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 PAWR_HUMAN Reviewed; 340 AA. AC Q96IZ0; O75796; Q6FHY9; Q8N700; DT 24-MAY-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 183. DE RecName: Full=PRKC apoptosis WT1 regulator protein; DE AltName: Full=Prostate apoptosis response 4 protein; DE Short=Par-4; GN Name=PAWR; Synonyms=PAR4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND RP INTERACTION WITH WT1. RX PubMed=8943350; DOI=10.1128/mcb.16.12.6945; RA Johnstone R.W., See R.H., Sells S.F., Wang J., Muthukkumar S., Englert C., RA Haber D.A., Licht J.D., Sugrue S.P., Roberts T., Rangnekar V.M., Shi Y.; RT "A novel repressor, par-4, modulates transcription and growth suppression RT functions of the Wilms' tumor suppressor WT1."; RL Mol. Cell. Biol. 16:6945-6956(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-78. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-42; ARG-78; ALA-137 AND RP ALA-202. RG NIEHS SNPs program; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-64. RC TISSUE=Blood; RX PubMed=12242017; DOI=10.1016/s0378-1119(02)00826-0; RA Hsu S.-C., Kirschenbaum F., Miller J., Cordell B., McCarthy J.V.; RT "Structural and functional characterization of the upstream regulatory RT region of the human gene encoding prostate apoptosis response factor-4."; RL Gene 295:109-116(2002). RN [6] RP FUNCTION IN APOPTOSIS AND TUMOR REGRESSION. RX PubMed=11585763; RA Chakraborty M., Qiu S.G., Vasudevan K.M., Rangnekar V.M.; RT "Par-4 drives trafficking and activation of Fas and Fasl to induce prostate RT cancer cell apoptosis and tumor regression."; RL Cancer Res. 61:7255-7263(2001). RN [7] RP INTERACTION WITH SQSTM1 AND PRKCZ. RX PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0; RA Chang S., Kim J.H., Shin J.; RT "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4- RT induced PKCzeta inhibition."; RL FEBS Lett. 510:57-61(2002). RN [8] RP SUBCELLULAR LOCATION, AND INTERACTION WITH THAP1. RX PubMed=12717420; DOI=10.1038/sj.onc.1206271; RA Roussigne M., Cayrol C., Clouaire T., Amalric F., Girard J.-P.; RT "THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis- RT response-4 (Par-4) to PML nuclear bodies."; RL Oncogene 22:2432-2442(2003). RN [9] RP INTERACTION WITH AATF. RX PubMed=14627703; DOI=10.1074/jbc.m309811200; RA Guo Q., Xie J.; RT "AATF inhibits aberrant production of amyloid beta peptide 1-42 by RT interacting directly with Par-4."; RL J. Biol. Chem. 279:4596-4603(2004). RN [10] RP INTERACTION WITH BACE1. RX PubMed=15671026; DOI=10.1074/jbc.m411933200; RA Xie J., Guo Q.; RT "PAR-4 is involved in regulation of beta-secretase cleavage of the RT Alzheimer amyloid precursor protein."; RL J. Biol. Chem. 280:13824-13832(2005). RN [11] RP INTERACTION WITH SPSB1 AND SPSB2, AND MUTAGENESIS OF ASN-72. RX PubMed=17189197; DOI=10.1016/j.molcel.2006.11.009; RA Woo J.S., Suh H.Y., Park S.Y., Oh B.H.; RT "Structural basis for protein recognition by B30.2/SPRY domains."; RL Mol. Cell 24:967-976(2006). RN [12] RP REVIEW ON FUNCTION IN APOPTOSIS AND NEURODEGENERATIVE DISEASES. RX PubMed=12565819; DOI=10.1016/s0014-4827(02)00016-2; RA El-Guendy N., Rangnekar V.M.; RT "Apoptosis by Par-4 in cancer and neurodegenerative diseases."; RL Exp. Cell Res. 283:51-66(2003). RN [13] RP REVIEW. RX PubMed=14755681; DOI=10.1002/jcb.20000; RA Gurumurthy S., Rangnekar V.M.; RT "Par-4 inducible apoptosis in prostate cancer cells."; RL J. Cell. Biochem. 91:504-512(2004). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-231, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [20] {ECO:0007744|PDB:2JK9} RP X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) OF 67-74 IN COMPLEX WITH SPSB1, RP INTERACTION WITH SPSB1; SPSB2 AND SPSB4, MUTAGENESIS OF ALA-66; GLU-68; RP LEU-69; ASN-71 AND ASN-72, AND MOTIF. RX PubMed=20561531; DOI=10.1016/j.jmb.2010.06.017; RA Filippakopoulos P., Low A., Sharpe T.D., Uppenberg J., Yao S., Kuang Z., RA Savitsky P., Lewis R.S., Nicholson S.E., Norton R.S., Bullock A.N.; RT "Structural basis for Par-4 recognition by the SPRY domain- and SOCS box- RT containing proteins SPSB1, SPSB2, and SPSB4."; RL J. Mol. Biol. 401:389-402(2010). CC -!- FUNCTION: Pro-apoptotic protein capable of selectively inducing CC apoptosis in cancer cells, sensitizing the cells to diverse apoptotic CC stimuli and causing regression of tumors in animal models. Induces CC apoptosis in certain cancer cells by activation of the Fas prodeath CC pathway and coparallel inhibition of NF-kappa-B transcriptional CC activity. Inhibits the transcriptional activation and augments the CC transcriptional repression mediated by WT1. Down-regulates the anti- CC apoptotic protein BCL2 via its interaction with WT1. Also seems to be a CC transcriptional repressor by itself. May be directly involved in CC regulating the amyloid precursor protein (APP) cleavage activity of CC BACE1. {ECO:0000269|PubMed:11585763}. CC -!- SUBUNIT: Homooligomer. Interacts (via the C-terminal region) with WT1 CC (PubMed:8943350). Interacts with THAP1 (PubMed:12717420). Interacts CC with AATF (PubMed:14627703). Interacts with BACE1 (PubMed:15671026). CC Interacts with SPSB1 (via B30.2/SPRY domain); this interaction is CC direct and occurs in association with the Elongin BC complex CC (PubMed:17189197, PubMed:20561531). Interacts with SPSB2 (via CC B30.2/SPRY domain); this interaction occurs in association with the CC Elongin BC complex (PubMed:17189197, PubMed:20561531). Interacts with CC SPSB4 (via B30.2/SPRY domain) (PubMed:20561531); this interaction CC occurs in association with the Elongin BC complex (PubMed:20561531). CC Component of a ternary complex composed of SQSTM1 and PRKCZ CC (PubMed:11755531). Interacts with actin (By similarity). CC {ECO:0000250|UniProtKB:Q62627, ECO:0000250|UniProtKB:Q925B0, CC ECO:0000269|PubMed:11755531, ECO:0000269|PubMed:12717420, CC ECO:0000269|PubMed:14627703, ECO:0000269|PubMed:15671026, CC ECO:0000269|PubMed:17189197, ECO:0000269|PubMed:20561531, CC ECO:0000269|PubMed:8943350}. CC -!- INTERACTION: CC Q96IZ0; Q01094: E2F1; NbExp=2; IntAct=EBI-595869, EBI-448924; CC Q96IZ0; P11021: HSPA5; NbExp=8; IntAct=EBI-595869, EBI-354921; CC Q96IZ0; Q96BD6: SPSB1; NbExp=2; IntAct=EBI-595869, EBI-2659201; CC Q96IZ0; Q99619: SPSB2; NbExp=2; IntAct=EBI-595869, EBI-2323209; CC Q96IZ0; Q96A44: SPSB4; NbExp=2; IntAct=EBI-595869, EBI-2323233; CC Q96IZ0; P08670: VIM; NbExp=2; IntAct=EBI-595869, EBI-353844; CC Q96IZ0; Q9D5L7: Spsb1; Xeno; NbExp=2; IntAct=EBI-595869, EBI-8821912; CC Q96IZ0; O88838: Spsb2; Xeno; NbExp=6; IntAct=EBI-595869, EBI-8820410; CC Q96IZ0; Q8R5B6: Spsb4; Xeno; NbExp=3; IntAct=EBI-595869, EBI-8821982; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Mainly cytoplasmic in CC absence of apoptosis signal and in normal cells. Nuclear in most cancer CC cell lines. Nuclear entry seems to be essential but not sufficient for CC apoptosis (By similarity). Nuclear localization includes nucleoplasm CC and PML nuclear bodies. {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Widely expressed. Expression is elevated in various CC neurodegenerative diseases such as amyotrophic lateral sclerosis, CC Alzheimer, Parkinson and Huntington diseases and stroke. Down-regulated CC in several cancers. {ECO:0000269|PubMed:8943350}. CC -!- INDUCTION: By apoptosis. CC -!- DOMAIN: The leucine-zipper domain is not essential for apoptosis, but CC is required for sensitization of cells to exogenous apoptotic insults CC and for interaction with its partners. {ECO:0000250}. CC -!- DOMAIN: The SAC domain is a death-inducing domain selective for CC apoptosis induction in cancer cells. This domain is essential for CC nuclear entry, Fas activation, inhibition of NF-kappa-B activity and CC induction of apoptosis in cancer cells (By similarity). {ECO:0000250}. CC -!- DOMAIN: The B30.2/SPRY domain-binding motif mediates recognition by CC proteins containing a B30.2/SPRY domain. {ECO:0000269|PubMed:20561531}. CC -!