ID GRN_HUMAN Reviewed; 593 AA. AC P28799; D3DX55; P23781; P23782; P23783; P23784; Q53HQ8; Q53Y88; Q540U8; AC Q9BWE7; Q9H8S1; Q9UCH0; DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot. DT 11-OCT-2005, sequence version 2. DT 28-JAN-2026, entry version 244. DE RecName: Full=Progranulin {ECO:0000303|PubMed:16862116}; DE Short=PGRN {ECO:0000303|PubMed:16862116}; DE AltName: Full=Acrogranin {ECO:0000250|UniProtKB:P28798}; DE AltName: Full=Epithelin precursor {ECO:0000303|PubMed:1618805}; DE AltName: Full=Glycoprotein of 88 Kda {ECO:0000250|UniProtKB:P28798}; DE Short=GP88; DE Short=Glycoprotein 88; DE AltName: Full=Granulin precursor {ECO:0000303|PubMed:1542665}; DE AltName: Full=PC cell-derived growth factor {ECO:0000250|UniProtKB:P28798}; DE Short=PCDGF {ECO:0000303|Ref.4}; DE AltName: Full=Proepithelin {ECO:0000303|PubMed:12526812, ECO:0000303|PubMed:1618805}; DE Short=PEPI {ECO:0000303|PubMed:12526812}; DE Contains: DE RecName: Full=Paragranulin; DE Contains: DE RecName: Full=Granulin-1; DE AltName: Full=Granulin G; DE Contains: DE RecName: Full=Granulin-2; DE AltName: Full=Granulin F; DE Contains: DE RecName: Full=Granulin-3; DE AltName: Full=Epithelin-2 {ECO:0000250|UniProtKB:P23785}; DE AltName: Full=Granulin B; DE Contains: DE RecName: Full=Granulin-4; DE AltName: Full=Epithelin-1 {ECO:0000250|UniProtKB:P23785}; DE AltName: Full=Granulin A; DE Contains: DE RecName: Full=Granulin-5; DE AltName: Full=Granulin C; DE Contains: DE RecName: Full=Granulin-6; DE AltName: Full=Granulin D; DE Contains: DE RecName: Full=Granulin-7; DE AltName: Full=Granulin E; DE Flags: Precursor; GN Name=GRN {ECO:0000312|HGNC:HGNC:4601}; 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 SEQUENCE REVISION. RX PubMed=1417868; DOI=10.1016/0006-291x(92)92349-3; RA Bhandari V., Bateman A.; RT "Structure and chromosomal location of the human granulin gene."; RL Biochem. Biophys. Res. Commun. 188:57-63(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Kidney; RX PubMed=1618805; DOI=10.1016/s0021-9258(18)42382-4; RA Plowman G.D., Green J.M., Neubauer M.G., Buckley S.D., McDonald V.L., RA Todaro G.J., Shoyab M.; RT "The epithelin precursor encodes two proteins with opposing activities on RT epithelial cell growth."; RL J. Biol. Chem. 267:13073-13078(1992). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Bone marrow; RX PubMed=1542665; DOI=10.1073/pnas.89.5.1715; RA Bhandari V., Palfree R.G.E., Bateman A.; RT "Isolation and sequence of the granulin precursor cDNA from human bone RT marrow reveals tandem cysteine-rich granulin domains."; RL Proc. Natl. Acad. Sci. U.S.A. 89:1715-1719(1992). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Lu R., Tian C., Serrero G.; RT "PCDGF sequence from lambda phage human Jurkat T cell cDNA library RT (Clontech)."; RL Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RA Yu W., Gibbs R.A.; RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Ovary; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Adipose tissue; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Cervix, and Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP PROTEIN SEQUENCE OF 51-62; 122-131; 351-357; 