DR CTD; 5071; -. DR DisGeNET; 5071; -. DR GeneCards; PRKN; -. DR GeneReviews; PRKN; -. DR HGNC; HGNC:8607; PRKN. DR HPA; ENSG00000185345; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; PRKN; -. DR MIM; 168600; phenotype. DR MIM; 600116; phenotype. DR MIM; 602544; gene. DR OpenTargets; ENSG00000185345; -. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000185345; -. DR eggNOG; KOG0006; Eukaryota. DR GeneTree; ENSGT00390000011034; -. DR HOGENOM; CLU_050804_0_0_1; -. DR InParanoid; O60260; -. DR OMA; DPKWDIK; -. DR OrthoDB; 1431934at2759; -. DR PAN-GO; O60260; 15 GO annotations based on evolutionary models. DR PhylomeDB; O60260; -. DR BRENDA; 2.3.2.27; 2681. DR BRENDA; 2.3.2.31; 2681. DR PathwayCommons; O60260; -. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-5689877; Josephin domain DUBs. DR Reactome; R-HSA-9646399; Aggrephagy. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; O60260; -. DR SIGNOR; O60260; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000185345; -. DR BioGRID-ORCS; 5071; 13 hits in 1187 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PARK2; human. DR EvolutionaryTrace; O60260; -. DR GeneWiki; Parkin_(ligase); -. DR GenomeRNAi; 5071; -. DR Pharos; O60260; Tbio. DR PRO; PR:O60260; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O60260; protein. DR Bgee; ENSG00000185345; Expressed in sural nerve and 107 other cell types or tissues. DR ExpressionAtlas; O60260; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:Ensembl. DR GO; GO:0097413; C:Lewy body; TAS:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProt. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:ParkinsonsUK-UCL. DR GO; GO:1990452; C:Parkin-FBXW7-Cul1 ubiquitin ligase complex; IPI:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0097602; F:cullin family protein binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:1990444; F:F-box domain binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0001664; F:G protein-coupled receptor binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0031072; F:heat shock protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042826; F:histone deacetylase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL. DR GO; GO:0043274; F:phospholipase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:BHF-UCL. DR GO; GO:0017124; F:SH3 domain binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0003714; F:transcription corepressor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0015631; F:tubulin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IMP:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008270; F:zinc ion binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL. DR GO; GO:0070842; P:aggresome assembly; IMP:BHF-UCL. DR GO; GO:1990000; P:amyloid fibril formation; TAS:Reactome. DR GO; GO:0000422; P:autophagy of mitochondrion; IDA:UniProtKB. DR GO; GO:1903351; P:cellular response to dopamine; TAS:ParkinsonsUK-UCL. DR GO; GO:1904881; P:cellular response to hydrogen sulfide; IEA:Ensembl. DR GO; GO:1905232; P:cellular response to L-glutamate; IEA:Ensembl. DR GO; GO:1904845; P:cellular response to L-glutamine; IEA:Ensembl. DR GO; GO:0071287; P:cellular response to manganese ion; TAS:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; TAS:ParkinsonsUK-UCL. DR GO; GO:0097237; P:cellular response to toxic substance; IMP:ParkinsonsUK-UCL. DR GO; GO:0034620; P:cellular response to unfolded protein; TAS:ParkinsonsUK-UCL. DR GO; GO:0007417; P:central nervous system development; TAS:ProtInc. DR GO; GO:0042417; P:dopamine metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IEA:Ensembl. DR GO; GO:0036503; P:ERAD pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0010994; P:free ubiquitin chain polymerization; IMP:ParkinsonsUK-UCL. DR GO; GO:0044828; P:host-mediated suppression of viral genome replication; IDA:AgBase. DR GO; GO:0007612; P:learning; IEA:Ensembl. DR GO; GO:0016236; P:macroautophagy; TAS:Reactome. DR GO; GO:0000266; P:mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IEA:Ensembl. DR GO; GO:0051646; P:mitochondrion localization; IEA:Ensembl. DR GO; GO:0007005; P:mitochondrion organization; ISS:ParkinsonsUK-UCL. DR GO; GO:0099074; P:mitochondrion to lysosome vesicle-mediated transport; IDA:ParkinsonsUK-UCL. DR GO; GO:0000423; P:mitophagy; IDA:UniProtKB. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0032232; P:negative regulation of actin filament bundle assembly; IDA:BHF-UCL. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1902236; P:negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903382; P:negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:1903542; P:negative regulation of exosomal secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0033132; P:negative regulation of glucokinase activity; IDA:MGI. DR GO; GO:0046676; P:negative regulation of insulin secretion; IDA:MGI. DR GO; GO:1905366; P:negative regulation of intralumenal vesicle formation; IMP:ParkinsonsUK-UCL. DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IMP:ParkinsonsUK-UCL. DR GO; GO:0046329; P:negative regulation of JNK cascade; ISS:ParkinsonsUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IEA:Ensembl. DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; ISS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:ParkinsonsUK-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; IEA:Ensembl. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IDA:BHF-UCL. DR GO; GO:1904049; P:negative regulation of spontaneous neurotransmitter secretion; IMP:ParkinsonsUK-UCL. DR GO; GO:0051967; P:negative regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:ParkinsonsUK-UCL. DR GO; GO:0070050; P:neuron cellular homeostasis; ISS:ParkinsonsUK-UCL. DR GO; GO:0042415; P:norepinephrine metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:ParkinsonsUK-UCL. DR GO; GO:1903861; P:positive regulation of dendrite extension; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ParkinsonsUK-UCL. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0090141; P:positive regulation of mitochondrial fission; ISS:ParkinsonsUK-UCL. DR GO; GO:0010636; P:positive regulation of mitochondrial fusion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IEA:Ensembl. DR GO; GO:1901526; P:positive regulation of mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0051582; P:positive regulation of neurotransmitter uptake; IMP:ParkinsonsUK-UCL. DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; IGI:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1902530; P:positive regulation of protein linear polyubiquitination; IGI:ParkinsonsUK-UCL. DR GO; GO:1905477; P:positive regulation of protein localization to membrane; IMP:ParkinsonsUK-UCL. DR GO; GO:1905281; P:positive regulation of retrograde transport, endosome to Golgi; NAS:ParkinsonsUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:1905091; P:positive regulation of type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:BHF-UCL. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0016579; P:protein deubiquitination; TAS:Reactome. DR GO; GO:0070979; P:protein K11-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0044314; P:protein K27-linked ubiquitination; IDA:UniProt. DR GO; GO:0035519; P:protein K29-linked ubiquitination; TAS:ParkinsonsUK-UCL. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0085020; P:protein K6-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070585; P:protein localization to mitochondrion; IEA:Ensembl. DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB. DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0010506; P:regulation of autophagy; IDA:UniProtKB. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0042053; P:regulation of dopamine metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:ParkinsonsUK-UCL. DR GO; GO:0010906; P:regulation of glucose metabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0032368; P:regulation of lipid transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0010821; P:regulation of mitochondrion organization; IDA:ParkinsonsUK-UCL. DR GO; GO:0060544; P:regulation of necroptotic process; TAS:Reactome. DR GO; GO:0099072; P:regulation of postsynaptic membrane neurotransmitter receptor levels; IEA:Ensembl. DR GO; GO:0031647; P:regulation of protein stability; IMP:ParkinsonsUK-UCL. DR GO; GO:1903214; P:regulation of protein targeting to mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0031396; P:regulation of protein ubiquitination; IMP:ParkinsonsUK-UCL. DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:UniProtKB. DR GO; GO:1900242; P:regulation of synaptic vesicle endocytosis; IEA:Ensembl. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; NAS:ParkinsonsUK-UCL. DR GO; GO:0140251; P:regulation protein catabolic process at presynapse; IEA:Ensembl. DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl. DR GO; GO:1904643; P:response to curcumin; IEA:Ensembl. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:ParkinsonsUK-UCL. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0001964; P:startle response; IEA:Ensembl. DR GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0061734; P:type 2 mitophagy; IDA:ParkinsonsUK-UCL. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd20340; BRcat_RBR_parkin; 1. DR CDD; cd20357; Rcat_RBR_parkin; 1. DR CDD; cd16627; RING-HC_RBR_parkin; 1. DR CDD; cd21382; RING0_parkin; 1. DR CDD; cd01798; Ubl_parkin; 1. DR DisProt; DP01849; -. DR FunFam; 1.20.120.1750:FF:000009; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 2.20.25.20:FF:000008; E3 ubiquitin-protein ligase parkin; 1. DR FunFam; 3.10.20.90:FF:000142; E3 ubiquitin-protein ligase parkin; 1. DR Gene3D; 1.20.120.1750; -; 1. DR Gene3D; 2.20.25.20; -; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00008; -. DR InterPro; IPR047534; BRcat_RBR_parkin. DR InterPro; IPR002867; IBR_dom. DR InterPro; IPR003977; Parkin. DR InterPro; IPR054694; Parkin-like_IBR. DR InterPro; IPR041565; Parkin_Znf-RING. DR InterPro; IPR047536; Rcat_RBR_parkin. DR InterPro; IPR047535; RING-HC_RBR_parkin. DR InterPro; IPR044066; TRIAD_supradom. DR InterPro; IPR015496; Ubiquilin. DR InterPro; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR InterPro; IPR041170; Znf-RING_14. DR PANTHER; PTHR10677; UBIQUILIN; 1. DR PANTHER; PTHR10677:SF40; UBIQUITIN-LIKE DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF22605; IBR_2; 1. DR Pfam; PF00240; ubiquitin; 1. DR Pfam; PF17976; zf-RING_12; 1. DR Pfam; PF17978; zf-RING_14; 1. DR PIRSF; PIRSF037880; Parkin; 1. DR PRINTS; PR01475; PARKIN. DR SMART; SM00647; IBR; 2. DR SMART; SM00213; UBQ; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS51873; TRIAD; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autophagy; Cell projection; Cytoplasm; KW Disease variant; Endoplasmic reticulum; Isopeptide bond; Membrane; KW Metal-binding; Mitochondrion; Mitochondrion outer membrane; KW Neurodegeneration; Nucleus; Parkinson disease; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW S-nitrosylation; Synapse; Transcription; Transcription regulation; KW Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..465 FT /note="E3 ubiquitin-protein ligase parkin" FT /id="PRO_0000058576" FT DOMAIN 1..76 FT /note="Ubiquitin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT ZN_FING 141..225 FT /note="RING-type 0; atypical" FT ZN_FING 238..293 FT /note="RING-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 313..377 FT /note="IBR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT ZN_FING 418..449 FT /note="RING-type 2; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 77..237 FT /note="Necessary for PINK1-dependent localization to FT mitochondria" FT /evidence="ECO:0000269|PubMed:18957282" FT REGION 77..99 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 204..238 FT /note="SYT11 binding 1" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 234..465 FT /note="TRIAD supradomain" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT REGION 257..293 FT /note="SYT11 binding 2" FT /evidence="ECO:0000269|PubMed:12925569" FT REGION 378..410 FT /note="REP" FT /evidence="ECO:0000250|UniProtKB:Q9JK66" FT ACT_SITE 431 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 238 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 241 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 253 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 257 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 260 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 263 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 289 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 293 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 332 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 337 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 352 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 360 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 365 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 368 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 373 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 377 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 418 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 421 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 436 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 441 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 446 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221, FT ECO:0000269|PubMed:23770917" FT BINDING 449 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 457 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT BINDING 461 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01221" FT MOD_RES 65 FT /note="Phosphoserine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282, FT ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MOD_RES 175 FT /note="Phosphothreonine; by PINK1" FT /evidence="ECO:0000269|PubMed:18957282" FT MOD_RES 217 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:18957282" FT CROSSLNK 349 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT CROSSLNK 369 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ISG15)" FT /evidence="ECO:0000269|PubMed:27534820" FT VAR_SEQ 1..191 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011705" FT VAR_SEQ 1..79 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011706" FT VAR_SEQ 58..206 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_041563" FT VAR_SEQ 179..206 FT /note="Missing (in isoform 2 and isoform 7)" FT /evidence="ECO:0000303|PubMed:9560156, ECO:0000303|Ref.4" FT /id="VSP_011707" FT VAR_SEQ 290 FT /note="V -> VGTGDTVVLRGALGGFRRGV (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011708" FT VAR_SEQ 291..297 FT /note="AGCPNSL -> VCLLPGM (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011709" FT VAR_SEQ 298..465 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_011710" FT VAR_SEQ 312..361 FT /note="Missing (in isoform 7 and isoform 8)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_053651" FT VAR_SEQ 362..368 FT /note="FAFCREC -> YGQRRTK (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011711" FT VAR_SEQ 369..465 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011712" FT VARIANT 15 FT /note="V -> M (in PARK2; dbSNP:rs532703934)" FT /evidence="ECO:0000269|PubMed:12397156" FT /id="VAR_019733" FT VARIANT 33 FT /note="R -> Q (in PARK2; dbSNP:rs147757966)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019734" FT VARIANT 37 FT /note="P -> L (in PARK2; dbSNP:rs148990138)" FT /evidence="ECO:0000269|PubMed:12112109" FT /id="VAR_019735" FT VARIANT 42 FT /note="R -> P (in PARK2 and PARK; induces a conformational FT change in the PSMD4-binding site of Ubl resulting in FT impaired proteasomal binding; decreases ubiquitination and FT degradation; increased aggregation; impairs the ability to FT ubiquitinate and degrade SYT11; dbSNP:rs368134308)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19229105, FT ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:29311685" FT /id="VAR_019736" FT VARIANT 46 FT /note="A -> P (in PARK2)" FT /evidence="ECO:0000269|PubMed:12362318" FT /id="VAR_019737" FT VARIANT 56 FT /note="V -> E (in PARK2; dbSNP:rs137853059)" FT /evidence="ECO:0000269|PubMed:12056932" FT /id="VAR_070078" FT VARIANT 82 FT /note="A -> E (in PARK2; dbSNP:rs55774500)" FT /evidence="ECO:0000269|PubMed:11487568, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12730996" FT /id="VAR_019738" FT VARIANT 92 FT /note="A -> V (in PARK2; dbSNP:rs566229879)" FT /id="VAR_019739" FT VARIANT 100 FT /note="Q -> H (in dbSNP:rs1256316516)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019740" FT VARIANT 161 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs137853057)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974" FT /id="VAR_019741" FT VARIANT 167 FT /note="S -> N (in dbSNP:rs1801474)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10511432, ECO:0000269|PubMed:10965160, FT ECO:0000269|PubMed:12629236" FT /id="VAR_019742" FT VARIANT 192 FT /note="M -> L (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:11971093" FT /id="VAR_054107" FT VARIANT 192 FT /note="M -> V (in PARK2; uncertain significance; FT dbSNP:rs9456735)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019743" FT VARIANT 211 FT /note="K -> N (in PARK2; severely compromises the FT mitochondrial localization; fails to stabilize BCL2; loss FT of activity towards MIRO1; dbSNP:rs137853060)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:12114481, FT ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:20404107, FT ECO:0000269|PubMed:22396657" FT /id="VAR_019744" FT VARIANT 212 FT /note="C -> Y (in PARK2; dbSNP:rs137853058)" FT /evidence="ECO:0000269|PubMed:11163284, FT ECO:0000269|PubMed:12056932" FT /id="VAR_019746" FT VARIANT 240 FT /note="T -> M (in PARK2; dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:12629236" FT /id="VAR_019747" FT VARIANT 240 FT /note="T -> R (in PARK2; impairs the ability to FT ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; FT severely compromises the mitochondrial localization; FT dbSNP:rs137853054)" FT /evidence="ECO:0000269|PubMed:10888878, FT ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889974, FT ECO:0000269|PubMed:9731209" FT /id="VAR_019748" FT VARIANT 253 FT /note="C -> Y (in PARK; late onset; dbSNP:rs747427602)" FT /evidence="ECO:0000269|PubMed:12730996" FT /id="VAR_019749" FT VARIANT 256 FT /note="R -> C (in PARK2 and PARK; uncertain significance; FT impairs the ability to ubiquitinate SNCAIP and ZNF746; FT decreased binding to the TP53 promoter; abolishes TP53 FT transcriptional repression; dbSNP:rs150562946)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972" FT /id="VAR_019750" FT VARIANT 271 FT /note="R -> S (in dbSNP:rs772622421)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019751" FT VARIANT 275 FT /note="R -> W (in PARK2 and PARK; impairs the ability to FT ubiquitinate SNCAIP; abolishes p53/TP53 transcriptional FT repression; impairs the ability to ubiquitinate and degrade FT SYT11; dbSNP:rs34424986)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11179010, FT ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19801972, FT ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22956510, FT ECO:0000269|PubMed:29311685" FT /id="VAR_019752" FT VARIANT 280 FT /note="D -> N (in PARK; does not affect PINK-1 dependent FT localization to depolarized mitochondria; FT dbSNP:rs72480422)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20404107" FT /id="VAR_019753" FT VARIANT 284 FT /note="G -> R (in PARK2; dbSNP:rs751037529)" FT /id="VAR_019754" FT VARIANT 289 FT /note="C -> G (in PARK2; increased aggregation; fails to FT ubiquitinate SYT11; loses ability to bind SYT11; impaired FT relocalization to damaged mitochondria; loss of function in FT mitophagy; dbSNP:rs55961220)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:20889486" FT /id="VAR_019755" FT VARIANT 311 FT /note="Q -> R (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062672" FT VARIANT 328 FT /note="G -> E (in PARK2; does not affect PINK-1 dependent FT localization to depolarized mitochondria)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:20404107" FT /id="VAR_019756" FT VARIANT 334 FT /note="R -> C (in dbSNP:rs199657839)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:27535533" FT /id="VAR_019757" FT VARIANT 339 FT /note="A -> S (in dbSNP:rs1554274880)" FT /evidence="ECO:0000269|PubMed:12781599" FT /id="VAR_019758" FT VARIANT 351 FT /note="T -> P (in PARK2; impairs folding of IBR domain; FT dbSNP:rs1554274861)" FT /evidence="ECO:0000269|PubMed:12112109, FT ECO:0000269|PubMed:17360614" FT /id="VAR_019759" FT VARIANT 366 FT /note="R -> W (in dbSNP:rs56092260)" FT /evidence="ECO:0000269|PubMed:10965160" FT /id="VAR_019760" FT VARIANT 371 FT /note="A -> T (in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:19501131" FT /id="VAR_062673" FT VARIANT 380 FT /note="V -> L (in dbSNP:rs1801582)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10965160, ECO:0000269|PubMed:12397156, FT ECO:0000269|PubMed:12730996" FT /id="VAR_019761" FT VARIANT 394 FT /note="D -> N (in dbSNP:rs1801334)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12730996" FT /id="VAR_019762" FT VARIANT 402 FT /note="R -> C (in PARK2; dbSNP:rs55830907)" FT /evidence="ECO:0000269|PubMed:15584030" FT /id="VAR_070079" FT VARIANT 415 FT /note="T -> N (in PARK2; loss of activity and self- FT ubiquitination; impairs the ability to ubiquitinate SNCAIP; FT no effect on polyubiquitination or mitophagy; does not FT affect turnover of CDCRE1; impairs PINK1-dependent FT localization to dysfunctional depolarized mitochondria; FT dbSNP:rs778125254)" FT /evidence="ECO:0000269|PubMed:10072423, FT ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19966284, FT ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23770917, FT ECO:0000269|PubMed:32047033" FT /id="VAR_019763" FT VARIANT 418 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; fails FT to ubiquitinate SYT11 but does not loose ability to bind FT SYT11; dbSNP:rs1554252200)" FT /evidence="ECO:0000269|PubMed:12925569, FT ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:19801972" FT /id="VAR_070080" FT VARIANT 430 FT /note="G -> D (in PARK2; loss of self-ubiquitination; FT impairs PINK1-dependent localization to dysfunctional FT depolarized mitochondria; impaired E3 ubiquitin-protein FT ligase toward ZNF746; dbSNP:rs191486604)" FT /evidence="ECO:0000269|PubMed:10824074, FT ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12730996, FT ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:21376232, FT ECO:0000269|PubMed:23770917" FT /id="VAR_019764" FT VARIANT 431 FT /note="C -> F (in PARK2; impaired E3 ubiquitin-protein FT ligase toward ZNF746 and BCL2; dbSNP:rs397514694)" FT /evidence="ECO:0000269|PubMed:10939576, FT ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232" FT /id="VAR_019765" FT VARIANT 437 FT /note="P -> L (in PARK2; impaired E3 ubiquitin-protein FT ligase toward BCL2; dbSNP:rs149953814)" FT /evidence="ECO:0000269|PubMed:11971093, FT ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12629236, FT ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:20889974" FT /id="VAR_019766" FT VARIANT 441 FT /note="C -> R (in PARK2; decreased binding to the TP53 FT promoter; abolishes TP53 transcriptional repression; FT dbSNP:rs778305273)" FT /evidence="ECO:0000269|PubMed:12116199, FT ECO:0000269|PubMed:19801972" FT /id="VAR_019767" FT MUTAGEN 65 FT /note="S->A: Loss of phosphorylation. Undergoes FT autoubiquitination in the presence of phosphorylated FT ubiquitin." FT /evidence="ECO:0000269|PubMed:25474007" FT MUTAGEN 65 FT /note="S->E: Phosphomimetic mutant; still requires PINK1 FT for activation. PRKN is activated in presence of FT phosphorylated ubiquitin." FT /evidence="ECO:0000269|PubMed:24660806, FT ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:25474007" FT MUTAGEN 175 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 175 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-217." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->A: Loss of phosphorylation. Reduced mitochondrial FT localization; when associated with A-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 217 FT /note="T->E: Phosphomimetic mutant. Mostly localizes to the FT mitochondria; when associated with E-175." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 238 FT /note="C->S: Loss of mitochondrial localization." FT /evidence="ECO:0000269|PubMed:18957282" FT MUTAGEN 332 FT /note="C->S: Impairs folding of IBR domain." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 337 FT /note="C->A: Impairs the ability to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439" FT MUTAGEN 365 FT /note="C->S: Impairs protein folding." FT /evidence="ECO:0000269|PubMed:17360614" FT MUTAGEN 403 FT /note="W->A: Decreased autoinhibition and increased E3 FT activity." FT /evidence="ECO:0000269|PubMed:24784582" FT MUTAGEN 421 FT /note="C->A: Impairs the ability of self-ubiquitination and FT to ubiquitinate SNCAIP." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:18541373" FT MUTAGEN 429 FT /note="G->E: Reduced self-ubiquitination." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:23770917" FT MUTAGEN 431 FT /note="C->S: Impairs the ability to ubiquitinate target FT proteins. No effect on translocation to mitochondria." FT /evidence="ECO:0000269|PubMed:11590439, FT ECO:0000269|PubMed:23727886, ECO:0000269|PubMed:23770887, FT ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:32047033" FT MUTAGEN 433 FT /note="H->N,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT MUTAGEN 444 FT /note="E->Q,A: Impaired activity." FT /evidence="ECO:0000269|PubMed:23727886, FT ECO:0000269|PubMed:23770887" FT CONFLICT 223 FT /note="S -> P (in Ref. 1; BAA25751 and 3; AAM21458/ FT AAM21457)" FT /evidence="ECO:0000305" FT CONFLICT 289..290 FT /note="CV -> MI (in Ref. 2; AAM21461)" FT /evidence="ECO:0000305" FT CONFLICT 339 FT /note="A -> V (in Ref. 9; AAS88422)" FT /evidence="ECO:0000305" FT STRAND 2..11 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 13..16 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 19..21 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 23..34 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 38..40 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 41..45 FT /evidence="ECO:0007829|PDB:5C1Z" FT STRAND 48..50 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 52..55 FT /evidence="ECO:0007829|PDB:1IYF" FT HELIX 56..59 FT /evidence="ECO:0007829|PDB:5C1Z" FT TURN 62..64 FT /evidence="ECO:0007829|PDB:5N2W" FT STRAND 66..71 FT /evidence="ECO:0007829|PDB:5C1Z" FT HELIX 102..104 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 147..150 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 152..154 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 156..166 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 167..169 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 174..178 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 183..187 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 188..190 FT /evidence="ECO:0007829|PDB:8WZO" FT STRAND 192..196 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 198..200 FT /evidence="ECO:0007829|PDB:5N38" FT STRAND 205..212 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 223..225 FT /evidence="ECO:0007829|PDB:4I1H" FT TURN 239..241 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 246..250 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 257..260 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 261..273 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 281..283 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 284..286 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 290..292 FT /evidence="ECO:0007829|PDB:6N13" FT HELIX 301..307 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 309..326 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 335..337 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:6GLC" FT STRAND 348..351 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 355..358 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 363..365 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 366..368 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 374..376 FT /evidence="ECO:0007829|PDB:6GLC" FT HELIX 379..381 FT /evidence="ECO:0007829|PDB:4BM9" FT HELIX 395..400 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 403..406 FT /evidence="ECO:0007829|PDB:8WZN" FT STRAND 414..417 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 419..421 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 424..426 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 429..431 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 433..435 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 439..441 FT /evidence="ECO:0007829|PDB:4I1F" FT STRAND 444..446 FT /evidence="ECO:0007829|PDB:4I1F" FT TURN 447..449 FT /evidence="ECO:0007829|PDB:4I1F" FT HELIX 455..461 FT /evidence="ECO:0007829|PDB:4I1F" SQ SEQUENCE 465 AA; 51641 MW; 9A8BB802A3FC84C3 CRC64; MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL RNDWTVQNCD LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ SLTRVDLSSS VLPGDSVGLA VILHTDSRKD SPPAGSPAGR SIYNSFYVYC KGPCQRVQPG KLRVQCSTCR QATLTLTQGP SCWDDVLIPN RMSGECQSPH CPGTSAEFFF KCGAHPTSDK ETSVALHLIA TNSRNITCIT CTDVRSPVLV FQCNSRHVIC LDCFHLYCVT RLNDRQFVHD PQLGYSLPCV AGCPNSLIKE LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEPDQRKV TCEGGNGLGC GFAFCRECKE AYHEGECSAV FEASGTTTQA YRVDERAAEQ ARWEAASKET IKKTTKPCPR CHVPVEKNGG CMHMKCPQPQ CRLEWCWNCG CEWNRVCMGD HWFDV // ID PRKRA_HUMAN Reviewed; 313 AA. AC O75569; A8K3I6; Q53G24; Q6X7T5; Q8NDK4; DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 28-JAN-2026, entry version 212. DE RecName: Full=Interferon-inducible double-stranded RNA-dependent protein kinase activator A; DE AltName: Full=PKR-associated protein X; DE AltName: Full=PKR-associating protein X; DE AltName: Full=Protein activator of the interferon-induced protein kinase; DE AltName: Full=Protein kinase, interferon-inducible double-stranded RNA-dependent activator; GN Name=PRKRA {ECO:0000312|HGNC:HGNC:9438}; Synonyms=PACT, RAX; GN ORFNames=HSD-14, HSD14; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND INTERACTION WITH RP EIF2AK2. RC TISSUE=Placenta; RX PubMed=9687506; DOI=10.1093/emboj/17.15.4379; RA Patel R.C., Sen G.C.; RT "PACT, a protein activator of the interferon-induced protein kinase, PKR."; RL EMBO J. 17:4379-4390(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=10336432; DOI=10.1074/jbc.274.22.15427; RA Ito T., Yang M., May W.S.; RT "RAX, a cellular activator for double-stranded RNA-dependent protein kinase RT during stress signaling."; RL J. Biol. Chem. 274:15427-15432(1999). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Testis; RA Hu T.H., Miao S.Y., Zhang X.D., Qiao Y., Liang G., Wang L.F.; RT "A new spermatogenesis-related gene."; RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Brain; RX PubMed=11230166; DOI=10.1101/gr.gr1547r; RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B., RA Klein M., Poustka A.; RT "Towards a catalog of human genes and proteins: sequencing and analysis of RT 500 novel complete protein coding human cDNAs."; RL Genome Res. 11:422-435(2001). RN [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 MRNA] (ISOFORM 1). RC TISSUE=Heart; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE 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 [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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP FUNCTION, AND INTERACTION WITH EIF2AK2. RX PubMed=11238927; DOI=10.1128/mcb.21.6.1908-1920.2001; RA Peters G.A., Hartmann R., Qin J., Sen G.C.; RT "Modular structure of PACT: distinct domains for binding and activating RT PKR."; RL Mol. Cell. Biol. 21:1908-1920(2001). RN [13] 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 [14] RP FUNCTION, INTERACTION WITH DICER1; AGO2 AND TARBP2, SUBCELLULAR LOCATION, RP AND MUTAGENESIS OF 298-ALA-ALA-299. RX PubMed=16424907; DOI=10.1038/sj.emboj.7600942; RA Lee Y., Hur I., Park S.-Y., Kim Y.