- PTM: Preferentially phosphorylated at the Thr-163 by PKC in cancer CC cells. {ECO:0000250}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41641/PAWR"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U63809; AAC24947.1; -; mRNA. DR EMBL; CR536549; CAG38786.1; -; mRNA. DR EMBL; AY300794; AAP43693.1; -; Genomic_DNA. DR EMBL; BC007018; AAH07018.1; -; mRNA. DR EMBL; AF503628; AAM27453.1; -; Genomic_DNA. DR CCDS; CCDS31863.1; -. DR RefSeq; NP_001341661.1; NM_001354732.2. DR RefSeq; NP_002574.2; NM_002583.4. DR RefSeq; XP_047284872.1; XM_047428916.1. DR RefSeq; XP_054228126.1; XM_054372151.1. DR PDB; 2JK9; X-ray; 1.79 A; B=67-81. DR PDBsum; 2JK9; -. DR AlphaFoldDB; Q96IZ0; -. DR SMR; Q96IZ0; -. DR BioGRID; 111108; 137. DR CORUM; Q96IZ0; -. DR DIP; DIP-29003N; -. DR ELM; Q96IZ0; -. DR FunCoup; Q96IZ0; 1301. DR IntAct; Q96IZ0; 40. DR MINT; Q96IZ0; -. DR STRING; 9606.ENSP00000328088; -. DR BindingDB; Q96IZ0; -. DR DrugBank; DB14942; BMS-986141. DR GlyGen; Q96IZ0; 12 sites, 1 O-linked glycan (12 sites). DR iPTMnet; Q96IZ0; -. DR PhosphoSitePlus; Q96IZ0; -. DR BioMuta; PAWR; -. DR DMDM; 66773935; -. DR jPOST; Q96IZ0; -. DR MassIVE; Q96IZ0; -. DR PaxDb; 9606-ENSP00000328088; -. DR PeptideAtlas; Q96IZ0; -. DR ProteomicsDB; 76870; -. DR Pumba; Q96IZ0; -. DR TopDownProteomics; Q96IZ0; -. DR Antibodypedia; 1824; 392 antibodies from 41 providers. DR DNASU; 5074; -. DR Ensembl; ENST00000328827.9; ENSP00000328088.4; ENSG00000177425.12. DR GeneID; 5074; -. DR KEGG; hsa:5074; -. DR MANE-Select; ENST00000328827.9; ENSP00000328088.4; NM_002583.4; NP_002574.2. DR UCSC; uc001syx.4; human. DR AGR; HGNC:8614; -. DR ClinPGx; PA32954; -. DR CTD; 5074; -. DR DisGeNET; 5074; -. DR GeneCards; PAWR; -. DR HGNC; HGNC:8614; PAWR. DR HPA; ENSG00000177425; Low tissue specificity. DR MIM; 601936; gene. DR OpenTargets; ENSG00000177425; -. DR VEuPathDB; HostDB:ENSG00000177425; -. DR eggNOG; ENOG502QVUF; Eukaryota. DR GeneTree; ENSGT00390000000406; -. DR HOGENOM; CLU_076619_0_0_1; -. DR InParanoid; Q96IZ0; -. DR OMA; NCIPLAR; -. DR OrthoDB; 6286739at2759; -. DR PAN-GO; Q96IZ0; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q96IZ0; -. DR PathwayCommons; Q96IZ0; -. DR SignaLink; Q96IZ0; -. DR SIGNOR; Q96IZ0; -. DR Agora; ENSG00000177425; -. DR BioGRID-ORCS; 5074; 29 hits in 1161 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR ChiTaRS; PAWR; human. DR EvolutionaryTrace; Q96IZ0; -. DR GeneWiki; PAWR; -. DR GenomeRNAi; 5074; -. DR Pharos; Q96IZ0; Tbio. DR PRO; PR:Q96IZ0; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q96IZ0; protein. DR Bgee; ENSG00000177425; Expressed in germinal epithelium of ovary and 186 other cell types or tissues. DR ExpressionAtlas; Q96IZ0; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0005884; C:actin filament; IBA:GO_Central. DR GO; GO:0000785; C:chromatin; IEA:Ensembl. DR GO; GO:0097542; C:ciliary tip; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0003779; F:actin binding; ISS:UniProtKB. DR GO; GO:0019899; F:enzyme binding; IDA:UniProtKB. DR GO; GO:0043522; F:leucine zipper domain binding; IPI:UniProtKB. DR GO; GO:0003714; F:transcription corepressor activity; TAS:ProtInc. DR GO; GO:0051017; P:actin filament bundle assembly; ISS:UniProtKB. DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB. DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0030889; P:negative regulation of B cell proliferation; IEA:Ensembl. DR GO; GO:0048147; P:negative regulation of fibroblast proliferation; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl. DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:ProtInc. DR GO; GO:0042986; P:positive regulation of amyloid precursor protein biosynthetic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IBA:GO_Central. DR GO; GO:2000774; P:positive regulation of cellular senescence; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl. DR GO; GO:1901300; P:positive regulation of hydrogen peroxide-mediated programmed cell death; IEA:Ensembl. DR DisProt; DP01603; -. DR IDEAL; IID00177; -. DR InterPro; IPR026117; Par-4. DR PANTHER; PTHR15093:SF1; PRKC APOPTOSIS WT1 REGULATOR PROTEIN; 1. DR PANTHER; PTHR15093; PROSTATE APOPTOSIS RESPONSE PROTEIN PAR-4; 1. PE 1: Evidence at protein level; KW 3D-structure; Apoptosis; Coiled coil; Cytoplasm; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Transcription; KW Transcription regulation. FT CHAIN 1..340 FT /note="PRKC apoptosis WT1 regulator protein" FT /id="PRO_0000058236" FT REGION 1..253 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..203 FT /note="Selective for apoptosis induction in cancer cells FT (SAC)" FT REGION 300..340 FT /note="Leucine-zipper" FT COILED 186..206 FT /evidence="ECO:0000255" FT MOTIF 68..72 FT /note="B30.2/SPRY domain-binding motif" FT /evidence="ECO:0000269|PubMed:20561531" FT MOTIF 145..161 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250" FT COMPBIAS 1..18 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 47..82 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 182..192 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 193..203 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 242..253 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 108 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 163 FT /note="Phosphothreonine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q62627" FT MOD_RES 231 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VARIANT 42 FT /note="P -> L (in dbSNP:rs8176804)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_022465" FT VARIANT 78 FT /note="P -> R (in dbSNP:rs8176805)" FT /evidence="ECO:0000269|Ref.2, ECO:0000269|Ref.3" FT /id="VAR_022466" FT VARIANT 137 FT /note="G -> A (in dbSNP:rs8176806)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_022467" FT VARIANT 202 FT /note="E -> A (in dbSNP:rs8176870)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_022468" FT MUTAGEN 66 FT /note="A->D: No loss of interaction with SPSB1, SPSB2 and FT SPSB4." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 68 FT /note="E->D: Increased interaction with SPSB2. Only FT slightly increased interaction with SPSB4. Increased FT interaction with SPSB1, SPSB2 and SPSB4; when associated FT with A-69." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 69 FT /note="L->I: Only slightly increased interaction with FT SPSB2. Only slightly increased interaction with SPSB4. FT Increased interaction with SPSB1, SPSB2 and SPSB4; when FT associated with A-68." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 71 FT /note="N->A: Loss of interaction with SPSB1, SPSB2 and FT SPSB4." FT /evidence="ECO:0000269|PubMed:20561531" FT MUTAGEN 72 FT /note="N->A: Loss of interaction with SPSB1-Elongin BC FT complex and SPSB2 and SPSB4." FT /evidence="ECO:0000269|PubMed:17189197, FT ECO:0000269|PubMed:20561531" FT CONFLICT 102..103 FT /note="AP -> PPAR (in Ref. 1; AAC24947)" FT /evidence="ECO:0000305" FT CONFLICT 199 FT /note="I -> M (in Ref. 2; CAG38786)" FT /evidence="ECO:0000305" FT CONFLICT 281 FT /note="R -> T (in Ref. 1; AAC24947)" FT /evidence="ECO:0000305" SQ SEQUENCE 340 AA; 36568 MW; 7E7515455402DBF8 CRC64; MATGGYRTSS GLGGSTTDFL EEWKAKREKM RAKQNPPGPA PPGGGSSDAA GKPPAGALGT PAAAAANELN NNLPGGAPAA PAVPGPGGVN CAVGSAMLTR AAPGPRRSED EPPAASASAA PPPQRDEEEP DGVPEKGKSS GPSARKGKGQ IEKRKLREKR RSTGVVNIPA AECLDEYEDD EAGQKERKRE DAITQQNTIQ NEAVNLLDPG SSYLLQEPPR TVSGRYKSTT SVSEEDVSSR YSRTDRSGFP RYNRDANVSG TLVSSSTLEK KIEDLEKEVV RERQENLRLV RLMQDKEEMI GKLKEEIDLL NRDLDDIEDE NEQLKQENKT LLKVVGQLTR // ID PCS1N_HUMAN Reviewed; 260 AA. AC Q9UHG2; Q4VC04; DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 165. DE RecName: Full=ProSAAS; DE AltName: Full=Proprotein convertase subtilisin/kexin type 1 inhibitor; DE Short=Proprotein convertase 1 inhibitor; DE AltName: Full=pro-SAAS; DE Contains: DE RecName: Full=KEP; DE Contains: DE RecName: Full=Big SAAS; DE Short=b-SAAS; DE Contains: DE RecName: Full=Little SAAS; DE Short=l-SAAS; DE AltName: Full=N-proSAAS; DE Contains: DE RecName: Full=Big PEN-LEN; DE Short=b-PEN-LEN; DE AltName: Full=SAAS CT(1-49); DE Contains: DE RecName: Full=PEN; DE Contains: DE RecName: Full=Little LEN; DE Short=l-LEN; DE Contains: DE RecName: Full=Big LEN; DE Short=b-LEN; DE AltName: Full=SAAS CT(25-40); DE Flags: Precursor; GN Name=PCSK1N; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RX PubMed=10632593; DOI=10.1523/jneurosci.20-02-00639.2000; RA Fricker L., McKinzie A.A., Sun J., Curran E., Qian Y., Yan L., RA Patterson S.D., Courchesne P.L., Richards B., Levin N., Mzhavia N., RA Devi L.A., Douglass J.; RT "Identification and characterization of proSAAS, a granin-like RT neuroendocrine peptide precursor that inhibits prohormone processing."; RL J. Neurosci. 