361-367; 435-446 AND 517-526, RP INTERACTION WITH SLPI, PROTEOLYTIC CLEAVAGE, AND FUNCTION. RX PubMed=12526812; DOI=10.1016/s0092-8674(02)01141-8; RA Zhu J., Nathan C., Jin W., Sim D., Ashcroft G.S., Wahl S.M., Lacomis L., RA Erdjument-Bromage H., Tempst P., Wright C.D., Ding A.; RT "Conversion of proepithelin to epithelins: roles of SLPI and elastase in RT host defense and wound repair."; RL Cell 111:867-878(2002). RN [12] RP PROTEIN SEQUENCE OF 206-233; 281-336; 364-396 AND 442-447. RC TISSUE=Leukocyte; RX PubMed=2268320; DOI=10.1016/s0006-291x(05)80908-8; RA Bateman A., Belcourt D.R., Bennett H.P., Lazure C., Solomon S.; RT "Granulins, a novel class of peptide from leukocytes."; RL Biochem. Biophys. Res. Commun. 173:1161-1168(1990). RN [13] RP PROTEIN SEQUENCE OF 281-295. RX PubMed=8471426; DOI=10.1038/bjc.1993.127; RA Kardana A., Bagshawe K.D., Coles B., Read D., Taylor M.; RT "Characterisation of UGP and its relationship with beta-core fragment."; RL Br. J. Cancer 67:686-692(1993). RN [14] RP INVOLVEMENT IN FTD2. RX PubMed=16862116; DOI=10.1038/nature05016; RA Baker M., Mackenzie I.R., Pickering-Brown S.M., Gass J., Rademakers R., RA Lindholm C., Snowden J., Adamson J., Sadovnick A.D., Rollinson S., RA Cannon A., Dwosh E., Neary D., Melquist S., Richardson A., Dickson D., RA Berger Z., Eriksen J., Robinson T., Zehr C., Dickey C.A., Crook R., RA McGowan E., Mann D., Boeve B., Feldman H., Hutton M.; RT "Mutations in progranulin cause tau-negative frontotemporal dementia linked RT to chromosome 17."; RL Nature 442:916-919(2006). RN [15] RP FUNCTION. RX PubMed=18378771; DOI=10.1083/jcb.200712039; RA Van Damme P., Van Hoecke A., Lambrechts D., Vanacker P., Bogaert E., RA van Swieten J., Carmeliet P., Van Den Bosch L., Robberecht W.; RT "Progranulin functions as a neurotrophic factor to regulate neurite RT outgrowth and enhance neuronal survival."; RL J. Cell Biol. 181:37-41(2008). RN [16] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-265. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [17] RP GLYCOSYLATION AT ASN-118; ASN-265; ASN-368 AND ASN-530. RX PubMed=20188224; DOI=10.1016/j.jprot.2010.02.013; RA Songsrirote K., Li Z., Ashford D., Bateman A., Thomas-Oates J.; RT "Development and application of mass spectrometric methods for the analysis RT of progranulin N-glycosylation."; RL J. Proteomics 73:1479-1490(2010). RN [18] RP INTERACTION WITH SORT1, AND SUBCELLULAR LOCATION. RX PubMed=21092856; DOI=10.1016/j.neuron.2010.09.034; RA Hu F., Padukkavidana T., Vaegter C.B., Brady O.A., Zheng Y., RA Mackenzie I.R., Feldman H.H., Nykjaer A., Strittmatter S.M.; RT "Sortilin-mediated endocytosis determines levels of the frontotemporal RT dementia protein, progranulin."; RL Neuron 68:654-667(2010). RN [19] RP INVOLVEMENT IN CLN11. RX PubMed=22608501; DOI=10.1016/j.ajhg.2012.04.021; RA Smith K.R., Damiano J., Franceschetti S., Carpenter S., Canafoglia L., RA Morbin M., Rossi G., Pareyson D., Mole S.E., Staropoli J.F., Sims K.B., RA Lewis J., Lin W.L., Dickson D.W., Dahl H.H., Bahlo M., Berkovic S.F.; RT "Strikingly different clinicopathological phenotypes determined by RT progranulin-mutation dosage."; RL Am. J. Hum. Genet. 