-K., Suh M.R., Kim V.N.; RT "The role of PACT in the RNA silencing pathway."; RL EMBO J. 25:522-532(2006). RN [15] RP FUNCTION, INTERACTION WITH EIF2AK2, SUBCELLULAR LOCATION, PHOSPHORYLATION RP AT SER-246 AND SER-287, AND MUTAGENESIS OF SER-18; GLN-243; SER-246; RP ASP-260; ASP-262; SER-265; GLN-271; SER-279; SER-287; GLY-288 AND CYS-291. RX PubMed=16982605; DOI=10.1074/jbc.m607714200; RA Peters G.A., Li S., Sen G.C.; RT "Phosphorylation of specific serine residues in the PKR activation domain RT of PACT is essential for its ability to mediate apoptosis."; RL J. Biol. Chem. 281:35129-35136(2006). RN [16] RP FUNCTION, SELF-ASSOCIATION, INTERACTION WITH DICER1 AND TARBP2, AND RP SUBCELLULAR LOCATION. RX PubMed=17452327; DOI=10.1074/jbc.m611768200; RA Kok K.H., Ng M.-H., Ching Y.-P., Jin D.-Y.; RT "Human TRBP and PACT directly interact with each other and associate with RT dicer to facilitate the production of small interfering RNA."; RL J. Biol. Chem. 282:17649-17657(2007). RN [17] RP INTERACTION WITH DUS2L. RX PubMed=18096616; DOI=10.1093/nar/gkm1129; RA Mittelstadt M., Frump A., Khuu T., Fowlkes V., Handy I., Patel C.V., RA Patel R.C.; RT "Interaction of human tRNA-dihydrouridine synthase-2 with interferon- RT induced protein kinase PKR."; RL Nucleic Acids Res. 36:998-1008(2008). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [19] RP SELF-ASSOCIATION, INTERACTION WITH EIF2AK2 AND TARBP2, AND SUBCELLULAR RP LOCATION. RX PubMed=18421256; DOI=10.4161/rna.5.2.6069; RA Laraki G., Clerzius G., Daher A., Melendez-Pena C., Daniels S., RA Gatignol A.; RT "Interactions between the double-stranded RNA-binding proteins TRBP and RT PACT define the Medipal domain that mediates protein-protein RT interactions."; RL RNA Biol. 5:92-103(2008). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, 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 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 [22] RP INTERACTION WITH EBOLAVIRUS VP35 (MICROBIAL INFECTION). RX PubMed=21228243; DOI=10.1128/jvi.01160-10; RA Fabozzi G., Nabel C.S., Dolan M.A., Sullivan N.J.; RT "Ebolavirus proteins suppress the effects of small interfering RNA by RT direct interaction with the mammalian RNA interference pathway."; RL J. Virol. 85:2512-2523(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, 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 [24] RP SUBCELLULAR LOCATION. RX PubMed=22214662; DOI=10.4161/cc.11.2.18999; RA Bennett R.L., Pan Y., Christian J., Hui T., May W.S. Jr.; RT "The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and RT activation, leading to G(1) arrest."; RL Cell Cycle 11:407-417(2012). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18 AND SER-167, 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 [26] RP INTERACTION WITH EBOLAVIRUS PROTEIN VP35 (MICROBIAL INFECTION) AND RIGI. RX PubMed=23870315; DOI=10.1016/j.chom.2013.06.010; RA Luthra P., Ramanan P., Mire C.E., Weisend C., Tsuda Y., Yen B., Liu G., RA Leung D.W., Geisbert T.W., Ebihara H., Amarasinghe G.K., Basler C.F.; RT "Mutual antagonism between the Ebola virus VP35 protein and the RIG-I RT activator PACT determines infection outcome."; RL Cell Host Microbe 14:74-84(2013). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [28] RP INTERACTION WITH HUMAN HERPES VIRUS 8 PROTEIN KTA/ORF57 (MICROBIAL RP INFECTION). RX PubMed=29084250; DOI=10.1371/journal.ppat.1006677; RA Sharma N.R., Majerciak V., Kruhlak M.J., Zheng Z.M.; RT "KSHV inhibits stress granule formation by viral ORF57 blocking PKR RT activation."; RL PLoS Pathog. 13:e1006677-e1006677(2017). RN [29] RP STRUCTURE BY NMR OF 32-104. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the DSRM domain of protein activator of the RT interferon-induced protein kinase."; RL Submitted (SEP-2006) to the PDB data bank. RN [30] RP VARIANT DYT16 LEU-222. RX PubMed=18243799; DOI=10.1016/s1474-4422(08)70022-x; RA Camargos S., Scholz S., Simon-Sanchez J., Paisan-Ruiz C., Lewis P., RA Hernandez D., Ding J., Gibbs J.R., Cookson M.R., Bras J., Guerreiro R., RA Oliveira C.R., Lees A., Hardy J., Cardoso F., Singleton A.B.; RT "DYT16, a novel young-onset dystonia-parkinsonism disorder: identification RT of a segregating mutation in the stress-response protein PRKRA."; RL Lancet Neurol. 7:207-215(2008). RN [31] RP INVOLVEMENT IN DYT16. RX PubMed=18420150; DOI=10.1016/s1474-4422(08)70075-9; RA Seibler P., Djarmati A., Langpap B., Hagenah J., Schmidt A., RA Brueggemann N., Siebner H., Jabusch H.-C., Altenmueller E., Muenchau A., RA Lohmann K., Klein C.; RT "A heterozygous frameshift mutation in PRKRA (DYT16) associated with RT generalised dystonia in a German patient."; RL Lancet Neurol. 7:380-381(2008). CC -!- FUNCTION: Activates EIF2AK2/PKR in the absence of double-stranded RNA CC (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition CC of translation and induction of apoptosis. Required for siRNA CC production by DICER1 and for subsequent siRNA-mediated post- CC transcriptional gene silencing. Does not seem to be required for CC processing of pre-miRNA to miRNA by DICER1. Promotes UBC9-p53/TP53 CC association and sumoylation and phosphorylation of p53/TP53 at 'Lys- CC 386' at 'Ser-392' respectively and enhances its activity in a CC EIF2AK2/PKR-dependent manner (By similarity). May function as regulator CC of gastric epithelial differentiation (By similarity). {ECO:0000250, CC ECO:0000250|UniProtKB:Q9WTX2, ECO:0000269|PubMed:10336432, CC ECO:0000269|PubMed:11238927, ECO:0000269|PubMed:16424907, CC ECO:0000269|PubMed:16982605, ECO:0000269|PubMed:17452327, CC ECO:0000269|PubMed:9687506}. CC -!- SUBUNIT: Homodimer. Interacts with EIF2AK2/PKR through its DRBM CC domains. Interacts with DICER1, AGO2 and TARBP2. Also able to interact CC with dsRNA. Interacts with UBC9 (By similarity). Forms a complex with CC UBC9 and p53/TP53 (By similarity). Interacts with DUS2L (via DRBM CC domain). Interacts with RIGI. {ECO:0000250, CC ECO:0000269|PubMed:11238927, ECO:0000269|PubMed:16424907, CC ECO:0000269|PubMed:16982605, ECO:0000269|PubMed:17452327, CC ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18421256, CC ECO:0000269|PubMed:23870315, ECO:0000269|PubMed:9687506}. CC -!- SUBUNIT: (Microbial infection) Interacts with ebolavirus protein VP35; CC this interaction inhibits the interaction between RIGI and PRKRA. In CC addition, this interaction disrupts the interaction between VP35 and CC the viral polymerase L. So the VP35-PRKRA interaction plays a critical CC role in determining the outcome of ebolavirus infection CC (PubMed:23870315). The interaction PRKRA-VP35 also prevents PRKRA CC binding to DICER1 and thus allows the virus to counteract host RNA CC silencing (PubMed:21228243). {ECO:0000269|PubMed:21228243, CC ECO:0000269|PubMed:23870315}. CC -!- SUBUNIT: (Microbial infection) Interacts with human herpesvirus 8 CC protein MTA/ORF57; this interaction inhibits stress granule formation. CC {ECO:0000269|PubMed:29084250}. CC -!- INTERACTION: CC O75569; P78563-4: ADARB1; NbExp=3; IntAct=EBI-713955, EBI-12002366; CC O75569; Q9UKV8: AGO2; NbExp=5; IntAct=EBI-713955, EBI-528269; CC O75569; Q03701: CEBPZ; NbExp=3; IntAct=EBI-713955, EBI-1046778; CC O75569; Q9UPY3: DICER1; NbExp=9; IntAct=EBI-713955, EBI-395506; CC O75569; Q08426: EHHADH; NbExp=3; IntAct=EBI-713955, EBI-2339219; CC O75569; P19525: EIF2AK2; NbExp=6; IntAct=EBI-713955, EBI-640775; CC O75569; Q9BYX4: IFIH1; NbExp=4; IntAct=EBI-713955, EBI-6115771; CC O75569; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-713955, EBI-739832; CC O75569; Q9NX58: LYAR; NbExp=7; IntAct=EBI-713955, EBI-713507; CC O75569; O15226: NKRF; NbExp=6; IntAct=EBI-713955, EBI-766011; CC O75569; O75928-2: PIAS2; NbExp=3; IntAct=EBI-713955, EBI-348567; CC O75569; O75569: PRKRA; NbExp=6; IntAct=EBI-713955, EBI-713955; CC O75569; O95786: RIGI; NbExp=5; IntAct=EBI-713955, EBI-995350; CC O75569; Q9Y3U8: RPL36; NbExp=3; IntAct=EBI-713955, EBI-1057689; CC O75569; O95793: STAU1; NbExp=5; IntAct=EBI-713955, EBI-358174; CC O75569; Q96SI9: STRBP; NbExp=4; IntAct=EBI-713955, EBI-740355; CC O75569; Q15633: TARBP2; NbExp=15; IntAct=EBI-713955, EBI-978581; CC O75569; Q9HA38: ZMAT3; NbExp=3; IntAct=EBI-713955, EBI-2548480; CC O75569; Q9H898-2: ZMAT4; NbExp=4; IntAct=EBI-713955, EBI-11529334; CC O75569; P38732: EFM1; Xeno; NbExp=4; IntAct=EBI-713955, EBI-24379; CC O75569; P03416: N; Xeno; NbExp=6; IntAct=EBI-713955, EBI-25639341; CC O75569; P0DTC9: N; Xeno; NbExp=8; IntAct=EBI-713955, EBI-25475856; CC O75569; P59595: N; Xeno; NbExp=6; IntAct=EBI-713955, EBI-7602718; CC O75569; P03496: NS; Xeno; NbExp=3; IntAct=EBI-713955, EBI-2547442; CC O75569; Q67020: PA; Xeno; NbExp=3; IntAct=EBI-713955, EBI-11514477; CC O75569; Q05127: VP35; Xeno; NbExp=2; IntAct=EBI-713955, EBI-6148294; CC O75569-1; P19525: EIF2AK2; NbExp=3; IntAct=EBI-15588172, EBI-640775; CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region. Cytoplasm. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O75569-1; Sequence=Displayed; CC Name=2; CC IsoId=O75569-2; Sequence=VSP_017283; CC Name=3; CC IsoId=O75569-3; Sequence=VSP_017282; CC -!- DOMAIN: Self-association may occur via interactions between DRBM CC domains as follows: DRBM 1/DRBM 1, DRBM 1/DRBM 2, DRBM 2/DRBM 2 or DRBM CC 3/DRBM3. CC -!- PTM: Phosphorylated at Ser-246 in unstressed cells and at Ser-287 in CC stressed cells. Phosphorylation at Ser-246 appears to be a prerequisite CC for subsequent phosphorylation at Ser-287. Phosphorylation at Ser-246 CC and Ser-287 are necessary for activation of EIF2AK2/PKR under CC conditions of stress. {ECO:0000269|PubMed:16982605}. CC -!- DISEASE: Dystonia 16 (DYT16) [MIM:612067]: An early-onset dystonia- CC parkinsonism disorder. Dystonia is defined by the presence of sustained CC involuntary muscle contraction, often leading to abnormal postures. CC DYT16 patients have progressive, generalized dystonia with axial muscle CC involvement, oro-mandibular (sardonic smile) and laryngeal dystonia CC and, in some cases, parkinsonian features. CC {ECO:0000269|PubMed:18243799, ECO:0000269|PubMed:18420150}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the PRKRA 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; AF072860; AAC25672.1; -; mRNA. DR EMBL; AF083033; AAD33099.1; -; mRNA. DR EMBL; AY251164; AAP20061.1; -; mRNA. DR EMBL; AL136615; CAB66550.1; -; mRNA. DR EMBL; AL833867; CAD38725.1; -; Transcribed_RNA. DR EMBL; BT007243; AAP35907.1; -; mRNA. DR EMBL; AK290601; BAF83290.1; -; mRNA. DR EMBL; CR533525; CAG38556.1; -; mRNA. DR EMBL; AK223107; BAD96827.1; -; mRNA. DR EMBL; AC009948; AAX88882.1; -; Genomic_DNA. DR EMBL; CH471058; EAX11036.1; -; Genomic_DNA. DR EMBL; BC009470; AAH09470.1; -; mRNA. DR CCDS; CCDS2279.1; -. [O75569-1] DR CCDS; CCDS46460.1; -. [O75569-2] DR CCDS; CCDS46461.1; -. [O75569-3] DR RefSeq; NP_001132989.1; NM_001139517.1. [O75569-2] DR RefSeq; NP_001132990.1; NM_001139518.1. [O75569-3] DR RefSeq; NP_003681.1; NM_003690.5. [O75569-1] DR PDB; 2DIX; NMR; -; A=33-103. DR PDB; 8ZU6; NMR; -; A/B=240-309. DR PDBsum; 2DIX; -. DR PDBsum; 8ZU6; -. DR AlphaFoldDB; O75569; -. DR EMDB; EMD-5604; -. DR EMDB; EMD-5605; -. DR EMDB; EMD-5606; -. DR SMR; O75569; -. DR BioGRID; 114143; 434. DR ComplexPortal; CPX-1072; RISC-loading complex, PRKRA variant. DR DIP; DIP-41809N; -. DR FunCoup; O75569; 1598. DR IntAct; O75569; 353. DR MINT; O75569; -. DR STRING; 9606.ENSP00000318176; -. DR GlyGen; O75569; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; O75569; -. DR PhosphoSitePlus; O75569; -. DR SwissPalm; O75569; -. DR BioMuta; PRKRA; -. DR CPTAC; CPTAC-994; -. DR jPOST; O75569; -. DR MassIVE; O75569; -. DR PaxDb; 9606-ENSP00000318176; -. DR PeptideAtlas; O75569; -. DR ProteomicsDB; 50088; -. [O75569-1] DR ProteomicsDB; 50089; -. [O75569-2] DR ProteomicsDB; 50090; -. [O75569-3] DR Pumba; O75569; -. DR Antibodypedia; 3306; 380 antibodies from 38 providers. DR DNASU; 8575; -. DR Ensembl; ENST00000325748.9; ENSP00000318176.4; ENSG00000180228.15. [O75569-1] DR Ensembl; ENST00000432031.6; ENSP00000393883.2; ENSG00000180228.15. [O75569-2] DR Ensembl; ENST00000487082.5; ENSP00000430604.1; ENSG00000180228.15. [O75569-3] DR GeneID; 8575; -. DR KEGG; hsa:8575; -. DR MANE-Select; ENST00000325748.9; ENSP00000318176.4; NM_003690.5; NP_003681.1. DR UCSC; uc002umd.4; human. [O75569-1] DR AGR; HGNC:9438; -. DR ClinPGx; PA33780; -. DR CTD; 8575; -. DR DisGeNET; 8575; -. DR GeneCards; PRKRA; -. DR HGNC; HGNC:9438; PRKRA. DR HPA; ENSG00000180228; Low tissue specificity. DR MalaCards; PRKRA; -. DR MIM; 603424; gene. DR MIM; 612067; phenotype. DR OpenTargets; ENSG00000180228; -. DR Orphanet; 210571; Dystonia 16. DR VEuPathDB; HostDB:ENSG00000180228; -. DR eggNOG; KOG3732; Eukaryota. DR GeneTree; ENSGT00940000157618; -. DR HOGENOM; CLU_048292_0_0_1; -. DR InParanoid; O75569; -. DR OMA; PEYEFEK; -. DR OrthoDB; 10056847at2759; -. DR PAN-GO; O75569; 8 GO annotations based on evolutionary models. DR PhylomeDB; O75569; -. DR PathwayCommons; O75569; -. DR Reactome; R-HSA-203927; MicroRNA (miRNA) biogenesis. DR Reactome; R-HSA-426486; Small interfering RNA (siRNA) biogenesis. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; O75569; -. DR SIGNOR; O75569; -. DR Agora; ENSG00000180228; -. DR BioGRID-ORCS; 8575; 382 hits in 1167 CRISPR screens. DR ChiTaRS; PRKRA; human. DR EvolutionaryTrace; O75569; -. DR GeneWiki; PRKRA; -. DR GenomeRNAi; 8575; -. DR Pharos; O75569; Tbio. DR PRO; PR:O75569; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; O75569; protein. DR Bgee; ENSG00000180228; Expressed in sperm and 210 other cell types or tissues. DR ExpressionAtlas; O75569; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0016442; C:RISC complex; IBA:GO_Central. DR GO; GO:0070578; C:RISC-loading complex; IDA:BHF-UCL. DR GO; GO:0003725; F:double-stranded RNA binding; IDA:BHF-UCL. DR GO; GO:0008047; F:enzyme activator activity; IDA:UniProt. DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0070883; F:pre-miRNA binding; IDA:BHF-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0035197; F:siRNA binding; IBA:GO_Central. DR GO; GO:0140374; P:antiviral innate immune response; IDA:UniProt. DR GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl. DR GO; GO:0006955; P:immune response; TAS:ProtInc. DR GO; GO:0042474; P:middle ear morphogenesis; IEA:Ensembl. DR GO; GO:0035196; P:miRNA processing; IDA:BHF-UCL. DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc. DR GO; GO:0042473; P:outer ear morphogenesis; IEA:Ensembl. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0031054; P:pre-miRNA processing; IDA:BHF-UCL. DR GO; GO:0050821; P:protein stabilization; IMP:BHF-UCL. DR GO; GO:0070920; P:regulation of regulatory ncRNA processing; IBA:GO_Central. DR GO; GO:0009615; P:response to virus; TAS:ProtInc. DR GO; GO:0070922; P:RISC complex assembly; IDA:ComplexPortal. DR GO; GO:0030422; P:siRNA processing; IDA:UniProtKB. DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl. DR CDD; cd19889; DSRM_PRKRA_rpt1; 1. DR CDD; cd19891; DSRM_PRKRA_rpt2; 1. DR CDD; cd19892; DSRM_PRKRA_rpt3; 1. DR FunFam; 3.30.160.20:FF:000005; Putative double-stranded RNA-specific adenosine deaminase; 1. DR FunFam; 3.30.160.20:FF:000019; RISC-loading complex subunit TARBP2; 1. DR FunFam; 3.30.160.20:FF:000018; RISC-loading complex subunit TARBP2 isoform X3; 1. DR Gene3D; 3.30.160.20; -; 3. DR InterPro; IPR014720; dsRBD_dom. DR InterPro; IPR044465; PRKRA_DSRM_1. DR InterPro; IPR044466; PRKRA_DSRM_2. DR InterPro; IPR044467; PRKRA_DSRM_3. DR InterPro; IPR051247; RLC_Component. DR PANTHER; PTHR46205:SF2; INTERFERON-INDUCIBLE DOUBLE-STRANDED RNA-DEPENDENT PROTEIN KINASE ACTIVATOR A; 1. DR PANTHER; PTHR46205; LOQUACIOUS, ISOFORM B; 1. DR Pfam; PF00035; dsrm; 2. DR SMART; SM00358; DSRM; 3. DR SUPFAM; SSF54768; dsRNA-binding domain-like; 3. DR PROSITE; PS50137; DS_RBD; 3. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant; Dystonia; KW Host-virus interaction; Parkinsonism; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; RNA-binding; KW RNA-mediated gene silencing. FT CHAIN 1..313 FT /note="Interferon-inducible double-stranded RNA-dependent FT protein kinase activator A" FT /id="PRO_0000223609" FT DOMAIN 34..101 FT /note="DRBM 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266" FT DOMAIN 126..194 FT /note="DRBM 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266" FT DOMAIN 240..308 FT /note="DRBM 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266" FT REGION 1..103 FT /note="Sufficient for self-association and interaction with FT TARBP2" FT REGION 1..21 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 102..195 FT /note="Sufficient for self-association and interaction with FT TARBP2" FT REGION 195..313 FT /note="Sufficient for self-association and interaction with FT TARBP2" FT COMPBIAS 1..18 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 18 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 167 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 246 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:16982605" FT MOD_RES 287 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:16982605" FT VAR_SEQ 1..25 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_017282" FT VAR_SEQ 1..21 FT /note="MSQSRHRAEAPPLEREDSGTF -> MQSTPFCGFC (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11230166" FT /id="VSP_017283" FT VARIANT 222 FT /note="P -> L (in DYT16; dbSNP:rs121434410)" FT /evidence="ECO:0000269|PubMed:18243799" FT /id="VAR_046213" FT MUTAGEN 18 FT /note="S->A: No effect on apoptosis induction under FT conditions of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 18 FT /note="S->D: Does not induce apoptosis." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 243 FT /note="Q->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 246 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress and binding to EIF2AK2. Prevents activation of FT EIF2AK2 in stressed cells; when associated with A-287." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 246 FT /note="S->D: Induces activation of EIF2AK2 and apoptosis in FT unstressed cells; when associated with D-287." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 260 FT /note="D->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 262 FT /note="D->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 265 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 271 FT /note="Q->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 279 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 287 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress. Prevents activation of EIF2AK2 in stressed FT cells; when associated with A-246." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 287 FT /note="S->D: Induces activation of EIF2AK2 and apoptosis in FT unstressed cells; when associated with D-246." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 288 FT /note="G->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 291 FT /note="C->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 298..299 FT /note="AA->KK: Abrogates interaction with DICER1 but does FT not affect interaction with AGO2." FT /evidence="ECO:0000269|PubMed:16424907" FT CONFLICT 282 FT /note="T -> A (in Ref. 8; BAD96827)" FT /evidence="ECO:0000305" FT HELIX 35..45 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 51..58 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 60..63 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 65..72 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 75..79 FT /evidence="ECO:0007829|PDB:2DIX" FT HELIX 86..101 FT /evidence="ECO:0007829|PDB:2DIX" SQ SEQUENCE 313 AA; 34404 MW; 9B01637E6194827E CRC64; MSQSRHRAEA PPLEREDSGT FSLGKMITAK PGKTPIQVLH EYGMKTKNIP VYECERSDVQ IHVPTFTFRV TVGDITCTGE GTSKKLAKHR AAEAAINILK ANASICFAVP DPLMPDPSKQ PKNQLNPIGS LQELAIHHGW RLPEYTLSQE GGPAHKREYT TICRLESFME TGKGASKKQA KRNAAEKFLA KFSNISPENH ISLTNVVGHS LGCTWHSLRN SPGEKINLLK RSLLSIPNTD YIQLLSEIAK EQGFNITYLD IDELSANGQY QCLAELSTSP ITVCHGSGIS CGNAQSDAAH NALQYLKIIA ERK // 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 PTPA_HUMAN Reviewed; 358 AA. AC Q15257; A2A347; A9IZU4; B4DXM4; Q15258; Q53GZ3; Q5TZQ2; Q9BUK1; Q9NNZ7; AC Q9NNZ8; Q9NNZ9; DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 3. DT 28-JAN-2026, entry version 211. DE RecName: Full=Serine/threonine-protein phosphatase 2A activator; DE EC=5.2.1.8 {ECO:0000250|UniProtKB:Q28717}; DE AltName: Full=PP2A, subunit B', PR53 isoform; DE AltName: Full=Phosphotyrosyl phosphatase activator; DE Short=PTPA; DE AltName: Full=Serine/threonine-protein phosphatase 2A regulatory subunit 4; DE AltName: Full=Serine/threonine-protein phosphatase 2A regulatory subunit B'; GN Name=PTPA {ECO:0000312|HGNC:HGNC:9308}; Synonyms=PPP2R4; 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 PARTIAL PROTEIN SEQUENCE. RC TISSUE=Heart; RX PubMed=8195217; DOI=10.1016/s0021-9258(17)40733-2; RA Cayla X., Van Hoof C., Bosch M., Waelkens E., Peeters B., Merlevede W., RA Goris J.; RT "Molecular cloning, expression, and characterization of PTPA, a protein RT that activates the tyrosyl phosphatase activity of protein phosphatase RT 2A."; RL J. Biol. Chem. 269:15668-15675(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RC TISSUE=Blood; RX PubMed=8530035; DOI=10.1006/geno.1995.1140; RA Van Hoof C., Aly M., Garcia A., Cayla X., Cassiman J.-J., Merlevede W., RA Goris J.; RT "Structure and chromosomal localization of the human gene of the RT phosphotyrosyl phosphatase activator (PTPA) of protein phosphatase 2A."; RL Genomics 28:261-272(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 2; 3 AND 4). RX PubMed=10880964; DOI=10.1046/j.1432-1327.2000.01486.x; RA Janssens V., van Hoof C., Martens E., de Baere I., Merlevede W., Goris J.; RT "Identification and characterization of alternative splice products encoded RT by the human phosphotyrosyl phosphatase activator gene."; RL Eur. J. Biochem. 267:4406-4413(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [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 (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT LEU-357. RC TISSUE=Liver; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [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 1). RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP FUNCTION IN APOPTOSIS, AND SUBCELLULAR LOCATION. RX PubMed=17333320; DOI=10.1007/s10495-006-0050-8; RA Azam S., Drobetsky E., Ramotar D.; RT "Overexpression of the cis/trans isomerase PTPA triggers caspase 3- RT dependent apoptosis."; RL Apoptosis 12:1243-1255(2007). RN [11] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [12] 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 [13] 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 [14] {ECO:0007744|PDB:2G62} RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 22-358. RX PubMed=16782712; DOI=10.1074/jbc.c600100200; RA Magnusdottir A., Stenmark P., Flodin S., Nyman T., Hammarstroem M., Ehn M., RA Bakali H.M.A., Berglund H., Nordlund P.; RT "The crystal structure of a human PP2A phosphatase activator reveals a RT novel fold and highly conserved cleft implicated in protein-protein RT interactions."; RL J. Biol. Chem. 281:22434-22438(2006). RN [15] {ECO:0007744|PDB:2IXM} RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 20-357. RX PubMed=16885030; DOI=10.1016/j.molcel.2006.07.008; RA Leulliot N., Vicentini G., Jordens J., Quevillon-Cheruel S., Schiltz M., RA Barford D., van Tilbeurgh H., Goris J.; RT "Crystal structure of the PP2A phosphatase activator: implications for its RT PP2A-specific PPIase activity."; RL Mol. Cell 23:413-424(2006). RN [16] {ECO:0007744|PDB:2HV6, ECO:0007744|PDB:2HV7} RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH ATP AND MG(2+), RP FUNCTION IN MODULATION OF PP2A SUBSTRATE SPECIFICITY, ATP-BINDING, RP MUTAGENESIS OF ASP-185; ALA-239; GLY-240; VAL-244; GLU-305; VAL-316; RP GLY-325; MET-329 AND LYS-337, AND INTERACTION WITH THE PP2A(D) COMPLEX. RX PubMed=16916641; DOI=10.1016/j.molcel.2006.07.027; RA Chao Y., Xing Y., Chen Y., Xu Y., Lin Z., Li Z., Jeffrey P.D., Stock J.B., RA Shi Y.; RT "Structure and mechanism of the phosphotyrosyl phosphatase activator."; RL Mol. Cell 23:535-546(2006). RN [17] {ECO:0007744|PDB:4NY3} RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 22-358 IN COMPLEX WITH PPP2CA RP 304-309, AND INTERACTION WITH PPP2CA. RX PubMed=25003389; DOI=10.1515/hsz-2014-0106; RA Low C., Quistgaard E.M., Kovermann M., Anandapadamanaban M., Balbach J., RA Nordlund P.; RT "Structural basis for PTPA interaction with the invariant C-terminal tail RT of PP2A."; RL Biol. Chem. 395:881-889(2014). RN [18] RP INVOLVEMENT IN PARK25, VARIANTS PARK25 ASP-171 AND ARG-298, AND FUNCTION. RX PubMed=36073231; DOI=10.1093/brain/awac326; RG French and Mediterranean Parkinson disease Genetics Study Group; RG International Parkinsonism Genetics Network; RA Fevga C., Tesson C., Carreras Mascaro A., Courtin T., van Coller R., RA Sakka S., Ferraro F., Farhat N., Bardien S., Damak M., Carr J., Ferrien M., RA Boumeester V., Hundscheid J., Grillenzoni N., Kessissoglou I.A., RA Kuipers D.J.S., Quadri M., Corvol J.C., Mhiri C., Hassan B.A., RA Breedveld G.J., Lesage S., Mandemakers W., Brice A., Bonifati V.; RT "PTPA variants and impaired PP2A activity in early-onset parkinsonism with RT intellectual disability."; RL Brain 146:1496-1510(2023). CC -!- FUNCTION: PPIases accelerate the folding of proteins. It catalyzes the CC cis-trans isomerization of proline imidic peptide bonds in CC oligopeptides (By similarity). Acts as a regulatory subunit for CC serine/threonine-protein phosphatase 2A (PP2A) (PubMed:16916641, CC PubMed:36073231). Modulates PP2A activity or substrate specificity, CC probably by inducing a conformational change in the catalytic subunit, CC a proposed direct target of the PPIase (PubMed:16916641). Can CC reactivate inactive phosphatase PP2A-phosphatase methylesterase CC complexes (PP2A(i)) in presence of ATP and Mg(2+) (By similarity). CC Reversibly stimulates the variable phosphotyrosyl phosphatase activity CC of PP2A core heterodimer PP2A(D) in presence of ATP and Mg(2+) (in CC vitro) (PubMed:16916641). The phosphotyrosyl phosphatase activity is CC dependent of an ATPase activity of the PP2A(D):PPP2R4 complex CC (PubMed:16916641). Is involved in apoptosis; the function appears to be CC independent from PP2A (PubMed:17333320). {ECO:0000250|UniProtKB:Q28717, CC ECO:0000269|PubMed:16916641, ECO:0000269|PubMed:17333320, CC ECO:0000269|PubMed:36073231}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[protein]-peptidylproline (omega=180) = [protein]- CC peptidylproline (omega=0); Xref=Rhea:RHEA:16237, Rhea:RHEA- CC COMP:10747, Rhea:RHEA-COMP:10748, ChEBI:CHEBI:83833, CC ChEBI:CHEBI:83834; EC=5.2.1.8; CC Evidence={ECO:0000250|UniProtKB:Q28717}; CC -!- SUBUNIT: Associates with PP2A heterodimeric core enzyme PP2A(D), CC composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa CC constant regulatory subunit (PR65 or subunit A) (PubMed:16916641). CC Interacts with the catalytic subunit PPP2CA (via C-terminus) CC (PubMed:25003389). Interacts with PPP2CB (By similarity). CC {ECO:0000250|UniProtKB:P58389, ECO:0000269|PubMed:16916641, CC ECO:0000269|PubMed:25003389}. CC -!- INTERACTION: CC Q15257; Q4VCS5-2: AMOT; NbExp=3; IntAct=EBI-1774121, EBI-3891843; CC Q15257; P60510: PPP4C; NbExp=3; IntAct=EBI-1774121, EBI-1046072; CC Q15257; Q9NY27: PPP4R2; NbExp=2; IntAct=EBI-1774121, EBI-1048740; CC Q15257-2; Q5JTZ9: AARS2; NbExp=3; IntAct=EBI-12164121, EBI-308736; CC Q15257-2; A2BDD9: AMOT; NbExp=3; IntAct=EBI-12164121, EBI-17286414; CC Q15257-2; Q86Z20: CCDC125; NbExp=3; IntAct=EBI-12164121, EBI-11977221; CC Q15257-2; Q9GZT8: NIF3L1; NbExp=3; IntAct=EBI-12164121, EBI-740897; CC Q15257-2; P30153: PPP2R1A; NbExp=3; IntAct=EBI-12164121, EBI-302388; CC Q15257-2; Q9NZD8: SPG21; NbExp=5; IntAct=EBI-12164121, EBI-742688; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17333320}. Nucleus CC {ECO:0000269|PubMed:17333320}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=2; Synonyms=Beta; CC IsoId=Q15257-1; Sequence=Displayed; CC Name=1; Synonyms=Alpha; CC IsoId=Q15257-2; Sequence=VSP_005123; CC Name=3; Synonyms=Delta; CC IsoId=Q15257-3; Sequence=VSP_005122; CC Name=4; Synonyms=Epsilon; CC IsoId=Q15257-4; Sequence=VSP_005124; CC -!- TISSUE SPECIFICITY: Widely expressed. CC -!- DISEASE: Parkinson disease 25, autosomal recessive early-onset, with CC impaired intellectual development (PARK25) [MIM:620482]: An autosomal CC recessive, early-onset form of Parkinson disease, a complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability, as well as by a CC clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the substantia CC nigra and the presence of Lewy bodies (intraneuronal accumulations of CC aggregated proteins), in surviving neurons in various areas of the CC brain. PARK25 is characterized by onset of parkinsonism in late CC childhood or adolescence, developmental delay and intellectual CC disability. Cognitive impairment is mild to moderate and non- CC progressive. {ECO:0000269|PubMed:36073231}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the PTPA-type PPIase family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41817/PPP2R4"; 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; X73478; CAA51873.1; -; mRNA. DR EMBL; X86428; CAA60163.1; -; Genomic_DNA. DR EMBL; X86429; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86430; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86432; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAA60163.1; JOINED; Genomic_DNA. DR EMBL; X86428; CAB77601.1; -; Genomic_DNA. DR EMBL; X86429; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86430; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86431; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86432; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAB77601.1; JOINED; Genomic_DNA. DR EMBL; X86428; CAB77602.1; -; Genomic_DNA. DR EMBL; X86429; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86432; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAB77602.1; JOINED; Genomic_DNA. DR EMBL; X86428; CAB77603.1; -; Genomic_DNA. DR EMBL; X86429; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86430; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86434; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86435; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86436; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86437; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86438; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; X86439; CAB77603.1; JOINED; Genomic_DNA. DR EMBL; AK302043; BAG63436.1; -; mRNA. DR EMBL; BT020119; AAV38922.1; -; mRNA. DR EMBL; AK222788; BAD96508.1; -; mRNA. DR EMBL; AL158151; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471090; EAW87876.1; -; Genomic_DNA. DR EMBL; CH471090; EAW87882.1; -; Genomic_DNA. DR EMBL; BC002545; AAH02545.1; -; mRNA. DR EMBL; BC011605; AAH11605.1; -; mRNA. DR CCDS; CCDS65156.1; -. [Q15257-3] DR CCDS; CCDS6920.1; -. [Q15257-2] DR PIR; A54021; A54021. DR RefSeq; NP_001180326.1; NM_001193397.1. DR RefSeq; NP_001258761.1; NM_001271832.2. [Q15257-3] DR RefSeq; NP_066954.2; NM_021131.4. [Q15257-2] DR RefSeq; NP_821067.1; NM_178000.3. [Q15257-2] DR RefSeq; NP_821068.1; NM_178001.3. [Q15257-1] DR RefSeq; NP_821070.1; NM_178003.3. [Q15257-4] DR PDB; 2G62; X-ray; 1.60 A; A=22-358. DR PDB; 2HV6; X-ray; 1.90 A; A/B=1-358. DR PDB; 2HV7; X-ray; 2.50 A; A/B/C/D/E/F/G/H=1-358. DR PDB; 2IXM; X-ray; 1.50 A; A=20-357. DR PDB; 4LAC; X-ray; 2.82 A; B=19-358. DR PDB; 4NY3; X-ray; 1.80 A; A/B=22-358. DR PDBsum; 2G62; -. DR PDBsum; 2HV6; -. DR PDBsum; 2HV7; -. DR PDBsum; 2IXM; -. DR PDBsum; 4LAC; -. DR PDBsum; 4NY3; -. DR AlphaFoldDB; Q15257; -. DR SMR; Q15257; -. DR BioGRID; 111516; 114. DR FunCoup; Q15257; 1883. DR IntAct; Q15257; 28. DR MINT; Q15257; -. DR STRING; 9606.ENSP00000377036; -. DR BindingDB; Q15257; -. DR ChEMBL; CHEMBL2505; -. DR GlyCosmos; Q15257; 1 site, 1 glycan. DR GlyGen; Q15257; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q15257; -. DR MetOSite; Q15257; -. DR PhosphoSitePlus; Q15257; -. DR SwissPalm; Q15257; -. DR BioMuta; PTPA; -. DR DMDM; 116242737; -. DR OGP; Q15257; -. DR CPTAC; CPTAC-259; -. DR CPTAC; CPTAC-260; -. DR jPOST; Q15257; -. DR MassIVE; Q15257; -. DR PaxDb; 9606-ENSP00000377036; -. DR PeptideAtlas; Q15257; -. DR ProteomicsDB; 60499; -. [Q15257-1] DR ProteomicsDB; 60500; -. [Q15257-2] DR ProteomicsDB; 60501; -. [Q15257-3] DR ProteomicsDB; 60502; -. [Q15257-4] DR Pumba; Q15257; -. DR Antibodypedia; 1074; 372 antibodies from 39 providers. DR CPTC; Q15257; 4 antibodies. DR DNASU; 5524; -. DR Ensembl; ENST00000337738.6; ENSP00000337448.1; ENSG00000119383.22. [Q15257-1] DR Ensembl; ENST00000355007.7; ENSP00000347109.3; ENSG00000119383.22. [Q15257-4] DR Ensembl; ENST00000357197.8; ENSP00000349726.4; ENSG00000119383.22. [Q15257-3] DR Ensembl; ENST00000393370.7; ENSP00000377036.2; ENSG00000119383.22. [Q15257-2] DR GeneID; 5524; -. DR KEGG; hsa:5524; -. DR MANE-Select; ENST00000393370.7; ENSP00000377036.2; NM_178000.3; NP_821067.1. [Q15257-2] DR UCSC; uc004bxl.3; human. [Q15257-1] DR AGR; HGNC:9308; -. DR ClinPGx; PA33671; -. DR CTD; 5524; -. DR DisGeNET; 5524; -. DR GeneCards; PTPA; -. DR HGNC; HGNC:9308; PTPA. DR HPA; ENSG00000119383; Low tissue specificity. DR MalaCards; PTPA; -. DR MIM; 600756; gene. DR MIM; 620482; phenotype. DR OpenTargets; ENSG00000119383; -. DR VEuPathDB; HostDB:ENSG00000119383; -. DR eggNOG; KOG2867; Eukaryota. DR GeneTree; ENSGT00390000011500; -. DR InParanoid; Q15257; -. DR OMA; SWIKINA; -. DR OrthoDB; 16120at2759; -. DR PAN-GO; Q15257; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q15257; -. DR PathwayCommons; Q15257; -. DR SignaLink; Q15257; -. DR SIGNOR; Q15257; -. DR Agora; ENSG00000119383; -. DR BioGRID-ORCS; 5524; 570 hits in 1181 CRISPR screens. DR ChiTaRS; PTPA; human. DR EvolutionaryTrace; Q15257; -. DR GeneWiki; PPP2R4; -. DR GenomeRNAi; 5524; -. DR Pharos; Q15257; Tchem. DR PRO; PR:Q15257; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; Q15257; protein. DR Bgee; ENSG00000119383; Expressed in endometrium epithelium and 210 other cell types or tissues. DR ExpressionAtlas; Q15257; baseline and differential. DR GO; GO:1904949; C:ATPase complex; IDA:HGNC-UCL. DR GO; GO:0034704; C:calcium channel complex; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0000159; C:protein phosphatase type 2A complex; IDA:HGNC-UCL. DR GO; GO:0005524; F:ATP binding; IDA:HGNC-UCL. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0003755; F:peptidyl-prolyl cis-trans isomerase activity; IBA:GO_Central. DR GO; GO:0019902; F:phosphatase binding; IDA:HGNC-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IDA:HGNC-UCL. DR GO; GO:0051721; F:protein phosphatase 2A binding; IDA:HGNC-UCL. DR GO; GO:0019888; F:protein phosphatase regulator activity; IDA:HGNC-UCL. DR GO; GO:0008160; F:protein tyrosine phosphatase activator activity; IDA:HGNC-UCL. DR GO; GO:0005102; F:signaling receptor binding; IPI:BHF-UCL. DR GO; GO:0007052; P:mitotic spindle organization; IBA:GO_Central. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR CDD; cd04087; PTPA; 1. DR FunFam; 1.20.120.1150:FF:000001; Serine/threonine-protein phosphatase 2A activator; 1. DR Gene3D; 1.20.120.1150; -; 1. DR InterPro; IPR004327; Phstyr_phstse_ac. DR InterPro; IPR043170; PTPA_C_lid. DR InterPro; IPR037218; PTPA_sf. DR PANTHER; PTHR10012; SERINE/THREONINE-PROTEIN PHOSPHATASE 2A REGULATORY SUBUNIT B; 1. DR PANTHER; PTHR10012:SF0; SERINE_THREONINE-PROTEIN PHOSPHATASE 2A ACTIVATOR; 1. DR Pfam; PF03095; PTPA; 1. DR PIRSF; PIRSF016325; Phstyr_phstse_ac; 1. DR SUPFAM; SSF140984; PTPA-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Cytoplasm; KW Direct protein sequencing; Disease variant; Intellectual disability; KW Isomerase; Magnesium; Metal-binding; Neurodegeneration; Nucleotide-binding; KW Nucleus; Parkinson disease; Parkinsonism; Proteomics identification; KW Reference proteome; Rotamase. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..358 FT /note="Serine/threonine-protein phosphatase 2A activator" FT /id="PRO_0000071524" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 183 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 188 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 189 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 243 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV6" FT BINDING 249 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV6" FT BINDING 339 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 342 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT BINDING 343 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:16916641, FT ECO:0007744|PDB:2HV7" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:19413330" FT VAR_SEQ 45..108 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_005122" FT VAR_SEQ 73..149 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_005124" FT VAR_SEQ 73..107 FT /note="Missing (in isoform 1)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:8195217, ECO:0000303|Ref.5, FT ECO:0000303|Ref.6" FT /id="VSP_005123" FT VARIANT 28 FT /note="K -> R (in dbSNP:rs17481693)" FT /id="VAR_028101" FT VARIANT 171 FT /note="A -> D (in PARK25; likely pathogenic; decreases PP2A FT complex levels; impairs PP2A phosphatase activation)" FT /evidence="ECO:0000269|PubMed:36073231" FT /id="VAR_089150" FT VARIANT 208 FT /note="R -> Q (in dbSNP:rs4836639)" FT /id="VAR_028102" FT VARIANT 298 FT /note="M -> R (in PARK25; likely pathogenic; decreases PP2A FT complex levels; impairs PP2A phosphatase activation)" FT /evidence="ECO:0000269|PubMed:36073231" FT /id="VAR_089151" FT VARIANT 357 FT /note="S -> L (in dbSNP:rs2480452)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_028103" FT MUTAGEN 185 FT /note="D->A: Impairs ATPase activity of the PP2A(D):PPP2R4 FT complex; no effect on interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 239 FT /note="A->D: Impairs ATPase activity of the PP2A(D):PPP2R4 FT complex; no effect on interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 240 FT /note="G->D: Impairs ATPase activity of the PP2A(D):PPP2R4 FT complex; no effect on interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 244 FT /note="V->D: Impairs interaction with the PP2A(D) complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 305 FT /note="E->A: Abolishes interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 316 FT /note="V->D: Impairs interaction with the PP2A(D) complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 325 FT /note="G->D: Abolishes interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 329 FT /note="M->D: Abolishes interaction with the PP2A(D) FT complex." FT /evidence="ECO:0000269|PubMed:16916641" FT MUTAGEN 337 FT /note="K->G: Impairs interaction with the PP2A(D) complex." FT /evidence="ECO:0000269|PubMed:16916641" FT CONFLICT 113 FT /note="V -> L (in Ref. 1; CAA51873, 2; CAA60163 and 3; FT CAB77601/CAB77602)" FT /evidence="ECO:0000305" FT CONFLICT 297 FT /note="Missing (in Ref. 2; CAA60163 and 3; CAB77601/ FT CAB77602/CAB77603)" FT /evidence="ECO:0000305" FT CONFLICT 357 FT /note="S -> V (in Ref. 1; AA sequence)" FT /evidence="ECO:0000305" FT HELIX 34..40 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 43..58 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 59..61 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 108..124 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 139..156 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 161..166 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 167..175 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 181..184 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 188..203 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 209..211 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 212..217 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 219..233 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 237..240 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 243..245 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 247..250 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 253..261 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 262..264 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 270..274 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 276..282 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 283..285 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 287..298 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 303..306 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 308..313 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 319..333 FT /evidence="ECO:0007829|PDB:2IXM" FT TURN 334..336 FT /evidence="ECO:0007829|PDB:2IXM" FT HELIX 338..341 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 348..350 FT /evidence="ECO:0007829|PDB:2IXM" FT STRAND 352..354 FT /evidence="ECO:0007829|PDB:2IXM" SQ SEQUENCE 358 AA; 40668 MW; 2A962521AF5B4CF7 CRC64; MAEGERQPPP DSSEEAPPAT QNFIIPKKEI HTVPDMGKWK RSQAYADYIG FILTLNEGVK GKKLTFEYRV SEMWNEVHEE KEQAAKQSVS CDECIPLPRA GHCAPSEAIE KLVALLNTLD RWIDETPPVD QPSRFGNKAY RTWYAKLDEE AENLVATVVP THLAAAVPEV AVYLKESVGN STRIDYGTGH EAAFAAFLCC LCKIGVLRVD DQIAIVFKVF NRYLEVMRKL QKTYRMEPAG SQGVWGLDDF QFLPFIWGSS QLIDHPYLEP RHFVDEKAVN ENHKDYMFLE CILFITEMKT GPFAEHSNQL WNISAVPSWS KVNQGLIRMY KAECLEKFPV IQHFKFGSLL PIHPVTSG // ID SEPT4_HUMAN Reviewed; 996 AA. AC O43236; A0A5F9ZHH3; B2RD42; B3KSX9; B4DXC6; B4DXV5; Q6IAP3; Q8N821; Q8NEP4; AC Q9H315; Q9UM58; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 28-JAN-2026, sequence version 2. DT 28-JAN-2026, entry version 207. DE RecName: Full=Septin-4 {ECO:0000312|HGNC:HGNC:9165}; DE AltName: Full=Bradeion beta {ECO:0000303|PubMed:11511094}; DE AltName: Full=Brain protein H5 {ECO:0000250|UniProtKB:P28661}; DE AltName: Full=CE5B3 beta {ECO:0000312|HGNC:HGNC:9165}; DE AltName: Full=Cell division control-related protein 2 {ECO:0000312|HGNC:HGNC:9165}; DE Short=hCDCREL-2 {ECO:0000312|HGNC:HGNC:9165}; DE AltName: Full=Peanut-like protein 2 {ECO:0000303|PubMed:9889007}; GN Name=SEPTIN4 {ECO:0000312|HGNC:HGNC:9165}; GN Synonyms=C17orf47 {ECO:0000312|HGNC:HGNC:9165}, GN PNUTL2 {ECO:0000303|PubMed:9889007}, SEP4 {ECO:0000312|HGNC:HGNC:9165}, GN SEPT4 {ECO:0000312|HGNC:HGNC:9165}; ORFNames=hucep-7; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RX PubMed=9889007; DOI=10.1006/geno.1998.5612; RA Paavola P., Horelli-Kuitunen N., Palotie A., Peltonen L.; RT "Characterization of a novel gene, PNUTL2, on human chromosome 17q22-q23 RT and its exclusion as the Meckel syndrome gene."; RL Genomics 55:122-125(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY. RC TISSUE=Brain, and Fetal brain; RX PubMed=11167005; DOI=10.1016/s0378-1119(00)00527-8; RA Zieger B., Tran H., Hainmann I., Wunderle D., Zgaga-Griesz A., Blaeser S., RA Ware J.; RT "Characterization and expression analysis of two human septin genes, PNUTL1 RT and PNUTL2."; RL Gene 261:197-203(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ARTS), FUNCTION (ISOFORM ARTS), TISSUE RP SPECIFICITY (ISOFORM ARTS), SUBCELLULAR LOCATION (ISOFORM ARTS), AND RP MUTAGENESIS OF 137-GLY--SER-139 (ISOFORM ARTS). RC TISSUE=Fetal brain; RX PubMed=11146656; DOI=10.1038/35046566; RA Larisch S., Yi Y., Lotan R., Kerner H., Eimerl S., Parks W.T., Yossi G., RA Reffey S.B., de Caestecker M.P., Danielpour D., Book-Melamed N., RA Timberg R., Duckett C., Lechleider R.J., Steller H., Orly J., Kim S.-J., RA Roberts A.B.; RT "A novel mitochondrial septin-like protein, ARTS, mediates apoptosis RT dependent on its P-loop motif."; RL Nat. Cell Biol. 2:915-921(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=11511094; DOI=10.1006/bbrc.2001.5413; RA Tanaka M., Tanaka T., Kijima H., Itoh J., Matsuda T., Hori S., Yamamoto M.; RT "Characterization of tissue- and cell-type-specific expression of a novel RT human septin family gene, Bradeion."; RL Biochem. Biophys. Res. Commun. 286:547-553(2001). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Yoshimoto M., Yazaki M., Matsumoto K., Takayama K.; RT "Molecular cloning of a new GTP binding protein from human brain."; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Zha D., Hu G.; RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases. RN [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3; 4; 5 AND 8). RC TISSUE=Amygdala, Brain cortex, Subthalamic nucleus, and Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [9] 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 [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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 8). RC TISSUE=Hippocampus, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP INTERACTION WITH SEPTIN8, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=15116257; DOI=10.1160/th03-09-0578; RA Blaeser S., Horn J., Wuermell P., Bauer H., Struempell S., Nurden P., RA Pagenstecher A., Busse A., Wunderle D., Hainmann I., Zieger B.; RT "The novel human platelet septin SEPT8 is an interaction partner of RT SEPT4."; RL Thromb. Haemost. 91:959-966(2004). RN [13] RP PROTEIN SEQUENCE OF 659-675 AND 800-808, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RC TISSUE=Fetal brain; RA Lubec G., Chen W.-Q.; RL Submitted (JAN-2009) to UniProtKB. RN [14] RP FUNCTION (ISOFORM ARTS). RX PubMed=15837787; DOI=10.1074/jbc.m501955200; RA Lotan R., Rotem A., Gonen H., Finberg J.P.M., Kemeny S., Steller H., RA Ciechanover A., Larisch S.; RT "Regulation of the proapoptotic ARTS protein by ubiquitin-mediated RT degradation."; RL J. Biol. Chem. 280:25802-25810(2005). RN [15] RP TISSUE SPECIFICITY. RX PubMed=15915442; DOI=10.1002/path.1789; RA Hall P.A., Jung K., Hillan K.J., Russell S.E.H.; RT "Expression profiling the human septin gene family."; RL J. Pathol. 206:269-278(2005). RN [16] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=17296554; DOI=10.1016/j.neuron.2007.01.019; RA Ihara M., Yamasaki N., Hagiwara A., Tanigaki A., Kitano A., Hikawa R., RA Tomimoto H., Noda M., Takanashi M., Mori H., Hattori N., Miyakawa T., RA Kinoshita M.; RT "Sept4, a component of presynaptic scaffold and Lewy bodies, is required RT for the suppression of alpha-synuclein neurotoxicity."; RL Neuron 53:519-533(2007). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-843, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=18318008; DOI=10.1002/pmic.200700884; RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D., RA Zou H., Gu J.; RT "Large-scale phosphoproteome analysis of human liver tissue by enrichment RT and fractionation of phosphopeptides with strong anion exchange RT chromatography."; RL Proteomics 8:1346-1361(2008). RN [18] RP INTERACTION WITH XIAP, AND SUBCELLULAR LOCATION. RX PubMed=21695558; DOI=10.1007/s10495-011-0622-0; RA Bornstein B., Gottfried Y., Edison N., Shekhtman A., Lev T., Glaser F., RA Larisch S.; RT "ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a RT mechanism that is different from other IAP-antagonists."; RL Apoptosis 16:869-881(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635; SER-636 AND SER-843, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [20] RP INTERACTION WITH SEPTIN9 HNA VARIANTS. RX PubMed=17546647; DOI=10.1002/humu.20554; RA Sudo K., Ito H., Iwamoto I., Morishita R., Asano T., Nagata K.; RT "SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are RT associated with altered interactions with SEPT4/SEPT11 and resistance to RT Rho/Rhotekin-signaling."; RL Hum. Mutat. 28:1005-1013(2007). RN [21] RP FUNCTION (ISOFORM ARTS), SUBCELLULAR LOCATION (ISOFORM ARTS), INTERACTION RP WITH XIAP (ISOFORM ARTS), AND MUTAGENESIS OF 137-GLY--SER-139 (ISOFORM RP ARTS). RX PubMed=15029247; DOI=10.1038/sj.emboj.7600155; RA Gottfried Y., Rotem A., Lotan R., Steller H., Larisch S.; RT "The mitochondrial ARTS protein promotes apoptosis through targeting RT XIAP."; RL EMBO J. 23:1627-1635(2004). RN [22] RP INTERACTION WITH AREL1, AND UBIQUITINATION. RX PubMed=23479728; DOI=10.1074/jbc.m112.436113; RA Kim J.B., Kim S.Y., Kim B.M., Lee H., Kim I., Yun J., Jo Y., Oh T., Jo Y., RA Chae H.D., Shin D.Y.; RT "Identification of a novel anti-apoptotic E3 ubiquitin ligase that RT ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, RT and ARTS."; RL J. Biol. Chem. 288:12014-12021(2013). RN [23] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=25588830; DOI=10.1242/jcs.158998; RA Kuo Y.C., Shen Y.R., Chen H.I., Lin Y.H., Wang Y.Y., Chen Y.R., Wang C.Y., RA Kuo P.L.; RT "SEPT12 orchestrates the formation of mammalian sperm annulus by organizing RT core octameric complexes with other SEPT proteins."; RL J. Cell Sci. 128:923-934(2015). RN [24] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH BCL2 AND XIAP, AND INTERACTION RP WITH BCL2 AND XIAP. RX PubMed=29020630; DOI=10.1016/j.celrep.2017.09.052; RA Edison N., Curtz Y., Paland N., Mamriev D., Chorubczyk N., RA Haviv-Reingewertz T., Kfir N., Morgenstern D., Kupervaser M., Kagan J., RA Kim H.T., Larisch S.; RT "Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis."; RL Cell Rep. 21:442-454(2017). RN [25] RP TISSUE SPECIFICITY. RX PubMed=30389919; DOI=10.1038/s41467-018-06941-4; RA Koren E., Yosefzon Y., Ankawa R., Soteriou D., Jacob A., Nevelsky A., RA Ben-Yosef R., Bar-Sela G., Fuchs Y.; RT "ARTS mediates apoptosis and regeneration of the intestinal stem cell RT niche."; RL Nat. Commun. 