20:639-648(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-31. RC TISSUE=Brain, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP MUTAGENESIS OF VAL-235; LEU-236; GLY-237; LEU-240; ARG-241; VAL-242; RP LYS-243; ARG-244; LEU-245 AND GLU-246. RX PubMed=11435430; DOI=10.1074/jbc.m104064200; RA Basak A., Koch P., Dupelle M., Fricker L.D., Devi L.A., Chretien M., RA Seidah N.G.; RT "Inhibitory specificity and potency of proSAAS-derived peptides toward RT proprotein convertase 1."; RL J. Biol. Chem. 276:32720-32728(2001). RN [4] RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS), AND PROTEOLYTIC PROCESSING. RX PubMed=12914799; DOI=10.1016/s0006-291x(03)01391-3; RA Kikuchi K., Arawaka S., Koyama S., Kimura H., Ren C.H., Wada M., RA Kawanami T., Kurita K., Daimon M., Kawakatsu S., Kadoya T., Goto K., RA Kato T.; RT "An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide RT precursor) is associated with tau inclusions in Pick's disease."; RL Biochem. Biophys. Res. Commun. 308:646-654(2003). RN [5] RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS). RX PubMed=14746899; DOI=10.1016/j.neulet.2003.11.028; RA Wada M., Ren C.H., Koyama S., Arawaka S., Kawakatsu S., Kimura H., RA Nagasawa H., Kawanami T., Kurita K., Daimon M., Hirano A., Kato T.; RT "A human granin-like neuroendocrine peptide precursor (proSAAS) RT immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism- RT dementia complex on Guam."; RL Neurosci. Lett. 356:49-52(2004). RN [6] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-53 AND THR-247, AND STRUCTURE RP OF CARBOHYDRATES. RC TISSUE=Cerebrospinal fluid; RX PubMed=19838169; DOI=10.1038/nmeth.1392; RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., RA Larson G.; RT "Enrichment of glycopeptides for glycan structure and attachment site RT identification."; RL Nat. Methods 6:809-811(2009). RN [7] RP GLYCOSYLATION AT THR-53; SER-228 AND THR-247, STRUCTURE OF CARBOHYDRATES, RP AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22171320; DOI=10.1074/mcp.m111.013649; RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.; RT "Human urinary glycoproteomics; attachment site specific analysis of N- and RT O-linked glycosylations by CID and ECD."; RL Mol. Cell. Proteomics 11:1-17(2012). RN [8] RP GLYCOSYLATION AT SER-228, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=23234360; DOI=10.1021/pr300963h; RA Halim A., Ruetschi U., Larson G., Nilsson J.; RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures RT of human cerebrospinal fluid glycoproteins."; RL J. Proteome Res. 12:573-584(2013). CC -!- FUNCTION: May function in the control of the neuroendocrine secretory CC pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS CC and Big PEN-LEN, both containing the C-terminal inhibitory domain, but CC not the further processed peptides reduce PCSK1 activity in the CC endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa CC form but not the autocatalytically derived 66 kDa form of PCSK1. CC Subsequent processing of proSAAS may eliminate the inhibition. Slows CC down convertase-mediated processing of proopiomelanocortin and CC proenkephalin. May control the intracellular timing of PCSK1 rather CC than its total level of activity (By similarity). CC {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- FUNCTION: [Big LEN]: Endogenous ligand for GPR171. Neuropeptide CC involved in the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- FUNCTION: [PEN]: Endogenous ligand for GPR83. Neuropeptide involved in CC the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- SUBUNIT: Interacts via the C-terminal inhibitory domain with PCSK1 66 CC kDa form. {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9QXV0}. Golgi CC apparatus, trans-Golgi network {ECO:0000250|UniProtKB:Q9QXV0}. Note=A CC N-terminal processed peptide, probably Big SAAS or Little SAAS, is CC accumulated in cytoplasmic protein tau deposits in frontotemporal CC dementia and parkinsonism linked to chromosome 17 (Pick disease), CC Alzheimer disease and amyotrophic lateral sclerosis- CC parkinsonism/dementia complex 1 (Guam disease). CC {ECO:0000269|PubMed:12914799, ECO:0000269|PubMed:14746899}. CC -!- TISSUE SPECIFICITY: Expressed in brain and pancreas. CC {ECO:0000269|PubMed:10632593}. CC -!- DOMAIN: ProSAAS(1-180) increases secretion of enzymatically inactive CC PCSK1. {ECO:0000250}. CC -!- DOMAIN: The C-terminal inhibitory domain is involved in inhibition of CC PCSK1. It corresponds to the probable processing intermediate Big PEN- CC LEN, binds to PCSK1 in vitro and contains the hexapeptide L-L-R-V-K-R, CC which, as a synthetic peptide, is sufficient for PCSK1 inhibition (By CC similarity). {ECO:0000250}. CC -!- DOMAIN: [Big LEN]: The four C-terminal amino acids of Big LEN are CC sufficient to bind and activate GPR171. {ECO:0000250|UniProtKB:Q9QXV0}. CC -!- PTM: Proteolytically cleaved in the Golgi. CC {ECO:0000269|PubMed:12914799}. CC -!- PTM: O-glycosylated with a core 1 or possibly core 8 glycan. CC {ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:22171320, CC ECO:0000269|PubMed:23234360}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF181562; AAF22643.1; -; mRNA. DR EMBL; BC002851; AAH02851.1; -; mRNA. DR CCDS; CCDS14307.1; -. DR RefSeq; NP_037403.1; NM_013271.5. DR AlphaFoldDB; Q9UHG2; -. DR SMR; Q9UHG2; -. DR BioGRID; 118156; 18. DR FunCoup; Q9UHG2; 287. DR IntAct; Q9UHG2; 17. DR MINT; Q9UHG2; -. DR STRING; 9606.ENSP00000218230; -. DR MEROPS; I49.001; -. DR GlyConnect; 743; 1 O-Linked glycan (3 sites). DR GlyCosmos; Q9UHG2; 3 sites, 2 glycans. DR GlyGen; Q9UHG2; 4 sites, 4 O-linked glycans (4 sites). DR iPTMnet; Q9UHG2; -. DR PhosphoSitePlus; Q9UHG2; -. DR BioMuta; PCSK1N; -. DR DMDM; 74735013; -. DR jPOST; Q9UHG2; -. DR MassIVE; Q9UHG2; -. DR PaxDb; 9606-ENSP00000218230; -. DR PeptideAtlas; Q9UHG2; -. DR ProteomicsDB; 84349; -. DR Antibodypedia; 579; 87 antibodies from 19 providers. DR DNASU; 27344; -. DR Ensembl; ENST00000218230.6; ENSP00000218230.5; ENSG00000102109.10. DR GeneID; 27344; -. DR KEGG; hsa:27344; -. DR MANE-Select; ENST00000218230.6; ENSP00000218230.5; NM_013271.5; NP_037403.1. DR UCSC; uc004dkz.6; human. DR AGR; HGNC:17301; -. DR ClinPGx; PA33090; -. DR CTD; 27344; -. DR DisGeNET; 27344; -. DR GeneCards; PCSK1N; -. DR HGNC; HGNC:17301; PCSK1N. DR HPA; ENSG00000102109; Group enriched (brain, pituitary gland). DR MIM; 300399; gene. DR OpenTargets; ENSG00000102109; -. DR VEuPathDB; HostDB:ENSG00000102109; -. DR eggNOG; ENOG502RYS0; Eukaryota. DR GeneTree; ENSGT00390000013488; -. DR HOGENOM; CLU_100077_0_0_1; -. DR InParanoid; Q9UHG2; -. DR OMA; VWGAPRT; -. DR OrthoDB; 8962476at2759; -. DR PAN-GO; Q9UHG2; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q9UHG2; -. DR PathwayCommons; Q9UHG2; -. DR SignaLink; Q9UHG2; -. DR Agora; ENSG00000102109; -. DR BioGRID-ORCS; 27344; 8 hits in 764 CRISPR screens. DR GenomeRNAi; 27344; -. DR Pharos; Q9UHG2; Tbio. DR PRO; PR:Q9UHG2; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; Q9UHG2; protein. DR Bgee; ENSG00000102109; Expressed in adenohypophysis and 138 other cell types or tissues. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0030141; C:secretory granule; IEA:Ensembl. DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl. DR GO; GO:0004866; F:endopeptidase inhibitor activity; IBA:GO_Central. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:Ensembl. DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc. DR GO; GO:0007218; P:neuropeptide signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0016486; P:peptide hormone processing; IEA:Ensembl. DR GO; GO:0009409; P:response to cold; IEA:Ensembl. DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl. DR InterPro; IPR010832; ProSAAS. DR PANTHER; PTHR15531; PROSAAS; 1. DR PANTHER; PTHR15531:SF0; PROSAAS; 1. DR Pfam; PF07259; ProSAAS; 1. PE 1: Evidence at protein level; KW Cleavage on pair of basic residues; Glycoprotein; Golgi apparatus; KW Neuropeptide; Proteomics identification; Reference proteome; Secreted; KW Signal. FT SIGNAL 1..33 FT /evidence="ECO:0000255" FT CHAIN 34..260 FT /note="ProSAAS" FT /id="PRO_0000259673" FT PEPTIDE 34..59 FT /note="Big SAAS" FT /evidence="ECO:0000250" FT /id="PRO_0000259675" FT PEPTIDE 34..40 FT /note="KEP" FT /evidence="ECO:0000250" FT /id="PRO_0000259674" FT PEPTIDE 42..59 FT /note="Little SAAS" FT /evidence="ECO:0000250" FT /id="PRO_0000259676" FT PEPTIDE 221..260 FT /note="Big PEN-LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259677" FT PEPTIDE 221..242 FT /note="PEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259678" FT PEPTIDE 245..260 FT /note="Big LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259679" FT PEPTIDE 245..254 FT /note="Little LEN" FT /evidence="ECO:0000250" FT /id="PRO_0000259680" FT