90:1102-1107(2012). RN [20] RP SUBUNIT. RX PubMed=23364791; DOI=10.1074/jbc.m112.441949; RA Nguyen A.D., Nguyen T.A., Cenik B., Yu G., Herz J., Walther T.C., RA Davidson W.S., Farese R.V. Jr.; RT "Secreted progranulin is a homodimer and is not a component of high density RT lipoproteins (HDL)."; RL J. Biol. Chem. 288:8627-8635(2013). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [22] RP INTERACTION WITH PSAP, AND SUBCELLULAR LOCATION. RX PubMed=26370502; DOI=10.1083/jcb.201502029; RA Zhou X., Sun L., Bastos de Oliveira F., Qi X., Brown W.J., Smolka M.B., RA Sun Y., Hu F.; RT "Prosaposin facilitates sortilin-independent lysosomal trafficking of RT progranulin."; RL J. Cell Biol. 210:991-1002(2015). RN [23] 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 [24] RP INTERACTION WITH GBA1 AND HSPA1A. RX PubMed=27789271; DOI=10.1016/j.ebiom.2016.10.010; RA Jian J., Tian Q.Y., Hettinghouse A., Zhao S., Liu H., Wei J., Grunig G., RA Zhang W., Setchell K.D.R., Sun Y., Overkleeft H.S., Chan G.L., Liu C.J.; RT "Progranulin Recruits HSP70 to beta-Glucocerebrosidase and Is Therapeutic RT Against Gaucher Disease."; RL EBioMedicine 13:212-224(2016). RN [25] RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION. RX PubMed=28073925; DOI=10.1093/hmg/ddx011; RA Tanaka Y., Suzuki G., Matsuwaki T., Hosokawa M., Serrano G., Beach T.G., RA Yamanouchi K., Hasegawa M., Nishihara M.; RT "Progranulin regulates lysosomal function and biogenesis through RT acidification of lysosomes."; RL Hum. Mol. Genet. 26:969-988(2017). RN [26] RP FUNCTION, AND INTERACTION WITH CTSD. RX PubMed=28453791; DOI=10.1093/hmg/ddx162; RA Beel S., Moisse M., Damme M., De Muynck L., Robberecht W., RA Van Den Bosch L., Saftig P., Van Damme P.; RT "Progranulin functions as a cathepsin D chaperone to stimulate axonal RT outgrowth in vivo."; RL Hum. Mol. Genet. 26:2850-2863(2017). RN [27] RP PROTEOLYTIC CLEAVAGE BY CTSL AND ELANE, IDENTIFICATION BY MASS RP SPECTROMETRY, AND SUBCELLULAR LOCATION. RX PubMed=28743268; DOI=10.1186/s13024-017-0196-6; RA Lee C.W., Stankowski J.N., Chew J., Cook C.N., Lam Y.W., Almeida S., RA Carlomagno Y., Lau K.F., Prudencio M., Gao F.B., Bogyo M., Dickson D.W., RA Petrucelli L.; RT "The lysosomal protein cathepsin L is a progranulin protease."; RL Mol. Neurodegener. 12:55-55(2017). RN [28] RP FUNCTION, INTERACTION WITH PSAP AND SORT1, AND SUBCELLULAR LOCATION. RX PubMed=28541286; DOI=10.1038/ncomms15277; RA Zhou X., Sun L., Bracko O., Choi J.W., Jia Y., Nana A.L., Brady O.A., RA Hernandez J.C.C., Nishimura N., Seeley W.W., Hu F.; RT "Impaired prosaposin lysosomal trafficking in frontotemporal lobar RT degeneration due to progranulin mutations."; RL Nat. Commun. 