9:4582-4582(2018). RN [26] RP INVOLVEMENT IN SPGF99, VARIANTS SPGF99 69-ARG--TYR-996 DEL AND RP 241-ARG--TYR-996 DEL, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=36135717; DOI=10.1002/humu.24475; RA Wang G., Zhu X., Gao Y., Lv M., Li K., Tang D., Wu H., Xu C., Geng H., RA Shen Q., Zha X., Duan Z., Zhang J., Hua R., Tao F., Zhou P., Wei Z., RA Cao Y., Guo R., He X.; RT "Biallelic loss-of-function mutations in SEPTIN4 (C17ORF47), encoding a RT conserved annulus protein, cause thin midpiece spermatozoa and male RT infertility in humans."; RL Hum. Mutat. 43:2079-2090(2022). CC -!- FUNCTION: Filament-forming cytoskeletal GTPase (Probable). Pro- CC apoptotic protein involved in LGR5-positive intestinal stem cell and CC Paneth cell expansion in the intestines, via its interaction with XIAP CC (By similarity). May also play a role in the regulation of cell fate in CC the intestine (By similarity). Positive regulator of apoptosis involved CC in hematopoietic stem cell homeostasis; via its interaction with XIAP CC (By similarity). Negative regulator of repair and hair follicle CC regeneration in response to injury, due to inhibition of hair follicle CC stem cell proliferation, potentially via its interaction with XIAP (By CC similarity). Plays an important role in male fertility and sperm CC motility (PubMed:36135717). During spermiogenesis, essential for the CC establishment of the annulus (a fibrous ring structure connecting the CC midpiece and the principal piece of the sperm flagellum) which is a CC requisite for the structural and mechanical integrity of the sperm CC (PubMed:36135717). Involved in the migration of cortical neurons and CC the formation of neuron leading processes during embryonic development CC (By similarity). Required for dopaminergic metabolism in presynaptic CC autoreceptors; potentially via activity as a presynaptic scaffold CC protein (By similarity). {ECO:0000250|UniProtKB:P28661, CC ECO:0000269|PubMed:36135717, ECO:0000305}. CC -!- FUNCTION: [Isoform ARTS]: Required for the induction of cell death CC mediated by TGF-beta and possibly by other apoptotic stimuli CC (PubMed:11146656, PubMed:15837787). Induces apoptosis through binding CC and inhibition of XIAP resulting in significant reduction in XIAP CC levels, leading to caspase activation and cell death (PubMed:15029247). CC Mediates the interaction between BCL2 and XIAP, thereby positively CC regulating the ubiquitination and degradation of BCL2 and promoting CC apoptosis (PubMed:29020630). {ECO:0000269|PubMed:11146656, CC ECO:0000269|PubMed:15029247, ECO:0000269|PubMed:15837787, CC ECO:0000269|PubMed:29020630}. CC -!- SUBUNIT: Septins polymerize into heterooligomeric protein complexes CC that form filaments, and can associate with cellular membranes, actin CC filaments and microtubules. GTPase activity is required for filament CC formation. Interacts with SEPTIN8 (PubMed:15116257). In a mesenchymal CC cell line, interacts with SEPTIN9 isoform 2 variants HNA Trp-106 and CC Phe-111, but not the wild type SEPTIN9 (PubMed:17546647). Component of CC a septin core octameric complex consisting of SEPTIN12, SEPTIN7, CC SEPTIN6 and SEPTIN2 or SEPTIN4 in the order 12-7-6-2-2-6-7-12 or 12-7- CC 6-4-4-6-7-12 (PubMed:25588830). Interacts with SEPTIN14 (via C- CC terminus) (By similarity). Interacts with DYRK1A (By similarity). CC Interacts with SLC6A3/DAT and SNCA/alpha-synuclein (By similarity). CC Interacts with STX1A; in the striatum (By similarity). Interacts with CC XIAP (via BIR3 domain) following the induction of apoptosis (By CC similarity). Interacts with AREL1 (via HECT domain); in the cytoplasm CC following induction of apoptosis (PubMed:23479728). CC {ECO:0000250|UniProtKB:P28661, ECO:0000269|PubMed:15116257, CC ECO:0000269|PubMed:17546647, ECO:0000269|PubMed:23479728, CC ECO:0000269|PubMed:25588830}. CC -!- SUBUNIT: [Isoform ARTS]: Part of a complex composed of SEPTIN4 isoform CC ARTS, XIAP and BCL2, within the complex interacts with both BCL2 (via CC BH3 domain) and XIAP, ARTS acts as a scaffold protein and stabilizes CC the complex (PubMed:29020630). Interacts with XIAP (via BIR3 domain) CC following the induction of apoptosis (PubMed:15029247, CC PubMed:21695558). {ECO:0000269|PubMed:15029247, CC ECO:0000269|PubMed:21695558, ECO:0000269|PubMed:29020630}. CC -!- INTERACTION: CC O43236; P05067: APP; NbExp=3; IntAct=EBI-1047513, EBI-77613; CC O43236; P63167: DYNLL1; NbExp=5; IntAct=EBI-1047513, EBI-349105; CC O43236; Q96FJ2: DYNLL2; NbExp=3; IntAct=EBI-1047513, EBI-742371; CC O43236; P42858: HTT; NbExp=3; IntAct=EBI-1047513, EBI-466029; CC O43236; Q8IYM1: SEPTIN12; NbExp=6; IntAct=EBI-1047513, EBI-2585067; CC O43236; P37840: SNCA; NbExp=3; IntAct=EBI-1047513, EBI-985879; CC O43236-6; Q8IUQ4: SIAH1; NbExp=2; IntAct=EBI-4372019, EBI-747107; CC O43236-6; P98170: XIAP; NbExp=4; IntAct=EBI-4372019, EBI-517127; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P28661}. Cell CC projection, cilium, flagellum {ECO:0000269|PubMed:25588830, CC ECO:0000269|PubMed:36135717}. Cytoplasmic vesicle, secretory vesicle CC {ECO:0000269|PubMed:15116257}. Cell projection, axon CC {ECO:0000250|UniProtKB:P28661}. Cell projection, dendrite CC {ECO:0000250|UniProtKB:P28661}. Perikaryon CC {ECO:0000250|UniProtKB:P28661}. Synapse {ECO:0000269|PubMed:17296554}. CC Note=In platelets, found in areas surrounding alpha-granules CC (PubMed:15116257). Found in the sperm annulus, a fibrous ring structure CC connecting the midpiece and the principal piece of the sperm flagellum CC (PubMed:25588830, PubMed:36135717). Expressed and colocalized with CC SLC6A3 and SNCA in axon terminals, especially at the varicosities (By CC similarity). {ECO:0000250|UniProtKB:P28661, CC ECO:0000269|PubMed:15116257, ECO:0000269|PubMed:25588830, CC ECO:0000269|PubMed:36135717}. CC -!- SUBCELLULAR LOCATION: [Isoform ARTS]: Mitochondrion CC {ECO:0000269|PubMed:11146656, ECO:0000269|PubMed:15029247, CC ECO:0000269|PubMed:21695558}. Nucleus {ECO:0000269|PubMed:11146656, CC ECO:0000269|PubMed:15029247}. Note=While predominantly localized in the CC mitochondria under resting conditions, translocates into the nucleus CC after TGF-beta treatment and apoptosis induction. CC {ECO:0000269|PubMed:11146656}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=7; CC IsoId=O43236-7; Sequence=Displayed; CC Name=1; Synonyms=PNUTL2, PNUTL2a, H5/CDCrel-2 CC {ECO:0000303|PubMed:11167005}, SEPT4_i1; CC IsoId=O43236-1; Sequence=VSP_062618; CC Name=2; Synonyms=PNUTL2b, CDCrel-1 {ECO:0000303|PubMed:11167005}; CC IsoId=O43236-2; Sequence=VSP_062619; CC Name=3; CC IsoId=O43236-3; Sequence=VSP_062621; CC Name=4; CC IsoId=O43236-4; Sequence=VSP_062620; CC Name=5; CC IsoId=O43236-5; Sequence=VSP_062617; CC Name=ARTS {ECO:0000303|PubMed:11146656}; Synonyms=SEPT4_i2; CC IsoId=O43236-6; Sequence=VSP_062619, VSP_062624, VSP_062625; CC Name=8; CC IsoId=O43236-8; Sequence=VSP_062622, VSP_062623; CC -!- TISSUE SPECIFICITY: Widely expressed in adult and fetal tissues with CC highest expression in adult brain (at protein level), heart, liver and CC adrenal gland and fetal heart, kidney, liver and lung. Expressed in CC presynaptic terminals of dopaminergic neurons projecting from the CC substantia nigra pars compacta to the striatum (at protein level) CC (PubMed:17296554). Expressed in axonal varicosities in dopaminergic CC nerve terminals (at protein level) (PubMed:17296554). Expressed in the CC putamen and in the adjacent cerebral cortex (at protein level) CC (PubMed:17296554). Expressed in colonic crypts (at protein level) CC (PubMed:30389919). Expressed in platelets. Expressed in spermatozoa (at CC protein level) (PubMed:36135717). {ECO:0000269|PubMed:11146656, CC ECO:0000269|PubMed:11167005, ECO:0000269|PubMed:11511094, CC ECO:0000269|PubMed:15116257, ECO:0000269|PubMed:15915442, CC ECO:0000269|PubMed:17296554, ECO:0000269|PubMed:30389919, CC ECO:0000269|PubMed:36135717, ECO:0000269|PubMed:9889007}. CC -!- TISSUE SPECIFICITY: [Isoform ARTS]: Highly expressed in the brain and CC heart. {ECO:0000269|PubMed:11146656}. CC -!- PTM: Phosphorylated by DYRK1A. {ECO:0000250|UniProtKB:P28661}. CC -!- PTM: Ubiquitinated by AREL1. {ECO:0000269|PubMed:23479728}. CC -!- DISEASE: Spermatogenic failure 99 (SPGF99) [MIM:621194]: An autosomal CC recessive, male infertility disorder characterized by CC asthenoteratozoospermia with markedly reduced sperm progressive CC motility, and abnormal sperm morphology. Patient sperm exhibit a thin CC midpiece, absence of the annulus, and disorganization of the CC mitochondrial sheath. {ECO:0000269|PubMed:36135717}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Colocalizes with alpha-synuclein in Lewy bodies in the CC substantia nigra pars compacta of Parkinson disease patients CC (PubMed:17296554). Shows reduced expression in dopaminergic nerve CC terminals of the striatum in sporadic Parkinson disease CC (PubMed:17296554). {ECO:0000269|PubMed:17296554}. CC -!- MISCELLANEOUS: [Isoform ARTS]: May be defective in GTP-binding. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like CC GTPase superfamily. Septin GTPase family. {ECO:0000255|PROSITE- CC ProRule:PRU01056}. 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; AF073312; AAC25673.1; -; mRNA. DR EMBL; U88829; AAD00653.1; -; mRNA. DR EMBL; U88870; AAD00657.1; -; mRNA. DR EMBL; AF176379; AAG45673.1; -; mRNA. DR EMBL; AB008753; BAB70695.1; -; mRNA. DR EMBL; D89278; BAB46922.1; -; mRNA. DR EMBL; AF035811; AAB88512.1; -; mRNA. DR EMBL; CR457111; CAG33392.1; -; mRNA. DR EMBL; AK315396; BAG37789.1; -; mRNA. DR EMBL; AK094579; BAG52891.1; -; mRNA. DR EMBL; AK294094; BAG57432.1; -; mRNA. DR EMBL; AK301914; BAG63338.1; -; mRNA. DR EMBL; AK302146; BAG63517.1; -; mRNA. DR EMBL; AK097440; BAC05054.1; -; mRNA. DR EMBL; AC005666; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471109; EAW94440.1; -; Genomic_DNA. DR EMBL; CH471109; EAW94442.1; -; Genomic_DNA. DR EMBL; BC018056; AAH18056.3; -; mRNA. DR EMBL; BC022189; AAH22189.2; -; mRNA. DR CCDS; CCDS11609.1; -. [O43236-2] DR CCDS; CCDS11610.1; -. [O43236-1] DR CCDS; CCDS32691.1; -. [O43236-8] DR CCDS; CCDS45743.1; -. [O43236-6] DR CCDS; CCDS56041.1; -. [O43236-3] DR CCDS; CCDS58581.1; -. [O43236-5] DR CCDS; CCDS58582.1; -. [O43236-4] DR CCDS; CCDS92368.1; -. [O43236-7] DR RefSeq; NP_001033793.3; NM_001038704.4. [O43236-8] DR RefSeq; NP_001185642.1; NM_001198713.2. [O43236-3] DR RefSeq; NP_001243711.1; NM_001256782.2. [O43236-4] DR RefSeq; NP_001243751.1; NM_001256822.2. [O43236-5] DR RefSeq; NP_001355700.1; NM_001368771.2. [O43236-7] DR RefSeq; NP_004565.1; NM_004574.5. [O43236-1] DR RefSeq; NP_536340.1; NM_080415.4. [O43236-6] DR RefSeq; NP_536341.1; NM_080416.4. [O43236-2] DR RefSeq; XP_006722018.1; XM_006721955.4. [O43236-5] DR RefSeq; XP_011523214.1; XM_011524912.3. [O43236-5] DR RefSeq; XP_024306576.1; XM_024450808.2. [O43236-5] DR RefSeq; XP_047292265.1; XM_047436309.1. [O43236-4] DR RefSeq; XP_054172497.1; XM_054316522.1. [O43236-4] DR RefSeq; XP_054172501.1; XM_054316526.1. [O43236-5] DR RefSeq; XP_054172502.1; XM_054316527.1. [O43236-5] DR RefSeq; XP_054172503.1; XM_054316528.1. [O43236-5] DR PDB; 6WB3; X-ray; 1.35 A; A/B=966-995. DR PDBsum; 6WB3; -. DR AlphaFoldDB; O43236; -. DR SMR; O43236; -. DR BioGRID; 111415; 28. DR BioGRID; 129753; 3. DR FunCoup; O43236; 359. DR IntAct; O43236; 27. DR MINT; O43236; -. DR STRING; 9606.ENSP00000354874; -. DR iPTMnet; O43236; -. DR PhosphoSitePlus; O43236; -. DR SwissPalm; O43236; -. DR BioMuta; C17orf47; -. DR BioMuta; SEPT4; -. DR DMDM; 300669697; -. DR jPOST; O43236; -. DR MassIVE; O43236; -. DR PaxDb; 9606-ENSP00000402000; -. DR PeptideAtlas; O43236; -. DR ProteomicsDB; 48814; -. [O43236-1] DR ProteomicsDB; 48815; -. [O43236-2] DR ProteomicsDB; 48816; -. [O43236-3] DR ProteomicsDB; 48817; -. [O43236-4] DR ProteomicsDB; 48818; -. [O43236-5] DR ProteomicsDB; 48819; -. [O43236-6] DR ProteomicsDB; 73193; -. DR Antibodypedia; 3484; 276 antibodies from 37 providers. DR DNASU; 284083; -. DR DNASU; 5414; -. DR Ensembl; ENST00000317256.10; ENSP00000321071.6; ENSG00000108387.16. [O43236-2] DR Ensembl; ENST00000317268.7; ENSP00000321674.3; ENSG00000108387.16. [O43236-1] DR Ensembl; ENST00000321691.3; ENSP00000354874.2; ENSG00000108387.16. [O43236-8] DR Ensembl; ENST00000393086.5; ENSP00000376801.1; ENSG00000108387.16. [O43236-2] DR Ensembl; ENST00000412945.7; ENSP00000414779.3; ENSG00000108387.16. [O43236-3] DR Ensembl; ENST00000426861.5; ENSP00000402348.1; ENSG00000108387.16. [O43236-6] DR Ensembl; ENST00000457347.6; ENSP00000402000.2; ENSG00000108387.16. [O43236-4] DR Ensembl; ENST00000583114.5; ENSP00000463768.1; ENSG00000108387.16. [O43236-5] DR Ensembl; ENST00000672673.2; ENSP00000500383.1; ENSG00000108387.16. [O43236-7] DR Ensembl; ENST00000672699.1; ENSP00000500355.1; ENSG00000108387.16. [O43236-4] DR GeneID; 5414; -. DR KEGG; hsa:5414; -. DR MANE-Select; ENST00000672673.2; ENSP00000500383.1; NM_001368771.2; NP_001355700.1. [O43236-7] DR UCSC; uc002iwm.4; human. [O43236-1] DR AGR; HGNC:9165; -. DR ClinPGx; PA33487; -. DR CTD; 5414; -. DR DisGeNET; 5414; -. DR GeneCards; SEPTIN4; -. DR HGNC; HGNC:9165; SEPTIN4. DR HPA; ENSG00000108387; Group enriched (brain, retina). DR MalaCards; SEPTIN4; -. DR MIM; 603696; gene. DR MIM; 621194; phenotype. DR OpenTargets; ENSG00000108387; -. DR Orphanet; 171709; Male infertility due to globozoospermia. DR VEuPathDB; HostDB:ENSG00000108387; -. DR eggNOG; ENOG502SETZ; Eukaryota. DR eggNOG; KOG2655; Eukaryota. DR GeneTree; ENSGT00390000018146; -. DR HOGENOM; CLU_575631_0_0_1; -. DR InParanoid; O43236; -. DR OMA; SSICTEP; -. DR OrthoDB; 416553at2759; -. DR PAN-GO; O43236; 11 GO annotations based on evolutionary models. DR PhylomeDB; O43236; -. DR PathwayCommons; O43236; -. DR Reactome; R-HSA-111457; Release of apoptotic factors from the mitochondria. [O43236-6] DR Reactome; R-HSA-111469; SMAC, XIAP-regulated apoptotic response. [O43236-6] DR SignaLink; O43236; -. DR SIGNOR; O43236; -. DR Agora; ENSG00000108387; -. DR BioGRID-ORCS; 284083; 14 hits in 1105 CRISPR screens. DR BioGRID-ORCS; 5414; 9 hits in 1084 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SEPT4; human. DR GeneWiki; SEPT4; -. DR GenomeRNAi; 5414; -. DR Pharos; O43236; Tbio. DR PRO; PR:Q8NEP4; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; O43236; protein. DR Bgee; ENSG00000108387; Expressed in C1 segment of cervical spinal cord and 149 other cell types or tissues. DR ExpressionAtlas; O43236; baseline and differential. DR GO; GO:0030424; C:axon; ISS:UniProtKB. DR GO; GO:0032153; C:cell division site; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030425; C:dendrite; ISS:UniProtKB. DR GO; GO:0098691; C:dopaminergic synapse; IDA:SynGO. DR GO; GO:0015630; C:microtubule cytoskeleton; IBA:GO_Central. DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; NAS:UniProtKB. DR GO; GO:0043204; C:perikaryon; ISS:UniProtKB. DR GO; GO:0098793; C:presynapse; IDA:SynGO. DR GO; GO:0031105; C:septin complex; IDA:UniProtKB. DR GO; GO:0005940; C:septin ring; IBA:GO_Central. DR GO; GO:0097227; C:sperm annulus; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IBA:GO_Central. DR GO; GO:0005525; F:GTP binding; IMP:CAFA. DR GO; GO:0003924; F:GTPase activity; IMP:CAFA. DR GO; GO:0042802; F:identical protein binding; IPI:CAFA. DR GO; GO:0000287; F:magnesium ion binding; IMP:CAFA. DR GO; GO:0060090; F:molecular adaptor activity; IBA:GO_Central. DR GO; GO:0005198; F:structural molecule activity; TAS:ProtInc. DR GO; GO:0006915; P:apoptotic process; NAS:UniProtKB. DR GO; GO:0061640; P:cytoskeleton-dependent cytokinesis; IBA:GO_Central. DR GO; GO:0030317; P:flagellated sperm motility; ISS:UniProtKB. DR GO; GO:0061484; P:hematopoietic stem cell homeostasis; ISS:UniProtKB. DR GO; GO:0008104; P:intracellular protein localization; IBA:GO_Central. DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB. DR GO; GO:0017157; P:regulation of exocytosis; IBA:GO_Central. DR GO; GO:0048515; P:spermatid differentiation; ISS:UniProtKB. DR CDD; cd01850; CDC_Septin; 1. DR DisProt; DP00537; -. DR DisProt; DP01325; -. [O43236-6] DR FunFam; 3.40.50.300:FF:000064; Septin 4; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR030379; G_SEPTIN_dom. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR016491; Septin. DR PANTHER; PTHR18884; SEPTIN; 1. DR Pfam; PF00735; Septin; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51719; G_SEPTIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell cycle; Cell division; KW Cell projection; Cilium; Coiled coil; Cytoplasm; Cytoplasmic vesicle; KW Differentiation; Direct protein sequencing; Disease variant; Flagellum; KW GTP-binding; Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Spermatogenesis; Synapse; KW Ubl conjugation. FT CHAIN 1..996 FT /note="Septin-4" FT /id="PRO_0000173519" FT DOMAIN 659..932 FT /note="Septin-type G" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT REGION 1..115 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 428..448 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 669..676 FT /note="G1 motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT REGION 726..729 FT /note="G3 motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT REGION 807..810 FT /note="G4 motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01056" FT COILED 965..996 FT /evidence="ECO:0000255" FT COMPBIAS 13..26 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 95..108 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 669..676 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 703 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 808..816 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 866 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT BINDING 881 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000250|UniProtKB:Q9UH03" FT MOD_RES 635 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 636 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 843 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18318008, FT ECO:0007744|PubMed:24275569" FT MOD_RES 950 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P28661" FT MOD_RES 952 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P28661" FT VAR_SEQ 1..665 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_062617" FT VAR_SEQ 1..538 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLKDEE -> MDRSLGWQGNSVPEDRTEAG (in isoform 1)" FT /id="VSP_062618" FT VAR_SEQ 1..538 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLKDEE -> M (in isoform 2 and isoform ARTS)" FT /evidence="ECO:0000303|PubMed:11146656, FT ECO:0000303|PubMed:11167005, ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_062619" FT VAR_SEQ 1..537 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLKDE -> MRSSPALFSSRAAPQKPRKEGSQAAGLLVFSDSL (in FT isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_062620" FT VAR_SEQ 1..535 FT /note="MVKTNKPGAKVAVSAQRGSEVTTNTSPQQGHGYVLASSHRSAAVSLNPSHRR FT SEAAHPTTPHSASDYPRSVSLQSGPGHYAVPTPRGPETGPRTESSRHSSPHLKSQKTQT FT LASHASSRQWKVSPPREEAARRGSESKSGREVGHHASSIPDAKSTHQLSFQDQKNNLQS FT QILEDDPPSKVQNPQGVRVPRRILSYPKDEAVQTEPIQRITTTSEIRSPRSPSLLEHGS FT SCVSADYQTAQRRVPVEESETGPYGPIPSKPKALYRNMNLDSLLKLSVLKDSDGVHRVS FT ARVDPESLHKYSAYPETKPSAKVLVSSQVESNVRTPIRGNSEVGRRVTISPGVQSVEPT FT HHVTVPSVSEGSHKSSMFVTPEPIYKQQTQKPPEITYMSQGPTPRYPELSQKPSIHAEL FT ELTPRPLPPRSLPRYGPDSSWWPLLNPEVETPQSQLTTPDFEPKCSPSLDLLLSGFKID FT SSPFCEDLKFQREKASLSPPSPPKEFPSWAPLSEVPQTPKHTCKQPIQRFTAFFLDVSE FT EMYNRVIWWLK -> MPGFYSVMT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_062621" FT VAR_SEQ 536..570 FT /note="DEEIKRFLEDTTDDGELSKFVKDFSGNASCHPPEA -> GLCFSLLWAHCGS FT LGDGRTGEEWHLCIYRAGSFRR (in isoform 8)" FT /id="VSP_062622" FT VAR_SEQ 571..996 FT /note="Missing (in isoform 8)" FT /id="VSP_062623" FT VAR_SEQ 785..811 FT /note="LRPLDVEFMKALHQRVNIVPILAKADT -> YGPSLRLLAPPGAVKGTGQEH FT QGQGCH (in isoform ARTS)" FT /evidence="ECO:0000303|PubMed:11146656" FT /id="VSP_062624" FT VAR_SEQ 812..996 FT /note="Missing (in isoform ARTS)" FT /evidence="ECO:0000303|PubMed:11146656" FT /id="VSP_062625" FT VARIANT 69..996 FT /note="Missing (in SPGF99; likely pathogenic; loss of FT protein expression)" FT /evidence="ECO:0000269|PubMed:36135717" FT /id="VAR_090727" FT VARIANT 88 FT /note="P -> T (in dbSNP:rs8071623)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334" FT /id="VAR_090728" FT VARIANT 241..996 FT /note="Missing (in SPGF99; likely pathogenic; loss of FT protein expression)" FT /evidence="ECO:0000269|PubMed:36135717" FT /id="VAR_090729" FT VARIANT 829 FT /note="E -> V (in dbSNP:rs17741424)" FT /id="VAR_051935" FT CONFLICT 187 FT /note="V -> A (in Ref. 8; BAC05054)" FT /evidence="ECO:0000305" FT CONFLICT 674 FT /note="G -> D (in Ref. 7; BAG37789)" FT /evidence="ECO:0000305" FT CONFLICT 900 FT /note="K -> E (in Ref. 7; BAG63517)" FT /evidence="ECO:0000305" FT HELIX 967..994 FT /evidence="ECO:0007829|PDB:6WB3" FT MUTAGEN O43236-6:137..139 FT /note="GKS->ENP: Loss of TGF-beta-induced apoptosis. No FT translocation to the nucleus following TGF-beta treatment. FT Loss of XIAP-binding." FT /evidence="ECO:0000269|PubMed:11146656, FT ECO:0000269|PubMed:15029247" SQ SEQUENCE 996 AA; 112439 MW; 8306167C9EF5CFF0 CRC64; MVKTNKPGAK VAVSAQRGSE VTTNTSPQQG HGYVLASSHR SAAVSLNPSH RRSEAAHPTT PHSASDYPRS VSLQSGPGHY AVPTPRGPET GPRTESSRHS SPHLKSQKTQ TLASHASSRQ WKVSPPREEA ARRGSESKSG REVGHHASSI PDAKSTHQLS FQDQKNNLQS QILEDDPPSK VQNPQGVRVP RRILSYPKDE AVQTEPIQRI TTTSEIRSPR SPSLLEHGSS CVSADYQTAQ RRVPVEESET GPYGPIPSKP KALYRNMNLD SLLKLSVLKD SDGVHRVSAR VDPESLHKYS AYPETKPSAK VLVSSQVESN VRTPIRGNSE VGRRVTISPG VQSVEPTHHV TVPSVSEGSH KSSMFVTPEP IYKQQTQKPP EITYMSQGPT PRYPELSQKP SIHAELELTP RPLPPRSLPR YGPDSSWWPL LNPEVETPQS QLTTPDFEPK CSPSLDLLLS GFKIDSSPFC EDLKFQREKA SLSPPSPPKE FPSWAPLSEV PQTPKHTCKQ PIQRFTAFFL DVSEEMYNRV IWWLKDEEIK RFLEDTTDDG ELSKFVKDFS GNASCHPPEA KTWASRPQVP EPRPQAPDLY DDDLEFRPPS RPQSSDNQQY FCAPAPLSPS ARPRSPWGKL DPYDSSEDDK EYVGFATLPN QVHRKSVKKG FDFTLMVAGE SGLGKSTLVN SLFLTDLYRD RKLLGAEERI MQTVEITKHA VDIEEKGVRL RLTIVDTPGF GDAVNNTECW KPVAEYIDQQ FEQYFRDESG LNRKNIQDNR VHCCLYFISP FGHGLRPLDV EFMKALHQRV NIVPILAKAD TLTPPEVDHK KRKIREEIEH FGIKIYQFPD CDSDEDEDFK LQDQALKESI PFAVIGSNTV VEARGRRVRG RLYPWGIVEV ENPGHCDFVK LRTMLVRTHM QDLKDVTRET HYENYRAQCI QSMTRLVVKE RNRNKLTRES GTDFPIPAVP PGTDPETEKL IREKDEELRR MQEMLHKIQK QMKENY // ID SHLP2_HUMAN Reviewed; 26 AA. AC A0A3G1DIU6; DT 28-JAN-2026, integrated into UniProtKB/Swiss-Prot. DT 13-FEB-2019, sequence version 1. DT 28-JAN-2026, entry version 4. DE RecName: Full=Small humanin-like peptide 2 {ECO:0000303|PubMed:27070352}; DE Short=SHLP2 {ECO:0000303|PubMed:27070352}; GN Name=MT-RNR2 {ECO:0000312|HGNC:HGNC:7471}; OS Homo sapiens (Human). OG Mitochondrion {ECO:0000269|PubMed:27070352}. OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AMZ80337.1}; RN [1] {ECO:0000312|EMBL:AMZ80337.1} RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION. RX PubMed=27070352; DOI=10.18632/aging.100943; RA Cobb L.J., Lee C., Xiao J., Yen K., Wong R.G., Nakamura H.K., Mehta H.H., RA Gao Q., Ashur C., Huffman D.M., Wan J., Muzumdar R., Barzilai N., Cohen P.; RT "Naturally occurring mitochondrial-derived peptides are age-dependent RT regulators of apoptosis, insulin sensitivity, and inflammatory markers."; RL Aging (Albany NY) 8:796-809(2016). RN [2] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=7219534; DOI=10.1038/290457a0; RA Anderson S., Bankier A.T., Barrell B.G., de Bruijn M.H.L., Coulson A.R., RA Drouin J., Eperon I.C., Nierlich D.P., Roe B.A., Sanger F., Schreier P.H., RA Smith A.J.H., Staden R., Young I.G.; RT "Sequence and organization of the human mitochondrial genome."; RL Nature 290:457-465(1981). RN [3] {ECO:0000305} RP FUNCTION. RX PubMed=28798389; DOI=10.1038/s41598-017-08372-5; RA Okada A.K., Teranishi K., Lobo F., Isas J.M., Xiao J., Yen K., Cohen P., RA Langen R.; RT "The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like RT Peptide 2, Exhibit Chaperone-like Activity."; RL Sci. Rep. 7:7802-7802(2017). RN [4] {ECO:0000305} RP ROLE IN PROTECTION AGAINST AMD. RX PubMed=30310092; DOI=10.1038/s41598-018-33290-5; RA Nashine S., Cohen P., Nesburn A.B., Kuppermann B.D., Kenney M.C.; RT "Characterizing the protective effects of SHLP2, a mitochondrial-derived RT peptide, in macular degeneration."; RL Sci. Rep. 8:15175-15175(2018). RN [5] {ECO:0000305} RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=37468558; DOI=10.1038/s41467-023-40082-7; RA Kim S.K., Tran L.T., NamKoong C., Choi H.J., Chun H.J., Lee Y.H., Cheon M., RA Chung C., Hwang J., Lim H.H., Shin D.M., Choi Y.H., Kim K.W.; RT "Mitochondria-derived peptide SHLP2 regulates energy homeostasis through RT the activation of hypothalamic neurons."; RL Nat. Commun. 14:4321-4321(2023). RN [6] {ECO:0000305} RP ERRATUM OF PUBMED:37468558. RX PubMed=37591868; DOI=10.1038/s41467-023-40832-7; RA Kim S.K., Tran L.T., NamKoong C., Choi H.J., Chun H.J., Lee Y.H., Cheon M., RA Chung C., Hwang J., Lim H.H., Shin D.M., Choi Y.H., Kim K.W.; RL Nat. Commun. 14:4995-4995(2023). RN [7] {ECO:0000305} RP VARIANT ARG-4, CHARACTERIZATION OF VARIANT ARG-4, INTERACTION WITH RP MITOCHONDRIAL COMPLEX I, SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=38167865; DOI=10.1038/s41380-023-02344-0; RA Kim S.J., Miller B., Hartel N.G., Ramirez R. II, Braniff R.G., RA Leelaprachakul N., Huang A., Wang Y., Arpawong T.E., Crimmins E.M., RA Wang P., Sun X., Liu C., Levy D., Yen K., Petzinger G.M., Graham N.A., RA Jakowec M.W., Cohen P.; RT "A naturally occurring variant of SHLP2 is a protective factor in RT Parkinson's disease."; RL Mol. Psychiatry 29:505-517(2024). RN [8] {ECO:0000305} RP VARIANT ARG-4. RX PubMed=38940474; DOI=10.1002/mds.29892; RG Global Parkinson's Genetics Program; RA Akcimen F., van Midden V., Akerman S.C., Makarious M.B., Rothstein J.D., RA Fang Z.H., Bandres-Ciga S.; RT "Investigating the Protective Role of the Mitochondrial 2158 T > C Variant RT in Parkinson's Disease."; RL Mov. Disord. 39:1645-1647(2024). CC -!- FUNCTION: Binds to and activates chemokine receptor ACKR3/CXCR7 which CC results in activation of proopiomelanocortin neurons in the arcuate CC nucleus of the hypothalamus, leading to suppression of food intake and CC increased energy expenditure (PubMed:37468558). Displays chaperone-like CC activity, inhibiting misfolding of IAPP and preventing IAPP amyloid CC formation (PubMed:28798389). Significantly reduces apoptosis and the CC generation of reactive oxygen species and improves mitochondrial CC metabolism in vitro (PubMed:27070352). {ECO:0000269|PubMed:27070352, CC ECO:0000269|PubMed:28798389, ECO:0000269|PubMed:37468558}. CC -!- SUBUNIT: Interacts with mitochondrial complex I. CC {ECO:0000269|PubMed:38167865}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:37468558}. CC Mitochondrion inner membrane {ECO:0000269|PubMed:38167865}. CC -!- MISCELLANEOUS: Encoded in the mitochondrial genome by the 16S ribosomal CC RNA gene MT-RNR2. {ECO:0000269|PubMed:27070352}. CC -!- MISCELLANEOUS: Treatment of an in vitro human transmitochondrial age- CC related macular degeneration (AMD) cell model with exogenous SHLP2 CC confers cellular and mitochondrial protection (PubMed:30310092). In the CC AMD cell model, SHLP2 stabilizes protein levels of mitochondrial OXPHOS CC complex subunits, prevents loss of mitochondria, increases CC mitochondrial DNA copy number, prevents loss of viable cells, reduces CC apoptosis, and protects against amyloid-beta-induced cell death and CC mitochondrial damage (PubMed:30310092). {ECO:0000269|PubMed:30310092}. CC -!- MISCELLANEOUS: In mouse models, administration of SHLP2 results in the CC suppression of food intake, activation of thermogenesis, and prevention CC of diet-induced obesity. {ECO:0000269|PubMed:37468558}. CC -!- MISCELLANEOUS: Increases glucose uptake and suppresses hepatic glucose CC production when intracerebrally infused into rats. CC {ECO:0000269|PubMed:27070352}. CC -!- MISCELLANEOUS: Serum levels are significantly decreased in both CC diabetic and obese patients compared to healthy individuals. CC {ECO:0000269|PubMed:37468558}. CC -!- CAUTION: Variant Arg-4 has been reported to be associated with a CC decreased risk of Parkinson disease (PD) with the mutated protein CC showing protective activity against mitochondrial dysfunction in both CC in vitro and in vivo models of PD (PubMed:38167865). However, a later CC report disputed this finding and found no link between this variant and CC reduced PD risk (PubMed:38940474). {ECO:0000269|PubMed:38167865, CC ECO:0000269|PubMed:38940474}. 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; KX067780; AMZ80337.1; -; Genomic_DNA. DR AlphaFoldDB; A0A3G1DIU6; -. DR HGNC; HGNC:7471; MT-RNR2. DR Proteomes; UP000005640; Mitochondrion MT. PE 1: Evidence at protein level; KW Membrane; Mitochondrion; Mitochondrion inner membrane; Reference proteome; KW Secreted. FT CHAIN 1..26 FT /note="Small humanin-like peptide 2" FT /id="PRO_0000462822" FT VARIANT 4 FT /note="K -> R (increases protein stability)" FT /evidence="ECO:0000269|PubMed:38167865, FT ECO:0000269|PubMed:38940474" FT /id="VAR_090679" SQ SEQUENCE 26 AA; 3018 MW; CBEE1C70D9C4A771 CRC64; MGVKFFTLST RFFPSVQRAV PLWTNS // 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 ZNT10_HUMAN Reviewed; 485 AA. AC Q6XR72; Q49AL9; Q9NPW0; DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 2. DT 28-JAN-2026, entry version 156. DE RecName: Full=Calcium/manganese antiporter SLC30A10 {ECO:0000305|PubMed:30755481}; DE AltName: Full=Solute carrier family 30 member 10 {ECO:0000312|HGNC:HGNC:25355}; DE AltName: Full=Zinc transporter 10; DE Short=ZnT-10; GN Name=SLC30A10 {ECO:0000312|HGNC:HGNC:25355}; GN Synonyms=ZNT10 {ECO:0000303|PubMed:22706290}, ZNT8 {ECO:0000303|Ref.1}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Huang L., Zhou B., Gitschier J.; RT "Characterization of a novel mammalian zinc transporter, ZNT8."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 90-485 (ISOFORM 3). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP TISSUE SPECIFICITY. RX PubMed=15154973; DOI=10.1186/1471-2164-5-32; RA Seve M., Chimienti F., Devergnas S., Favier A.; RT "In silico identification and expression of SLC30 family genes: an RT expressed sequence tag data mining strategy for the characterization of RT zinc transporters' tissue expression."; RL BMC Genomics 5:32-32(2004). RN [6] RP FUNCTION, INVOLVEMENT IN HMNDYT1, VARIANTS HMNDYT1 PRO-89; 105-ALA--PRO-107 RP DEL; VAL-256 DEL AND PRO-349, AND CHARACTERIZATION OF VARIANTS HMNDYT1 RP PRO-89. RX PubMed=22341972; DOI=10.1016/j.ajhg.2012.01.018; RA Tuschl K., Clayton P.T., Gospe S.M. Jr., Gulab S., Ibrahim S., Singhi P., RA Aulakh R., Ribeiro R.T., Barsottini O.G., Zaki M.S., Del Rosario M.L., RA Dyack S., Price V., Rideout A., Gordon K., Wevers R.A., Chong W.K., RA Mills P.B.; RT "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and RT hypermanganesemia caused by mutations in SLC30A10, a manganese transporter RT in man."; RL Am. J. Hum. Genet. 90:457-466(2012). RN [7] RP INVOLVEMENT IN HMNDYT1, VARIANT SER-167, INDUCTION BY MANGANESE, AND TISSUE RP SPECIFICITY. RX PubMed=22341971; DOI=10.1016/j.ajhg.2012.01.017; RA Quadri M., Federico A., Zhao T., Breedveld G.J., Battisti C., Delnooz C., RA Severijnen L.A., Di Toro Mammarella L., Mignarri A., Monti L., Sanna A., RA Lu P., Punzo F., Cossu G., Willemsen R., Rasi F., Oostra B.A., RA van de Warrenburg B.P., Bonifati V.; RT "Mutations in SLC30A10 cause parkinsonism and dystonia with RT hypermanganesemia, polycythemia, and chronic liver disease."; RL Am. J. Hum. Genet. 90:467-477(2012). RN [8] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=22706290; DOI=10.1039/c2mt20088k; RA Bosomworth H.J., Thornton J.K., Coneyworth L.J., Ford D., Valentine R.A.; RT "Efflux function, tissue-specific expression and intracellular trafficking RT of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis."; RL Metallomics 4:771-779(2012). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH RP SLC30A3, AND INDUCTION. RX PubMed=22427991; DOI=10.1371/journal.pone.0033211; RA Patrushev N., Seidel-Rogol B., Salazar G.; RT "Angiotensin II requires zinc and downregulation of the zinc transporters RT ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells."; RL PLoS ONE 7:E33211-E33211(2012). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF RP THR-196, AND CHARACTERIZATION OF VARIANTS HMNDYT1 PRO-89 AND RP 105-ALA--PRO-107 DEL. RX PubMed=25319704; DOI=10.1523/jneurosci.2329-14.2014; RA Leyva-Illades D., Chen P., Zogzas C.E., Hutchens S., Mercado J.M., RA Swaim C.D., Morrisett R.A., Bowman A.B., Aschner M., Mukhopadhyay S.; RT "SLC30A10 is a cell surface-localized manganese efflux transporter, and RT parkinsonism-causing mutations block its intracellular trafficking and RT efflux activity."; RL J. Neurosci. 34:14079-14095(2014). RN [11] RP INDUCTION. RX PubMed=25582195; DOI=10.1128/mcb.01298-14; RA Ogo O.A., Tyson J., Cockell S.J., Howard A., Valentine R.A., Ford D.; RT "The zinc finger protein ZNF658 regulates the transcription of genes RT involved in zinc homeostasis and affects ribosome biogenesis through the RT zinc transcriptional regulatory element."; RL Mol. Cell. Biol. 35:977-987(2015). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASN-43; CYS-52 AND LEU-242. RX PubMed=27226609; DOI=10.1074/jbc.m116.728014; RA Nishito Y., Tsuji N., Fujishiro H., Takeda T.A., Yamazaki T., Teranishi F., RA Okazaki F., Matsunaga A., Tuschl K., Rao R., Kono S., Miyajima H., RA Narita H., Himeno S., Kambe T.; RT "Direct comparison of manganese detoxification/efflux proteins and RT molecular characterization of ZnT10 protein as a manganese transporter."; RL J. Biol. Chem. 291:14773-14787(2016). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP GLU-25; ASP-40; ASN-43; ASP-47; ASN-127; HIS-244; ASP-248; HIS-333 AND RP HIS-350. RX PubMed=27307044; DOI=10.1074/jbc.m116.726935; RA Zogzas C.E., Aschner M., Mukhopadhyay S.; RT "Structural elements in the transmembrane and cytoplasmic domains of the RT metal transporter SLC30A10 are required for its manganese efflux RT activity."; RL J. Biol. Chem. 291:15940-15957(2016). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, INTERACTION WITH SLC30A2; SLC30A3 RP AND SLC30A4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-4. RX PubMed=26728129; DOI=10.1111/tra.12371; RA Zhao Y., Feresin R.G., Falcon-Perez J.M., Salazar G.; RT "Differential targeting of SLC30A10/ZnT10 heterodimers to endolysosomal RT compartments modulates EGF-induced MEK/ERK1/2 activity."; RL Traffic 17:267-288(2016). RN [15] RP FUNCTION, TRANSPORTER ACTIVITY, MUTAGENESIS OF ASN-43; ASP-47; HIS-244 AND RP ASP-248, AND SITE. RX PubMed=30755481; DOI=10.1074/jbc.ra118.006816; RA Levy M., Elkoshi N., Barber-Zucker S., Hoch E., Zarivach R., RA Hershfinkel M., Sekler I.; RT "Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn2+ is driven RT by an active Ca2+-coupled exchange."; RL J. Biol. Chem. 294:5879-5889(2019). CC -!- FUNCTION: Calcium:manganese antiporter of the plasma membrane mediating CC the efflux of intracellular manganese coupled to an active CC extracellular calcium exchange (PubMed:30755481). Required for CC intracellular manganese homeostasis, an essential cation for the CC function of several enzymes, including some crucially important for the CC metabolism of neurotransmitters and other neuronal metabolic pathways. CC Manganese can also be cytotoxic and induce oxidative stress, CC mitochondrial dysfunction and apoptosis (PubMed:22341972, CC PubMed:25319704, PubMed:26728129, PubMed:27226609, PubMed:27307044). CC Could also have an intracellular zinc ion transporter activity, CC directly regulating intracellular zinc ion homeostasis and more CC indirectly various signaling pathway and biological processes CC (PubMed:22427991, PubMed:26728129). {ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:25319704, CC ECO:0000269|PubMed:26728129, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Mn(2+)(out) + Ca(2+)(in) = Mn(2+)(in) + Ca(2+)(out); CC Xref=Rhea:RHEA:73059, ChEBI:CHEBI:29035, ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; CC -!- SUBUNIT: Forms homodimers. Forms heterodimers and high-molecular weight CC oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is CC mediated by covalent-bound tyrosine residues, occurs probably in a CC tissue-specific manner and could mediate the intracellular zinc CC transport activity into early endosomes and recycling endosomes. CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. CC -!- INTERACTION: CC Q6XR72; Q9BRI3: SLC30A2; NbExp=4; IntAct=EBI-13917996, EBI-8644112; CC Q6XR72; Q99726: SLC30A3; NbExp=3; IntAct=EBI-13917996, EBI-10294651; CC Q6XR72; O14863: SLC30A4; NbExp=2; IntAct=EBI-13917996, EBI-13918058; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22706290, CC ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:26728129, CC ECO:0000269|PubMed:27226609, ECO:0000269|PubMed:27307044}; Multi-pass CC membrane protein {ECO:0000255}. Golgi apparatus membrane CC {ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:27226609}; Multi-pass CC membrane protein {ECO:0000255}. Recycling endosome membrane CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. Early CC endosome membrane {ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; Multi-pass membrane protein CC {ECO:0000255}. Note=Localization to the Golgi and plasma membrane is CC regulated by zinc. {ECO:0000269|PubMed:22706290}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q6XR72-4; Sequence=Displayed; CC Name=2; CC IsoId=Q6XR72-2; Sequence=VSP_029863; CC Name=3; CC IsoId=Q6XR72-3; Sequence=VSP_029864, VSP_029865; CC -!- TISSUE SPECIFICITY: Specifically expressed in fetal liver and fetal CC brain (PubMed:15154973). Expressed in adult tissues with relative CC levels small intestine > liver > testes > brain > ovary > colon > CC cervix > prostate > placenta (PubMed:22706290). Expressed in liver and CC neurons of the nervous system (at protein level) (PubMed:22341971). CC {ECO:0000269|PubMed:15154973, ECO:0000269|PubMed:22341971, CC ECO:0000269|PubMed:22706290}. CC -!- INDUCTION: Down-regulated by zinc (PubMed:22427991, PubMed:22706290, CC PubMed:25582195). Down-regulated by angiotensin-2 (PubMed:22427991). CC Up-regulated by manganese (PubMed:22341971). CC {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:25582195}. CC -!- DISEASE: Hypermanganesemia with dystonia 1 (HMNDYT1) [MIM:613280]: A CC metabolic autosomal recessive disorder characterized by dystonia, CC parkinsonism, extrapyramidal signs, severe hypermanganesemia, CC polycythemia, and chronic hepatic disease, including steatosis and CC cirrhosis. {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:25319704}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: 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 cation diffusion facilitator (CDF) CC transporter (TC 2.A.4) family. SLC30A subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAP44332.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in position 427.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY212919; AAP44332.1; ALT_SEQ; mRNA. DR EMBL; AL359609; CAB94880.1; -; mRNA. DR EMBL; AC093562; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC036078; AAH36078.1; -; mRNA. DR CCDS; CCDS31026.1; -. [Q6XR72-4] DR PIR; T50628; T50628. DR RefSeq; NP_061183.2; NM_018713.2. [Q6XR72-4] DR AlphaFoldDB; Q6XR72; -. DR SMR; Q6XR72; -. DR BioGRID; 120703; 181. DR ComplexPortal; CPX-8462; ZNT10 calcium-coupled manganese antiporter homodimer. DR ComplexPortal; CPX-8463; ZNT2-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8464; ZNT3-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8465; ZNT4-ZNT10 proton-coupled zinc antiporter complex. DR FunCoup; Q6XR72; 245. DR IntAct; Q6XR72; 179. DR STRING; 9606.ENSP00000355893; -. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.4.2.5; the cation diffusion facilitator (cdf) family. DR GlyGen; Q6XR72; 1 site. DR iPTMnet; Q6XR72; -. DR PhosphoSitePlus; Q6XR72; -. DR BioMuta; SLC30A10; -. DR DMDM; 311033506; -. DR jPOST; Q6XR72; -. DR MassIVE; Q6XR72; -. DR PaxDb; 9606-ENSP00000355893; -. DR PeptideAtlas; Q6XR72; -. DR ProteomicsDB; 67813; -. [Q6XR72-4] DR ProteomicsDB; 67814; -. [Q6XR72-2] DR ProteomicsDB; 67815; -. [Q6XR72-3] DR Antibodypedia; 3072; 116 antibodies from 18 providers. DR DNASU; 55532; -. DR Ensembl; ENST00000356609.2; ENSP00000349018.2; ENSG00000196660.13. [Q6XR72-3] DR Ensembl; ENST00000366926.4; ENSP00000355893.4; ENSG00000196660.13. [Q6XR72-4] DR GeneID; 55532; -. DR KEGG; hsa:55532; -. DR MANE-Select; ENST00000366926.4; ENSP00000355893.4; NM_018713.3; NP_061183.2. DR UCSC; uc001hlw.4; human. [Q6XR72-4] DR AGR; HGNC:25355; -. DR ClinPGx; PA142670903; -. DR CTD; 55532; -. DR DisGeNET; 55532; -. DR GeneCards; SLC30A10; -. DR GeneReviews; SLC30A10; -. DR HGNC; HGNC:25355; SLC30A10. DR HPA; ENSG00000196660; Group enriched (intestine, liver). DR MalaCards; SLC30A10; -. DR MIM; 611146; gene. DR MIM; 613280; phenotype. DR OpenTargets; ENSG00000196660; -. DR Orphanet; 309854; Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome. DR VEuPathDB; HostDB:ENSG00000196660; -. DR eggNOG; KOG1483; Eukaryota. DR GeneTree; ENSGT00940000159967; -. DR HOGENOM; CLU_1239780_0_0_1; -. DR InParanoid; Q6XR72; -. DR OMA; FQDCASW; -. DR OrthoDB; 29444at2759; -. DR PAN-GO; Q6XR72; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q6XR72; -. DR PathwayCommons; Q6XR72; -. DR Reactome; R-HSA-425410; Metal ion SLC transporters. DR SignaLink; Q6XR72; -. DR Agora; ENSG00000196660; -. DR BioGRID-ORCS; 55532; 11 hits in 1155 CRISPR screens. DR ChiTaRS; SLC30A10; human. DR GenomeRNAi; 55532; -. DR Pharos; Q6XR72; Tbio. DR PRO; PR:Q6XR72; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q6XR72; protein. DR Bgee; ENSG00000196660; Expressed in jejunal mucosa and 75 other cell types or tissues. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB. DR GO; GO:0055038; C:recycling endosome membrane; IDA:UniProtKB. DR GO; GO:0140983; F:calcium:manganese antiporter activity; IDA:UniProtKB. DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:1904385; P:cellular response to angiotensin; IDA:UniProtKB. DR GO; GO:0010312; P:detoxification of zinc ion; IBA:GO_Central. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030026; P:intracellular manganese ion homeostasis; IDA:UniProtKB. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IDA:UniProtKB. DR GO; GO:0140048; P:manganese ion export across plasma membrane; IDA:UniProtKB. DR GO; GO:0006828; P:manganese ion transport; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0062111; P:zinc ion import into organelle; IDA:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IBA:GO_Central. DR Gene3D; 1.20.1510.10; Cation efflux protein transmembrane domain; 1. DR InterPro; IPR002524; Cation_efflux. DR InterPro; IPR027470; Cation_efflux_CTD. DR InterPro; IPR058533; Cation_efflux_TM. DR InterPro; IPR027469; Cation_efflux_TMD_sf. DR NCBIfam; TIGR01297; CDF; 1. DR PANTHER; PTHR45820:SF3; CALCIUM_MANGANESE ANTIPORTER SLC30A10; 1. DR PANTHER; PTHR45820; FI23527P1; 1. DR Pfam; PF01545; Cation_efflux; 1. DR Pfam; PF16916; ZT_dimer; 1. DR SUPFAM; SSF161111; Cation efflux protein transmembrane domain-like; 1. PE 1: Evidence at protein level; KW Alternative splicing; Antiport; Cell membrane; Disease variant; Dystonia; KW Endosome; Golgi apparatus; Ion transport; Manganese; Membrane; KW Neurodegeneration; Parkinsonism; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport; Zinc; KW Zinc transport. FT CHAIN 1..485 FT /note="Calcium/manganese antiporter SLC30A10" FT /id="PRO_0000312580" FT TOPO_DOM 1..10 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 11..31 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 32..40 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 41..61 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 62..81 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 82..102 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 103..113 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 114..134 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 135..244 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 245..265 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 266..278 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 279..299 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 300..485 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 167..196 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 308..485 FT /note="Required for plasma membrane localization" FT /evidence="ECO:0000269|PubMed:25319704" FT SITE 43 FT /note="Important for coupling of manganese to calcium FT transport" FT /evidence="ECO:0000269|PubMed:30755481" FT VAR_SEQ 1..245 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_029863" FT VAR_SEQ 214..223 FT /note="GDSFNTQNEP -> ELIHNTRFLL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029864" FT VAR_SEQ 224..485 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029865" FT VARIANT 89 FT /note="L -> P (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; loss of function in FT intracellular manganese ion homeostasis; FT dbSNP:rs281860284)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072573" FT VARIANT 105..107 FT /note="Missing (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; decreased function in FT intracellular manganese ion homeostasis)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072574" FT VARIANT 167 FT /note="F -> S (in dbSNP:rs281860286)" FT /evidence="ECO:0000269|PubMed:22341971" FT /id="VAR_072575" FT VARIANT 256 FT /note="Missing (in HMNDYT1)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072576" FT VARIANT 349 FT /note="L -> P (in HMNDYT1; dbSNP:rs281860291)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072577" FT MUTAGEN 4 FT /note="Y->F: Decreased interaction with SLC30A3. No effect FT on self-association. Decreased zinc ion transmembrane FT transporter activity. Decreased EGF-induced ERK1/2 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:26728129" FT MUTAGEN 25 FT /note="E->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 40 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 43 FT /note="N->A: No effect on localization to the plasma FT membrane. Changed calcium:manganese antiporter activity. FT Enhanced coupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:27307044, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->H: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity. FT Loss of calcium:manganese antiporter activity and increased FT zinc ion transmembrane transporter activity; when FT associated with V-52 and F-242." FT /evidence="ECO:0000269|PubMed:27226609, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->T: Loss of calcium:manganese antiporter activity. FT Uncoupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 47 FT /note="D->A: No effect on localization to the plasma FT membrane. No effect on calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 47 FT /note="D->E: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 52 FT /note="C->V: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and F-242." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 127 FT /note="N->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-244." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 196 FT /note="T->P: Loss of localization to the plasma membrane." FT /evidence="ECO:0000269|PubMed:25319704" FT MUTAGEN 242 FT /note="L->F: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and V-52." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 244 FT /note="H->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-127." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 244 FT /note="H->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 248 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of manganese ion export across plasma FT membrane." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 333 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 350 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" SQ SEQUENCE 485 AA; 52684 MW; 96A3495EF026DE94 CRC64; MGRYSGKTCR LLFMLVLTVA FFVAELVSGY LGNSIALLSD SFNMLSDLIS LCVGLSAGYI ARRPTRGFSA TYGYARAEVV GALSNAVFLT ALCFTIFVEA VLRLARPERI DDPELVLIVG VLGLLVNVVG LLIFQDCAAW FACCLRGRSR RLQQRQQLAE GCVPGAFGGP QGAEDPRRAA DPTAPGSDSA VTLRGTSVER KREKGATVFA NVAGDSFNTQ NEPEDMMKKE KKSEALNIRG VLLHVMGDAL GSVVVVITAI IFYVLPLKSE DPCNWQCYID PSLTVLMVII ILSSAFPLIK ETAAILLQMV PKGVNMEELM SKLSAVPGIS SVHEVHIWEL VSGKIIATLH IKYPKDRGYQ DASTKIREIF HHAGIHNVTI QFENVDLKEP LEQKDLLLLC NSPCISKGCA KQLCCPPGAL PLAHVNGCAE HNGGPSLDTY GSDGLSRRDA REVAIEVSLD SCLSDHGQSL NKTQEDQCYV NRTHF //