REGION 34..215 FT /note="ProSAAS(1-180)" FT /evidence="ECO:0000250" FT REGION 165..188 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 221..260 FT /note="C-terminal inhibitory domain; interacts with PCSK1" FT /evidence="ECO:0000250" FT MOTIF 239..244 FT /note="Sufficient for inhibition of PCSK1" FT COMPBIAS 179..188 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 53 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:22171320" FT CARBOHYD 228 FT /note="O-linked (GalNAc...) serine" FT /evidence="ECO:0000269|PubMed:22171320, FT ECO:0000269|PubMed:23234360" FT CARBOHYD 247 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:22171320" FT VARIANT 31 FT /note="A -> T (in dbSNP:rs11538176)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_028971" FT MUTAGEN 235 FT /note="V->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 236 FT /note="L->A: Greatly reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 237 FT /note="G->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 240 FT /note="L->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 241 FT /note="R->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 242 FT /note="V->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 243 FT /note="K->A: Abolishes inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 244 FT /note="R->A: Abolishes inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 245 FT /note="L->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" FT MUTAGEN 246 FT /note="E->A: Reduces inhibition of PCSK1." FT /evidence="ECO:0000269|PubMed:11435430" SQ SEQUENCE 260 AA; 27372 MW; FF8E2722784B7A5C CRC64; MAGSPLLWGP RAGGVGLLVL LLLGLFRPPP ALCARPVKEP RGLSAASPPL AETGAPRRFR RSVPRGEAAG AVQELARALA HLLEAERQER ARAEAQEAED QQARVLAQLL RVWGAPRNSD PALGLDDDPD APAAQLARAL LRARLDPAAL AAQLVPAPVP AAALRPRPPV YDDGPAGPDA EEAGDETPDV DPELLRYLLG RILAGSADSE GVAAPRRLRR AADHDVGSEL PPEGVLGALL RVKRLETPAP QVPARRLLPP // ID SPTC1_HUMAN Reviewed; 473 AA. AC O15269; A8K681; Q5VWB4; Q96IX6; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 28-JAN-2026, entry version 218. DE RecName: Full=Serine palmitoyltransferase 1; DE EC=2.3.1.50 {ECO:0000269|PubMed:19416851}; DE AltName: Full=Long chain base biosynthesis protein 1; DE Short=LCB 1; DE AltName: Full=Serine-palmitoyl-CoA transferase 1; DE Short=SPT 1; DE Short=SPT1; GN Name=SPTLC1; Synonyms=LCB1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Kidney; RX PubMed=9363775; DOI=10.1111/j.1432-1033.1997.00239.x; RA Weiss B., Stoffel W.; RT "Human and murine serine-palmitoyl-CoA transferase. Cloning, expression and RT characterization of the key enzyme in sphingolipid synthesis."; RL Eur. J. Biochem. 249:239-247(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANTS HSAN1A RP TRP-133; TYR-133 AND ASP-144. RX PubMed=11242114; DOI=10.1038/85879; RA Dawkins J.L., Hulme D.J., Brahmbhatt S.B., Auer-Grumbach M., RA Nicholson G.A.; RT "Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base RT subunit-1, cause hereditary sensory neuropathy type I."; RL Nat. Genet. 27:309-312(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP TISSUE SPECIFICITY. RX PubMed=17023427; DOI=10.1074/jbc.m608066200; RA Hornemann T., Richard S., Ruetti M.F., Wei Y., von Eckardstein A.; RT "Cloning and initial characterization of a new subunit for mammalian RT serine-palmitoyltransferase."; RL J. Biol. Chem. 281:37275-37281(2006). RN [8] RP FUNCTION. RX PubMed=19648650; DOI=10.1074/jbc.m109.023192; RA Hornemann T., Penno A., Ruetti M.F., Ernst D., Kivrak-Pfiffner F., RA Rohrer L., von Eckardstein A.; RT "The SPTLC3 subunit of serine palmitoyltransferase generates short chain RT sphingoid bases."; RL J. Biol. Chem. 284:26322-26330(2009). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE SPT COMPLEX, AND RP INTERACTION WITH SPTSSA AND SPTSSB. RX PubMed=19416851; DOI=10.1073/pnas.0811269106; RA Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P., Eichler F., RA Brown R.H. Jr., Harmon J.M., Dunn T.M.; RT "Identification of small subunits of mammalian serine palmitoyltransferase RT that confer distinct acyl-CoA substrate specificities."; RL Proc. Natl. Acad. Sci. U.S.A. 106:8186-8191(2009). RN [10] RP BIOPHYSICOCHEMICAL PROPERTIES, AND CHARACTERIZATION OF VARIANT HSAN1A RP TRP-133. RX PubMed=20504773; DOI=10.1074/jbc.m110.122259; RA Gable K., Gupta S.D., Han G., Niranjanakumari S., Harmon J.M., Dunn T.M.; RT "A disease-causing mutation in the active site of serine RT palmitoyltransferase causes catalytic promiscuity."; RL J. Biol. Chem. 285:22846-22852(2010). RN [11] RP INTERACTION WITH ORMDL3. RX PubMed=20182505; DOI=10.1038/nature08787; RA Breslow D.K., Collins S.R., Bodenmiller B., Aebersold R., Simons K., RA Shevchenko A., Ejsing C.S., Weissman J.S.; RT "Orm family proteins mediate sphingolipid homeostasis."; RL Nature 463:1048-1053(2010). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] RP INDUCTION IN ALZHEIMER DISEASE. RX PubMed=21994399; DOI=10.1523/jneurosci.3883-11.2011; RA Geekiyanage H., Chan C.; RT "MicroRNA-137/181c regulates serine palmitoyltransferase and in turn RT amyloid beta, novel targets in sporadic Alzheimer's disease."; RL J. Neurosci. 31:14820-14830(2011). RN [14] RP PHOSPHORYLATION AT TYR-164, AND MUTAGENESIS OF TYR-164. RX PubMed=23629659; DOI=10.1074/jbc.m112.409185; RA Taouji S., Higa A., Delom F., Palcy S., Mahon F.X., Pasquet J.M., Bosse R., RA Segui B., Chevet E.; RT "Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on RT tyrosine 164 inhibits its activity and promotes cell survival."; RL J. Biol. Chem. 288:17190-17201(2013). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP REGULATION OF SPT COMPLEX ACTIVITY BY ORMDL PROTEINS IN THE PRESENCE OF RP CERAMIDES. RX PubMed=30700557; DOI=10.1074/jbc.ra118.007291; RA Davis D.L., Gable K., Suemitsu J., Dunn T.M., Wattenberg B.W.; RT "The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly RT regulated by ceramide: Reconstitution of SPT regulation in isolated RT membranes."; RL J. Biol. Chem. 294:5146-5156(2019). RN [17] RP FUNCTION. RX PubMed=36170811; DOI=10.1016/j.celrep.2022.111415; RA Spears M.E., Lee N., Hwang S., Park S.J., Carlisle A.E., Li R., Doshi M.B., RA Armando A.M., Gao J., Simin K., Zhu L.J., Greer P.L., Quehenberger O., RA Torres E.M., Kim D.; RT "De novo sphingolipid biosynthesis necessitates detoxification in cancer RT cells."; RL Cell Rep. 40:111415-111415(2022). RN [18] {ECO:0007744|PDB:7K0I, ECO:0007744|PDB:7K0J, ECO:0007744|PDB:7K0K, ECO:0007744|PDB:7K0L, ECO:0007744|PDB:7K0M, ECO:0007744|PDB:7K0N, ECO:0007744|PDB:7K0O, ECO:0007744|PDB:7K0P, ECO:0007744|PDB:7K0Q} RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=33558761; DOI=10.1038/s41594-020-00551-9; RA Wang Y., Niu Y., Zhang Z., Gable K., Gupta S.D., Somashekarappa N., Han G., RA Zhao H., Myasnikov A.G., Kalathur R.C., Dunn T.M., Lee C.H.; RT "Structural insights into the regulation of human serine RT palmitoyltransferase complexes."; RL Nat. Struct. Mol. Biol. 28:240-248(2021). RN [19] {ECO:0007744|PDB:6M4N, ECO:0007744|PDB:6M4O, ECO:0007744|PDB:7CQI, ECO:0007744|PDB:7CQK} RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, FUNCTION, AND MUTAGENESIS OF PHE-138; PHE-337 AND RP SER-338. RX PubMed=33558762; DOI=10.1038/s41594-020-00553-7; RA Li S., Xie T., Liu P., Wang L., Gong X.; RT "Structural insights into the assembly and substrate selectivity of human RT SPT-ORMDL3 complex."; RL Nat. Struct. Mol. Biol. 28:249-257(2021). RN [20] {ECO:0007744|PDB:7YIU, ECO:0007744|PDB:7YIY, ECO:0007744|PDB:7YJ1, ECO:0007744|PDB:7YJ2} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, CHARACTERIZATION OF VARIANTS ALS27 PHE-23; LEU-39 DEL RP AND 40-PHE-SER-41 DEL, AND ACTIVITY REGULATION. RX PubMed=37308477; DOI=10.1038/s41467-023-39274-y; RA Xie T., Liu P., Wu X., Dong F., Zhang Z., Yue J., Mahawar U., Farooq F., RA Vohra H., Fang Q., Liu W., Wattenberg B.W., Gong X.; RT "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid RT homeostasis."; RL Nat. Commun. 14:3475-3475(2023). RN [21] RP VARIANT ALA-387. RX PubMed=15037712; DOI=10.1212/01.wnl.0000115388.10828.5c; RA Verhoeven K., Coen K., De Vriendt E., Jacobs A., Van Gerwen V., Smouts I., RA Pou-Serradell A., Martin J.-J., Timmerman V., De Jonghe P.; RT "SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type RT I."; RL Neurology 62:1001-1002(2004). RN [22] RP VARIANT LEU-151. RX PubMed=17060578; DOI=10.1212/01.wnl.0000240068.21499.f5; RA Meggouh F., Bienfait H.M.E., Weterman M.A.J., de Visser M., Baas F.; RT "Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene."; RL Neurology 67:1476-1478(2006). RN [23] RP VARIANT [LARGE SCALE ANALYSIS] TRP-239. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [24] RP VARIANTS HSAN1A PHE-331 AND VAL-352, AND VARIANT ALA-387. RX PubMed=19651702; DOI=10.1093/brain/awp198; RA Rotthier A., Baets J., De Vriendt E., Jacobs A., Auer-Grumbach M., Levy N., RA Bonello-Palot N., Kilic S.S., Weis J., Nascimento A., Swinkels M., RA Kruyt M.C., Jordanova A., De Jonghe P., Timmerman V.; RT "Genes for hereditary sensory and autonomic neuropathies: a genotype- RT phenotype correlation."; RL Brain 132:2699-2711(2009). RN [25] RP CHARACTERIZATION OF VARIANTS HSAN1A TYR-133; TRP-133 AND ASP-144, RP CHARACTERIZATION OF VARIANT ALA-387, LACK OF ASSOCIATION OF VARIANT ALA-387 RP WITH HSAN1A, AND INTERACTION WITH SPTLC2. RX PubMed=19132419; DOI=10.1007/s10048-008-0168-7; RA Hornemann T., Penno A., Richard S., Nicholson G., van Dijk F.S., RA Rotthier A., Timmerman V., von Eckardstein A.; RT "A systematic comparison of all mutations in hereditary sensory neuropathy RT type I (HSAN I) reveals that the G387A mutation is not disease RT associated."; RL Neurogenetics 10:135-143(2009). RN [26] RP VARIANT HSAN1A PHE-331, CHARACTERIZATION OF VARIANTS HSAN1A TRP-133; RP PHE-331 AND VAL-352, AND SUBCELLULAR LOCATION. RX PubMed=21618344; DOI=10.1002/humu.21481; RA Rotthier A., Penno A., Rautenstrauss B., Auer-Grumbach M., Stettner G.M., RA Asselbergh B., Van Hoof K., Sticht H., Levy N., Timmerman V., Hornemann T., RA Janssens K.; RT "Characterization of two mutations in the SPTLC1 subunit of serine RT palmitoyltransferase associated with hereditary sensory and autonomic RT neuropathy type I."; RL Hum. Mutat. 32:E2211-E2225(2011). RN [27] RP VARIANT HSAN1A TRP-133, AND VARIANT GLY-310. RX PubMed=22302274; DOI=10.1007/s00415-011-6397-y; RA Davidson G.L., Murphy S.M., Polke J.M., Laura M., Salih M.A., Muntoni F., RA Blake J., Brandner S., Davies N., Horvath R., Price S., Donaghy M., RA Roberts M., Foulds N., Ramdharry G., Soler D., Lunn M.P., Manji H., RA Davis M.B., Houlden H., Reilly M.M.; RT "Frequency of mutations in the genes associated with hereditary sensory and RT autonomic neuropathy in a UK cohort."; RL J. Neurol. 259:1673-1685(2012). RN [28] RP INVOLVEMENT IN HSAN1A, VARIANT HSAN1A TYR-331, AND CHARACTERIZATION OF RP VARIANT HSAN1A TYR-331. RX PubMed=23454272; DOI=10.1016/j.ejmg.2013.02.002; RA Auer-Grumbach M., Bode H., Pieber T.R., Schabhuettl M., Fischer D., RA Seidl R., Graf E., Wieland T., Schuh R., Vacariu G., Grill F., RA Timmerman V., Strom T.M., Hornemann T.; RT "Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a RT distinct syndromic phenotype."; RL Eur. J. Med. Genet. 56:266-269(2013). RN [29] RP VARIANT HSAN1A PHE-331. RX PubMed=24247255; DOI=10.3892/mmr.2013.1808; RA Suh B.C., Hong Y.B., Nakhro K., Nam S.H., Chung K.W., Choi B.O.; RT "Early-onset severe hereditary sensory and autonomic neuropathy type 1 with RT S331F SPTLC1 mutation."; RL Mol. Med. Report. 9:481-486(2014). RN [30] RP VARIANT HSAN1A ASP-144. RX PubMed=30420926; DOI=10.1155/2018/1898151; RA Ho K.W.D., Jerath N.U.; RT "V144D Mutation of SPTLC1 Can Present with Both Painful and Painless RT Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I."; RL Case Rep. Genet. 2018:1898151-1898151(2018). RN [31] RP INVOLVEMENT IN ALS27, AND VARIANTS ALS27 SER-20; LEU-39 DEL AND TYR-331. RX PubMed=34459874; DOI=10.1001/jamaneurol.2021.2598; RG FALS Sequencing Consortium; RG American Genome Center; RG International ALS Genomics Consortium; RG and ITALSGEN Consortium; RA Johnson J.O., Chia R., Miller D.E., Li R., Kumaran R., Abramzon Y., RA Alahmady N., Renton A.E., Topp S.D., Gibbs J.R., Cookson M.R., Sabir M.S., RA Dalgard C.L., Troakes C., Jones A.R., Shatunov A., Iacoangeli A., RA Al Khleifat A., Ticozzi N., Silani V., Gellera C., Blair I.P., RA Dobson-Stone C., Kwok J.B., Bonkowski E.S., Palvadeau R., Tienari P.J., RA Morrison K.E., Shaw P.J., Al-Chalabi A., Brown R.H. Jr., Calvo A., Mora G., RA Al-Saif H., Gotkine M., Leigh F., Chang I.J., Perlman S.J., Glass I., RA Scott A.I., Shaw C.E., Basak A.N., Landers J.E., Chio A., Crawford T.O., RA Smith B.N., Traynor B.J., Smith B.N., Ticozzi N., Fallini C., Gkazi A.S., RA Topp S.D., Scotter E.L., Kenna K.P., Keagle P., Tiloca C., Vance C., RA Troakes C., Colombrita C., King A., Pensato V., Castellotti B., Baas F., RA Ten Asbroek A.L.M.A., McKenna-Yasek D., McLaughlin R.L., Polak M., RA Asress S., Esteban-Perez J., Stevic Z., D'Alfonso S., Mazzini L., RA Comi G.P., Del Bo R., Ceroni M., Gagliardi S., Querin G., Bertolin C., RA van Rheenen W., Rademakers R., van Blitterswijk M., Lauria G., Duga S., RA Corti S., Cereda C., Corrado L., Soraru G., Williams K.L., Nicholson G.A., RA Blair I.P., Leblond-Manry C., Rouleau G.A., Hardiman O., Morrison K.E., RA Veldink J.H., van den Berg L.H., Al-Chalabi A., Pall H., Shaw P.J., RA Turner M.R., Talbot K., Taroni F., Garcia-Redondo A., Wu Z., Glass J.D., RA Gellera C., Ratti A., Brown R.H. Jr., Silani V., Shaw C.E., Landers J.E., RA Dalgard C.L., Adeleye A., Soltis A.R., Alba C., Viollet C., Bacikova D., RA Hupalo D.N., Sukumar G., Pollard H.B., Wilkerson M.D., Martinez E.M., RA Abramzon Y., Ahmed S., Arepalli S., Baloh R.H., Bowser R., Brady C.B., RA Brice A., Broach J., Campbell R.H., Camu W., Chia R., Cooper-Knock J., RA Ding J., Drepper C., Drory V.E., Dunckley T.L., Eicher J.D., England B.K., RA Faghri F., Feldman E., Floeter M.K., Fratta P., Geiger J.T., Gerhard G., RA Gibbs J.R., Gibson S.B., Glass J.D., Hardy J., Harms M.B., RA Heiman-Patterson T.D., Hernandez D.G., Jansson L., Kirby J., Kowall N.W., RA Laaksovirta H., Landeck N., Landi F., Le Ber I., Lumbroso S., RA MacGowan D.J.L., Maragakis N.J., Mora G., Mouzat K., Murphy N.A., RA Myllykangas L., Nalls M.A., Orrell R.W., Ostrow L.W., Pamphlett R., RA Pickering-Brown S., Pioro E.P., Pletnikova O., Pliner H.A., Pulst S.M., RA Ravits J.M., Renton A.E., Rivera A., Robberecht W., Rogaeva E., RA Rollinson S., Rothstein J.D., Scholz S.W., Sendtner M., Shaw P.J., RA Sidle K.C., Simmons Z., Singleton A.B., Smith N., Stone D.J., Tienari P.J., RA Troncoso J.C., Valori M., Van Damme P., Van Deerlin V.M., Van Den Bosch L., RA Zinman L., Landers J.E., Chio A., Traynor B.J., Angelocola S.M., RA Ausiello F.P., Barberis M., Bartolomei I., Battistini S., Bersano E., RA Bisogni G., Borghero G., Brunetti M., Cabona C., Calvo A., Canale F., RA Canosa A., Cantisani T.A., Capasso M., Caponnetto C., Cardinali P., RA Carrera P., Casale F., Chio A., Colletti T., Conforti F.L., Conte A., RA Conti E., Corbo M., Cuccu S., Dalla Bella E., D'Errico E., DeMarco G., RA Dubbioso R., Ferrarese C., Ferraro P.M., Filippi M., Fini N., Floris G., RA Fuda G., Gallone S., Gianferrari G., Giannini F., Grassano M., Greco L., RA Iazzolino B., Introna A., La Bella V., Lattante S., Lauria G., Liguori R., RA Logroscino G., Logullo F.O., Lunetta C., Mandich P., Mandrioli J., RA Manera U., Manganelli F., Marangi G., Marinou K., Marrosu M.G., RA Martinelli I., Messina S., Moglia C., Mora G., Mosca L., Murru M.R., RA Origone P., Passaniti C., Petrelli C., Petrucci A., Pozzi S., Pugliatti M., RA Quattrini A., Ricci C., Riolo G., Riva N., Russo M., Sabatelli M., RA Salamone P., Salivetto M., Salvi F., Santarelli M., Sbaiz L., Sideri R., RA Simone I., Simonini C., Spataro R., Tanel R., Tedeschi G., Ticca A., RA Torriello A., Tranquilli S., Tremolizzo L., Trojsi F., Vasta R., RA Vacchiano V., Vita G., Volanti P., Zollino M., Zucchi E.; RT "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic RT Lateral Sclerosis."; RL JAMA Neurol. 78:1236-1248(2021). RN [32] RP INVOLVEMENT IN ALS27, VARIANTS ALS27 SER-20; PHE-23; LEU-39 DEL AND RP 40-PHE-SER-41 DEL, CHARACTERIZATION OF VARIANTS ALS27 SER-20; PHE-23; RP LEU-39 DEL AND 40-PHE-SER-41 DEL, AND HOMEOSTATIC REGULATION BY ORMDL3 IN RP THE PRESENCE OF CERAMIDES. RX PubMed=34059824; DOI=10.1038/s41591-021-01346-1; RA Mohassel P., Donkervoort S., Lone M.A., Nalls M., Gable K., Gupta S.D., RA Foley A.R., Hu Y., Saute J.A.M., Moreira A.L., Kok F., Introna A., RA Logroscino G., Grunseich C., Nickolls A.R., Pourshafie N., Neuhaus S.B., RA Saade D., Gangfuss A., Koelbel H., Piccus Z., Le Pichon C.E., Fiorillo C., RA Ly C.V., Toepf A., Brady L., Specht S., Zidell A., Pedro H., Mittelmann E., RA Thomas F.P., Chao K.R., Konersman C.G., Cho M.T., Brandt T., Straub V., RA Connolly A.M., Schara U., Roos A., Tarnopolsky M., Hoeke A., Brown R.H., RA Lee C.H., Hornemann T., Dunn T.M., Boennemann C.G.; RT "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid RT synthesis."; RL Nat. Med. 27:1197-1204(2021). RN [33] RP INVOLVEMENT IN ALS27, AND VARIANT ALS27 ARG-38. RX PubMed=36204986; DOI=10.1080/21678421.2022.2096409; RA Liu X., He J., Yu W., Fan D.; RT "A de novo c.113 T > C: p.L38R mutation of SPTLC1: case report of a girl RT with sporadic juvenile amyotrophic lateral sclerosis."; RL Amyotroph. Lateral Scler. Frontotemporal Degener. 