8:15277-15277(2017). RN [29] RP STRUCTURE BY NMR OF 284-311. RX PubMed=10715107; DOI=10.1021/bi992130u; RA Tolkatchev D., Ng A., Vranken W., Ni F.; RT "Design and solution structure of a well-folded stack of two beta-hairpins RT based on the amino-terminal fragment of human granulin A."; RL Biochemistry 39:2878-2886(2000). RN [30] RP STRUCTURE BY NMR OF 123-179; 281-337 AND 364-417, AND DISULFIDE BONDS. RX PubMed=18359860; DOI=10.1110/ps.073295308; RA Tolkatchev D., Malik S., Vinogradova A., Wang P., Chen Z., Xu P., RA Bennett H.P., Bateman A., Ni F.; RT "Structure dissection of human progranulin identifies well-folded RT granulin/epithelin modules with unique functional activities."; RL Protein Sci. 17:711-724(2008). RN [31] RP VARIANT FTD2 ASP-9. RX PubMed=16983685; DOI=10.1002/ana.20963; RA Mukherjee O., Pastor P., Cairns N.J., Chakraverty S., Kauwe J.S.K., RA Shears S., Behrens M.I., Budde J., Hinrichs A.L., Norton J., Levitch D., RA Taylor-Reinwald L., Gitcho M., Tu P.-H., Tenenholz Grinberg L., RA Liscic R.M., Armendariz J., Morris J.C., Goate A.M.; RT "HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin- RT positive, tau-negative inclusions caused by a missense mutation in the RT signal peptide of progranulin."; RL Ann. Neurol. 60:314-322(2006). RN [32] RP CHARACTERIZATION OF VARIANT FTD2 ASP-9. RX PubMed=18183624; DOI=10.1002/humu.20681; RA Mukherjee O., Wang J., Gitcho M., Chakraverty S., Taylor-Reinwald L., RA Shears S., Kauwe J.S.K., Norton J., Levitch D., Bigio E.H., Hatanpaa K.J., RA White C.L., Morris J.C., Cairns N.J., Goate A.; RT "Molecular characterization of novel progranulin (GRN) mutations in RT frontotemporal dementia."; RL Hum. Mutat. 29:512-521(2008). RN [33] RP VARIANTS TRP-19; TRP-55; THR-69; ASN-119 DEL; TYR-120; MET-182; SER-221; RP LEU-275; ASN-376; LEU-398; GLN-433; ALA-515 AND HIS-564. RX PubMed=20020531; DOI=10.1002/humu.21152; RA Guerreiro R.J., Washecka N., Hardy J., Singleton A.; RT "A thorough assessment of benign genetic variability in GRN and MAPT."; RL Hum. Mutat. 31:E1126-E1140(2010). CC -!- FUNCTION: Secreted protein that acts as a key regulator of lysosomal CC function and as a growth factor involved in inflammation, wound healing CC and cell proliferation (PubMed:12526812, PubMed:18378771, CC PubMed:28073925, PubMed:28453791, PubMed:28541286). Regulates protein CC trafficking to lysosomes, and also the activity of lysosomal enzymes CC (PubMed:28453791, PubMed:28541286). Also facilitates the acidification CC of lysosomes, causing degradation of mature CTSD by CTSB CC (PubMed:28073925). In addition, functions as a wound-related growth CC factor that acts directly on dermal fibroblasts and endothelial cells CC to promote division, migration and the formation of capillary-like CC tubule structures (By similarity). Also promotes epithelial cell CC proliferation by blocking TNF-mediated neutrophil activation preventing CC release of oxidants and proteases (PubMed:12526812). Moreover, CC modulates inflammation in neurons by preserving neurons survival, CC axonal outgrowth and neuronal integrity (PubMed:18378771). CC {ECO:0000250|UniProtKB:P28798, ECO:0000269|PubMed:12526812, CC ECO:0000269|PubMed:18378771, ECO:0000269|PubMed:28073925, CC ECO:0000269|PubMed:28453791, ECO:0000269|PubMed:28541286}. CC -!- FUNCTION: [Granulin-4]: Promotes proliferation of the epithelial cell CC line A431 in culture. CC -!- FUNCTION: [Granulin-3]: Inhibits epithelial cell proliferation and CC induces epithelial cells to secrete IL-8. CC {ECO:0000269|PubMed:12526812}. CC -!- FUNCTION: [Granulin-7]: Stabilizes CTSD through interaction with CTSD CC leading to maintain its aspartic-type peptidase activity. CC {ECO:0000269|PubMed:28453791}. CC -!- SUBUNIT: Progranulin is secreted as a homodimer (PubMed:23364791). CC Interacts with SLPI; interaction protects progranulin from proteolysis CC (PubMed:12526812). Interacts (via region corresponding to granulin-7 CC peptide) with CTSD; stabilizes CTSD and increases its proteolytic CC activity (PubMed:28453791). Interacts (via region corresponding to CC granulin-7 peptide) with SORT1; this interaction mediates endocytosis CC and lysosome delivery of progranulin; interaction occurs at the CC neuronal cell surface in a stressed nervous system (PubMed:21092856). CC Interacts with PSAP; facilitates lysosomal delivery of progranulin from CC the extracellular space and the biosynthetic pathway (PubMed:26370502). CC Forms a complex with PSAP and M6PR; PSAP bridges the binding between CC progranulin and M6PR (PubMed:26370502). Forms a complex with PSAP and CC SORT1; progranulin bridges the interaction between PSAP and SORT1; CC facilitates lysosomal targeting of PSAP via SORT1; interaction enhances CC PSAP uptake in primary cortical neurons (PubMed:28541286). Interacts CC (via regions corresponding to granulin-2 and granulin-7 peptides) with CC GBA1; this interaction prevents aggregation of GBA1-SCARB2 complex via CC interaction with HSPA1A upon stress (PubMed:27789271). Interacts (via CC region corresponding to granulin-7 peptide) with HSPA1A; mediates CC recruitment of HSPA1A to GBA1 and prevents GBA1 aggregation in response CC to stress (PubMed:27789271). {ECO:0000269|PubMed:12526812, CC ECO:0000269|PubMed:21092856, ECO:0000269|PubMed:23364791, CC ECO:0000269|PubMed:26370502, ECO:0000269|PubMed:27789271, CC ECO:0000269|PubMed:28453791, ECO:0000269|PubMed:28541286}. CC -!- INTERACTION: CC P28799; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-747754, EBI-10173507; CC P28799; Q9UIJ7: AK3; NbExp=3; IntAct=EBI-747754, EBI-3916527; CC P28799; Q9NYG5: ANAPC11; NbExp=3; IntAct=EBI-747754, EBI-2130187; CC P28799; Q8N6T3: ARFGAP1; NbExp=3; IntAct=EBI-747754, EBI-716933; CC P28799; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-747754, EBI-10694449; CC P28799; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-747754, EBI-14199987; CC P28799; Q96DX5-3: ASB9; NbExp=3; IntAct=EBI-747754, EBI-25843552; CC P28799; Q6XD76: ASCL4; NbExp=3; IntAct=EBI-747754, EBI-10254793; CC P28799; Q96FT7-4: ASIC4; NbExp=3; IntAct=EBI-747754, EBI-9089489; CC P28799; Q8IXM2: BACC1; NbExp=3; IntAct=EBI-747754, EBI-4280811; CC P28799; P46379-2: BAG6; NbExp=3; IntAct=EBI-747754, EBI-10988864; CC P28799; Q16611: BAK1; NbExp=3; IntAct=EBI-747754, EBI-519866; CC P28799; Q14457: BECN1; NbExp=3; IntAct=EBI-747754, EBI-949378; CC P28799; Q96LC9: BMF; NbExp=3; IntAct=EBI-747754, EBI-3919268; CC P28799; Q9GZL8: BPESC1; NbExp=3; IntAct=EBI-747754, EBI-25861458; CC P28799; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-747754, EBI-2837444; CC P28799; Q9Y297: BTRC; NbExp=3; IntAct=EBI-747754, EBI-307461; CC P28799; Q8TAB5: C1orf216; NbExp=3; IntAct=EBI-747754, EBI-747505; CC