23:634-637(2022). CC -!- FUNCTION: Component of the serine palmitoyltransferase multisubunit CC enzyme (SPT) that catalyzes the initial and rate-limiting step in CC sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA CC (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex CC is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this CC complex, the heterodimer with SPTLC2 or SPTLC3 forms the catalytic core CC (PubMed:19416851, PubMed:33558762, PubMed:36170811). The composition of CC the serine palmitoyltransferase (SPT) complex determines the substrate CC preference (PubMed:19416851, PubMed:33558762). The SPTLC1-SPTLC2-SPTSSA CC complex shows a strong preference for C16-CoA substrate, while the CC SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as CC substrates, with a slight preference for C14-CoA (PubMed:19416851, CC PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong CC preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB CC isozyme displays an ability to use a broader range of acyl-CoAs, CC without apparent preference (PubMed:19416851, PubMed:19648650, CC PubMed:33558761, PubMed:33558762). Required for adipocyte cell CC viability and metabolic homeostasis (By similarity). CC {ECO:0000250|UniProtKB:O35704, ECO:0000269|PubMed:19416851, CC ECO:0000269|PubMed:19648650, ECO:0000269|PubMed:33558761, CC ECO:0000269|PubMed:33558762, ECO:0000269|PubMed:36170811}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-serine + hexadecanoyl-CoA + H(+) = 3-oxosphinganine + CO2 + CC CoA; Xref=Rhea:RHEA:14761, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, CC ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379, CC ChEBI:CHEBI:58299; EC=2.3.1.50; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14762; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=octadecanoyl-CoA + L-serine + H(+) = 3-oxoeicosasphinganine + CC CO2 + CoA; Xref=Rhea:RHEA:33683, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57394, ChEBI:CHEBI:65073; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33684; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=tetradecanoyl-CoA + L-serine + H(+) = 3-oxohexadecasphinganine CC + CO2 + CoA; Xref=Rhea:RHEA:35675, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57385, ChEBI:CHEBI:71007; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35676; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=dodecanoyl-CoA + L-serine + H(+) = 3-oxotetradecasphinganine + CC CO2 + CoA; Xref=Rhea:RHEA:35679, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57375, ChEBI:CHEBI:71008; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35680; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- COFACTOR: CC Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326; CC Evidence={ECO:0000250}; CC -!- ACTIVITY REGULATION: SPT complex catalytic activity is negatively CC regulated by ORMDL proteins, including ORMDL3, in the presence of CC ceramides (PubMed:37308477). This mechanism allows to maintain ceramide CC levels at sufficient concentrations for the production of complex CC sphingolipids, but which prevents the accumulation of ceramides to CC levels that trigger apoptosis (Probable). {ECO:0000269|PubMed:37308477, CC ECO:0000305}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.75 mM for L-serine {ECO:0000269|PubMed:20504773}; CC KM=0.3 mM for L-serine {ECO:0000269|PubMed:33558761}; CC Vmax=1350 pmol/min/mg enzyme {ECO:0000269|PubMed:20504773}; CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism. CC {ECO:0000269|PubMed:19416851}. CC -!- SUBUNIT: Component of the serine palmitoyltransferase (SPT) complex, CC which is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB CC (PubMed:19132419, PubMed:19416851, PubMed:33558761, PubMed:33558762, CC PubMed:37308477). The heterodimer consisting of SPTLC1 and CC SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or CC SPTSSB subunits determine substrate specificity (PubMed:33558762, CC PubMed:37308477). SPT also interacts with ORMDL proteins, especially CC ORMDL3, which negatively regulate SPT activity in the presence of CC ceramides (PubMed:20182505, PubMed:30700557, PubMed:33558762, CC PubMed:34059824, PubMed:37308477). Forms dimers of heterodimers with CC SPTLC2 (PubMed:33558761, PubMed:33558762). Interacts with RTN4 (isoform CC B) (By similarity). {ECO:0000250|UniProtKB:O35704, CC ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19416851, CC ECO:0000269|PubMed:20182505, ECO:0000269|PubMed:30700557, CC ECO:0000269|PubMed:33558761, ECO:0000269|PubMed:33558762, CC ECO:0000269|PubMed:34059824, ECO:0000269|PubMed:37308477}. CC -!- INTERACTION: CC O15269; Q8N138: ORMDL3; NbExp=6; IntAct=EBI-1044323, EBI-721750; CC O15269; O15270: SPTLC2; NbExp=5; IntAct=EBI-1044323, EBI-766136; CC O15269; Q9NUV7: SPTLC3; NbExp=3; IntAct=EBI-1044323, EBI-11614219; CC O15269; Q969W0: SPTSSA; NbExp=3; IntAct=EBI-1044323, EBI-723396; CC O15269-2; Q86SG2: ANKRD23; NbExp=3; IntAct=EBI-25912901, EBI-5661893; CC O15269-2; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-25912901, EBI-12891828; CC O15269-2; Q8IYM2: SLFN12; NbExp=3; IntAct=EBI-25912901, EBI-2822550; CC O15269-2; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-25912901, EBI-3942425; CC O15269-2; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-25912901, EBI-357085; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:21618344}; Single-pass membrane protein CC {ECO:0000250|UniProtKB:O35704}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O15269-1; Sequence=Displayed; CC Name=2; CC IsoId=O15269-2; Sequence=VSP_043127, VSP_043128; CC -!- TISSUE SPECIFICITY: Widely expressed. Not detected in small intestine. CC {ECO:0000269|PubMed:17023427}. CC -!- INDUCTION: Expression at protein level is highly increased in brains of CC patients with Alzheimer disease. No changes are observed at mRNA level. CC {ECO:0000269|PubMed:21994399}. CC -!- DOMAIN: The transmembrane domain is involved in the interaction with CC ORMDL3. {ECO:0000269|PubMed:33558762}. CC -!- PTM: Phosphorylation at Tyr-164 inhibits activity and promotes cell CC survival. {ECO:0000269|PubMed:23629659}. CC -!- DISEASE: Amyotrophic lateral sclerosis 27, juvenile (ALS27) CC [MIM:620285]: A form of amyotrophic lateral sclerosis, a CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. ALS27 is an autosomal CC dominant form manifesting as toe walking and gait abnormalities in CC early childhood. {ECO:0000269|PubMed:34059824, CC ECO:0000269|PubMed:34459874, ECO:0000269|PubMed:36204986, CC ECO:0000269|PubMed:37308477}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Variants associated with CC ALS27 tend to disrupt the normal homeostatic regulation of serine CC palmitoyltransferase (SPT) by ORMDL proteins, resulting in up-regulated CC SPT activity and elevated levels of canonical SPT products. CC {ECO:0000269|PubMed:34059824}. CC -!- DISEASE: Neuropathy, hereditary sensory and autonomic, 1A (HSAN1A) CC [MIM:162400]: A form of hereditary sensory and autonomic neuropathy, a CC genetically and clinically heterogeneous group of disorders CC characterized by degeneration of dorsal root and autonomic ganglion CC cells, and by prominent sensory abnormalities with a variable degree of CC motor and autonomic dysfunction. The neurological phenotype is often CC complicated by severe infections, osteomyelitis, and amputations. CC HSAN1A is an autosomal dominant axonal form with onset in the second or CC third decades. Initial symptoms are loss of pain, touch, heat, and cold CC sensation over the feet, followed by distal muscle wasting and CC weakness. Loss of pain sensation leads to chronic skin ulcers and CC distal amputations. {ECO:0000269|PubMed:11242114, CC ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702, CC ECO:0000269|PubMed:20504773, ECO:0000269|PubMed:21618344, CC ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:23454272, CC ECO:0000269|PubMed:24247255, ECO:0000269|PubMed:30420926}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. Variants associated with HSAN1A tend to increase serine CC palmitoyltransferase (SPT) usage of alanine or glycine rather than CC serine, resulting in deoxysphingolipid synthesis. Deoxysphingolipids CC cannot be efficiently degraded by the cell machinery and cause cell CC toxicity. {ECO:0000305|PubMed:34059824}. CC -!- SIMILARITY: Belongs to the class-II pyridoxal-phosphate-dependent CC aminotransferase family. {ECO:0000305}. 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; Y08685; CAA69941.1; -; mRNA. DR EMBL; AF286717; AAK29328.1; -; Genomic_DNA. DR EMBL; AF286703; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286704; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286705; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286706; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286707; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286708; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286709; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286710; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286711; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286712; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286713; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286714; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286715; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286716; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AK291546; BAF84235.1; -; mRNA. DR EMBL; AL391219; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL354751; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471089; EAW62804.1; -; Genomic_DNA. DR EMBL; BC007085; AAH07085.1; -; mRNA. DR CCDS; CCDS6692.1; -. [O15269-1] DR CCDS; CCDS6693.1; -. [O15269-2] DR RefSeq; NP_001268232.1; NM_001281303.1. DR RefSeq; NP_006406.1; NM_006415.4. [O15269-1] DR RefSeq; NP_847894.1; NM_178324.3. [O15269-2] DR PDB; 6M4N; EM; 3.80 A; A/E=1-473. DR PDB; 6M4O; EM; 3.40 A; B/S=1-473. DR PDB; 7CQI; EM; 3.20 A; C/S=1-473. DR PDB; 7CQK; EM; 3.30 A; C/S=1-473. DR PDB; 7K0I; EM; 3.30 A; A/D=1-473. DR PDB; 7K0J; EM; 3.10 A; A=1-473. DR PDB; 7K0K; EM; 2.60 A; A=1-473. DR PDB; 7K0L; EM; 3.40 A; A=1-473. DR PDB; 7K0M; EM; 2.90 A; A/E=1-473. DR PDB; 7K0N; EM; 3.10 A; A/E=1-473. DR PDB; 7K0O; EM; 3.10 A; A/E=1-473. DR PDB; 7K0P; EM; 3.10 A; A/E=1-473. DR PDB; 7K0Q; EM; 3.30 A; A=1-473. DR PDB; 7YIU; EM; 2.90 A; A/E=1-473. DR PDB; 7YIY; EM; 2.70 A; A/E=1-473. DR PDB; 7YJ1; EM; 3.10 A; A/E=1-473. DR PDB; 7YJ2; EM; 2.90 A; A/E=1-473. DR PDBsum; 6M4N; -. DR PDBsum; 6M4O; -. DR PDBsum; 7CQI; -. DR PDBsum; 7CQK; -. DR PDBsum; 7K0I; -. DR PDBsum; 7K0J; -. DR PDBsum; 7K0K; -. DR PDBsum; 7K0L; -. DR PDBsum; 7K0M; -. DR PDBsum; 7K0N; -. DR PDBsum; 7K0O; -. DR PDBsum; 7K0P; -. DR PDBsum; 7K0Q; -. DR PDBsum; 7YIU; -. DR PDBsum; 7YIY; -. DR PDBsum; 7YJ1; -. DR PDBsum; 7YJ2; -. DR AlphaFoldDB; O15269; -. DR EMDB; EMD-22598; -. DR EMDB; EMD-22599; -. DR EMDB; EMD-22600; -. DR EMDB; EMD-22601; -. DR EMDB; EMD-22602; -. DR EMDB; EMD-22604; -. DR EMDB; EMD-22605; -. DR EMDB; EMD-22606; -. DR EMDB; EMD-22608; -. DR EMDB; EMD-30079; -. DR EMDB; EMD-30080; -. DR EMDB; EMD-30081; -. DR EMDB; EMD-30082; -. DR EMDB; EMD-30441; -. DR EMDB; EMD-30442; -. DR EMDB; EMD-33864; -. DR EMDB; EMD-33866; -. DR EMDB; EMD-33868; -. DR EMDB; EMD-33869; -. DR SMR; O15269; -. DR BioGRID; 115809; 198. DR ComplexPortal; CPX-6663; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSA variant. DR ComplexPortal; CPX-6664; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSB variant. DR ComplexPortal; CPX-6665; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSA variant. DR ComplexPortal; CPX-6681; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSB variant. DR CORUM; O15269; -. DR DIP; DIP-45626N; -. DR FunCoup; O15269; 3163. DR IntAct; O15269; 137. DR MINT; O15269; -. DR STRING; 9606.ENSP00000262554; -. DR BindingDB; O15269; -. DR ChEMBL; CHEMBL1250343; -. DR DrugBank; DB00114; Pyridoxal phosphate. DR DrugBank; DB00133; Serine. DR GlyGen; O15269; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O15269; -. DR MetOSite; O15269; -. DR PhosphoSitePlus; O15269; -. DR SwissPalm; O15269; -. DR BioMuta; SPTLC1; -. DR jPOST; O15269; -. DR MassIVE; O15269; -. DR PaxDb; 9606-ENSP00000262554; -. DR PeptideAtlas; O15269; -. DR ProteomicsDB; 48557; -. [O15269-1] DR ProteomicsDB; 48558; -. [O15269-2] DR Pumba; O15269; -. DR Antibodypedia; 2269; 395 antibodies from 37 providers. DR DNASU; 10558; -. DR Ensembl; ENST00000262554.7; ENSP00000262554.2; ENSG00000090054.17. [O15269-1] DR Ensembl; ENST00000337841.4; ENSP00000337635.4; ENSG00000090054.17. [O15269-2] DR Ensembl; ENST00000690139.1; ENSP00000510483.1; ENSG00000090054.17. [O15269-2] DR GeneID; 10558; -. DR KEGG; hsa:10558; -. DR MANE-Select; ENST00000262554.7; ENSP00000262554.2; NM_006415.4; NP_006406.1. DR UCSC; uc004arl.3; human. [O15269-1] DR AGR; HGNC:11277; -. DR ClinPGx; PA36106; -. DR CTD; 10558; -. DR DisGeNET; 10558; -. DR GeneCards; SPTLC1; -. DR GeneReviews; SPTLC1; -. DR HGNC; HGNC:11277; SPTLC1. DR HPA; ENSG00000090054; Low tissue specificity. DR MalaCards; SPTLC1; -. DR MIM; 162400; phenotype. DR MIM; 605712; gene. DR MIM; 620285; phenotype. DR OpenTargets; ENSG00000090054; -. DR Orphanet; 36386; Hereditary sensory and autonomic neuropathy type 1. DR Orphanet; 300605; Juvenile amyotrophic lateral sclerosis. DR VEuPathDB; HostDB:ENSG00000090054; -. DR eggNOG; KOG1358; Eukaryota. DR GeneTree; ENSGT00550000074872; -. DR HOGENOM; CLU_015846_0_1_1; -. DR InParanoid; O15269; -. DR OMA; LTKYGCG; -. DR OrthoDB; 3168162at2759; -. DR PAN-GO; O15269; 4 GO annotations based on evolutionary models. DR PhylomeDB; O15269; -. DR BioCyc; MetaCyc:HS01673-MONOMER; -. DR BRENDA; 2.3.1.50; 2681. DR PathwayCommons; O15269; -. DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis. DR SABIO-RK; O15269; -. DR SignaLink; O15269; -. DR SIGNOR; O15269; -. DR UniPathway; UPA00222; -. DR Agora; ENSG00000090054; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 10558; 265 hits in 1179 CRISPR screens. DR ChiTaRS; SPTLC1; human. DR GeneWiki; SPTLC1; -. DR GenomeRNAi; 10558; -. DR Pharos; O15269; Tchem. DR PRO; PR:O15269; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; O15269; protein. DR Bgee; ENSG00000090054; Expressed in esophagus squamous epithelium and 210 other cell types or tissues. DR ExpressionAtlas; O15269; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0017059; C:serine palmitoyltransferase complex; IDA:UniProtKB. DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro. DR GO; GO:0004758; F:serine C-palmitoyltransferase activity; IDA:UniProtKB. DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:MGI. DR GO; GO:1904504; P:positive regulation of lipophagy; IDA:MGI. DR GO; GO:1904649; P:regulation of fat cell apoptotic process; ISS:UniProtKB. DR GO; GO:0046511; P:sphinganine biosynthetic process; IEA:Ensembl. DR GO; GO:0030148; P:sphingolipid biosynthetic process; IDA:MGI. DR GO; GO:0006665; P:sphingolipid metabolic process; TAS:ProtInc. DR GO; GO:0006686; P:sphingomyelin biosynthetic process; IEA:Ensembl. DR GO; GO:0046512; P:sphingosine biosynthetic process; IDA:ComplexPortal. DR FunFam; 3.40.640.10:FF:000049; serine palmitoyltransferase 1 isoform X1; 1. DR Gene3D; 3.90.1150.10; Aspartate Aminotransferase, domain 1; 1. DR Gene3D; 3.40.640.10; Type I PLP-dependent aspartate aminotransferase-like (Major domain); 1. DR InterPro; IPR004839; Aminotransferase_I/II_large. DR InterPro; IPR050087; AON_synthase_class-II. DR InterPro; IPR015424; PyrdxlP-dep_Trfase. DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major. DR InterPro; IPR015422; PyrdxlP-dep_Trfase_small. DR PANTHER; PTHR13693; CLASS II AMINOTRANSFERASE/8-AMINO-7-OXONONANOATE SYNTHASE; 1. DR PANTHER; PTHR13693:SF2; SERINE PALMITOYLTRANSFERASE 1; 1. DR Pfam; PF00155; Aminotran_1_2; 1. DR SUPFAM; SSF53383; PLP-dependent transferases; 1. PE 1: Evidence at protein level; KW 3D-structure; Acyltransferase; Alternative splicing; KW Amyotrophic lateral sclerosis; Disease variant; Endoplasmic reticulum; KW Lipid metabolism; Membrane; Neurodegeneration; Neuropathy; Phosphoprotein; KW Proteomics identification; Pyridoxal phosphate; Reference proteome; KW Sphingolipid metabolism; Transferase; Transmembrane; Transmembrane helix. FT CHAIN 1..473 FT /note="Serine palmitoyltransferase 1" FT /id="PRO_0000163853" FT TOPO_DOM 1..15 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 16..36 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 37..473 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 1..66 FT /note="Interaction with SPTLC2" FT /evidence="ECO:0000269|PubMed:33558762" FT MOD_RES 164 FT /note="Phosphotyrosine; by ABL" FT /evidence="ECO:0000269|PubMed:23629659" FT VAR_SEQ 143 FT /note="D -> E (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043127" FT VAR_SEQ 144..473 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043128" FT VARIANT 20 FT /note="A -> S (in ALS27; the underlying nucleotide FT substitution predominantly results in exon 2 skipping; in FT patient's whole blood sample, only exon 2 deletion was FT observed, but not the missense variant per se; when exon 2 FT deletion variant is expressed in induced pluripotent stem FT cells (iPSC) differentiated into motor neuron-like cells, FT increased production of sphinganine and ceramides is FT observed; when exon 2 deletion variant is transfected into FT HEK293 cells, decreased response to inhibition mediated by FT ORMDL3 or ceramide is observed; dbSNP:rs879254294)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:34459874" FT /id="VAR_088446" FT VARIANT 23 FT /note="Y -> F (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3; dbSNP:rs1554716504)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:37308477" FT /id="VAR_088447" FT VARIANT 38 FT /note="L -> R (in ALS27; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36204986" FT /id="VAR_088448" FT VARIANT 39 FT /note="Missing (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3; dbSNP:rs1197928094)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:34459874" FT /id="VAR_088449" FT VARIANT 40..41 FT /note="Missing (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3)" FT /evidence="ECO:0000269|PubMed:34059824" FT /id="VAR_088450" FT VARIANT 133 FT /note="C -> W (in HSAN1A; inactive in the heterodimeric SPT FT complex; largely reduced canonical activity towards serine; FT contrary to wild-type, uses alanine as substrate leading to FT the formation of 1-deoxysphinganine (1-deoxySa); does not FT affect the interaction with SPTLC2; dbSNP:rs119482082)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:20504773, FT ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:22302274" FT /id="VAR_011392" FT VARIANT 133 FT /note="C -> Y (in HSAN1A; reduced canonical activity FT towards serine; does not affect the interaction with FT SPTLC2; dbSNP:rs119482081)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419" FT /id="VAR_011393" FT VARIANT 144 FT /note="V -> D (in HSAN1A; reduced canonical activity FT towards serine; does not affect the interaction with FT SPTLC2; dbSNP:rs119482083)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:30420926" FT /id="VAR_011394" FT VARIANT 151 FT /note="R -> L (in dbSNP:rs45461899)" FT /evidence="ECO:0000269|PubMed:17060578" FT /id="VAR_037889" FT VARIANT 239 FT /note="R -> W (in a breast cancer sample; somatic mutation; FT dbSNP:rs542876370)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036610" FT VARIANT 310 FT /note="A -> G (found in a patient with HSAN1A; uncertain FT significance; dbSNP:rs768841574)" FT /evidence="ECO:0000269|PubMed:22302274" FT /id="VAR_068476" FT VARIANT 331 FT /note="S -> F (in HSAN1A; severe form with early onset; FT reduced canonical activity towards serine and increased FT production of deoxysphingolipids; no effect on subcellular FT location at the endoplasmic reticulum; dbSNP:rs267607087)" FT /evidence="ECO:0000269|PubMed:19651702, FT ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:24247255" FT /id="VAR_066245" FT VARIANT 331 FT /note="S -> Y (in ALS27 and HSAN1A; reduced canonical FT activity towards serine and increased production of FT deoxysphingolipids; dbSNP:rs267607087)" FT /evidence="ECO:0000269|PubMed:23454272, FT ECO:0000269|PubMed:34459874" FT /id="VAR_073294" FT VARIANT 352 FT /note="A -> V (in HSAN1A; reduced canonical activity FT towards serine and increased production of FT deoxysphingolipids; no effect on subcellular location at FT the endoplasmic reticulum; dbSNP:rs267607088)" FT /evidence="ECO:0000269|PubMed:19651702, FT ECO:0000269|PubMed:21618344" FT /id="VAR_066246" FT VARIANT 387 FT /note="G -> A (does not affect catalytic activity towards FT serine; does not affect the interaction with SPTLC2; FT dbSNP:rs119482084)" FT /evidence="ECO:0000269|PubMed:15037712, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702" FT /id="VAR_037890" FT MUTAGEN 138 FT /note="F->A: Decreased catalytic activity with L-serine and FT palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT MUTAGEN 164 FT /note="Y->F: Increased serine palmitoyltransferase activity FT and sphingolipid content." FT /evidence="ECO:0000269|PubMed:23629659" FT MUTAGEN 337 FT /note="F->A: Strongly decreased catalytic activity with L- FT serine and palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT MUTAGEN 338 FT /note="S->A: Decreased catalytic activity with L-serine and FT palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT HELIX 11..18 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 22..39 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 54..63 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 78..80 FT /evidence="ECO:0007829|PDB:7K0J" FT STRAND 85..87 FT /evidence="ECO:0007829|PDB:7YJ2" FT STRAND 90..97 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 99..103 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 108..110 FT /evidence="ECO:0007829|PDB:7K0J" FT HELIX 115..128 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 136..139 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 143..156 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 159..166 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 169..178 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 184..188 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 193..201 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 205..209 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 214..229 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 232..235 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 240..247 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 249..251 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 258..267 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 270..274 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 276..281 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 282..286 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 289..293 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 297..299 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 303..306 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 309..311 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 316..320 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 322..325 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 326..331 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 333..336 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 343..358 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 362..376 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 377..379 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 383..387 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 395..400 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 405..419 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 420..422 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 433..435 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 436..438 FT /evidence="ECO:0007829|PDB:6M4O" FT STRAND 443..445 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 450..452 FT /evidence="ECO:0007829|PDB:7YIU" FT HELIX 454..468 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 469..471 FT /evidence="ECO:0007829|PDB:7YIY" SQ SEQUENCE 473 AA; 52744 MW; BA9E056A869D2EA2 CRC64; MATATEQWVL VEMVQALYEA PAYHLILEGI LILWIIRLLF SKTYKLQERS DLTVKEKEEL IEEWQPEPLV PPVPKDHPAL NYNIVSGPPS HKTVVNGKEC INFASFNFLG LLDNPRVKAA ALASLKKYGV GTCGPRGFYG TFDVHLDLED RLAKFMKTEE AIIYSYGFAT IASAIPAYSK RGDIVFVDRA ACFAIQKGLQ ASRSDIKLFK HNDMADLERL LKEQEIEDQK NPRKARVTRR FIVVEGLYMN TGTICPLPEL VKLKYKYKAR IFLEESLSFG VLGEHGRGVT EHYGINIDDI DLISANMENA LASIGGFCCG RSFVIDHQRL SGQGYCFSAS LPPLLAAAAI EALNIMEENP GIFAVLKEKC GQIHKALQGI SGLKVVGESL SPAFHLQLEE STGSREQDVR LLQEIVDQCM NRSIALTQAR YLEKEEKCLP PPSIRVVVTV EQTEEELERA ASTIKEVAQA VLL // ID 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 //