P28799; Q6P5X5: C22orf39; NbExp=3; IntAct=EBI-747754, EBI-7317823; CC P28799; Q6P5X5-2: C22orf39; NbExp=3; IntAct=EBI-747754, EBI-10692329; CC P28799; Q53FE4: C4orf17; NbExp=3; IntAct=EBI-747754, EBI-715110; CC P28799; O00555: CACNA1A; NbExp=2; IntAct=EBI-747754, EBI-766279; CC P28799; Q96NX5: CAMK1G; NbExp=3; IntAct=EBI-747754, EBI-3920838; CC P28799; O75808: CAPN15; NbExp=3; IntAct=EBI-747754, EBI-6149008; CC P28799; Q8N5R6: CCDC33; NbExp=3; IntAct=EBI-747754, EBI-740841; CC P28799; P50750-2: CDK9; NbExp=3; IntAct=EBI-747754, EBI-12029902; CC P28799; O14646-2: CHD1; NbExp=3; IntAct=EBI-747754, EBI-10961487; CC P28799; Q9BRJ6: CHLSN; NbExp=3; IntAct=EBI-747754, EBI-751612; CC P28799; Q9Y3D0: CIAO2B; NbExp=3; IntAct=EBI-747754, EBI-744045; CC P28799; Q99967: CITED2; NbExp=3; IntAct=EBI-747754, EBI-937732; CC P28799; Q9Y240: CLEC11A; NbExp=3; IntAct=EBI-747754, EBI-3957044; CC P28799; Q9H2X3: CLEC4M; NbExp=2; IntAct=EBI-747754, EBI-1391211; CC P28799; Q96DZ5: CLIP3; NbExp=3; IntAct=EBI-747754, EBI-12823145; CC P28799; Q16740: CLPP; NbExp=3; IntAct=EBI-747754, EBI-1056029; CC P28799; Q9BT09: CNPY3; NbExp=3; IntAct=EBI-747754, EBI-2835965; CC P28799; Q6PJW8-3: CNST; NbExp=3; IntAct=EBI-747754, EBI-25836090; CC P28799; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-747754, EBI-350590; CC P28799; Q9UGL9: CRCT1; NbExp=3; IntAct=EBI-747754, EBI-713677; CC P28799; Q02930-3: CREB5; NbExp=3; IntAct=EBI-747754, EBI-10192698; CC P28799; Q49AN0: CRY2; NbExp=3; IntAct=EBI-747754, EBI-2212355; CC P28799; P01040: CSTA; NbExp=3; IntAct=EBI-747754, EBI-724303; CC P28799; P07339: CTSD; NbExp=4; IntAct=EBI-747754, EBI-2115097; CC P28799; P42830: CXCL5; NbExp=3; IntAct=EBI-747754, EBI-12175919; CC P28799; Q8TB03: CXorf38; NbExp=3; IntAct=EBI-747754, EBI-12024320; CC P28799; P00167: CYB5A; NbExp=3; IntAct=EBI-747754, EBI-1047284; CC P28799; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-747754, EBI-3867333; CC P28799; Q16643: DBN1; NbExp=5; IntAct=EBI-747754, EBI-351394; CC P28799; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-747754, EBI-25842815; CC P28799; Q9P1A6-3: DLGAP2; NbExp=3; IntAct=EBI-747754, EBI-12019838; CC P28799; Q07687: DLX2; NbExp=3; IntAct=EBI-747754, EBI-3908234; CC P28799; Q9NQL9: DMRT3; NbExp=3; IntAct=EBI-747754, EBI-9679045; CC P28799; P49184: DNASE1L1; NbExp=3; IntAct=EBI-747754, EBI-20894690; CC P28799; Q16610: ECM1; NbExp=3; IntAct=EBI-747754, EBI-947964; CC P28799; O75530-2: EED; NbExp=3; IntAct=EBI-747754, EBI-11132357; CC P28799; O60841: EIF5B; NbExp=3; IntAct=EBI-747754, EBI-928530; CC P28799; Q6UXG2-3: ELAPOR1; NbExp=3; IntAct=EBI-747754, EBI-12920100; CC P28799; Q8TE68-3: EPS8L1; NbExp=3; IntAct=EBI-747754, EBI-21574901; CC P28799; Q9H6S3: EPS8L2; NbExp=3; IntAct=EBI-747754, EBI-3940939; CC P28799; O15540: FABP7; NbExp=3; IntAct=EBI-747754, EBI-10697159; CC P28799; Q9UNN5: FAF1; NbExp=3; IntAct=EBI-747754, EBI-718246; CC P28799; Q6SJ93: FAM111B; NbExp=3; IntAct=EBI-747754, EBI-6309082; CC P28799; Q96AQ9: FAM131C; NbExp=4; IntAct=EBI-747754, EBI-741921; CC P28799; Q5HYJ3-3: FAM76B; NbExp=6; IntAct=EBI-747754, EBI-11956087; CC P28799; Q17RN3: FAM98C; NbExp=3; IntAct=EBI-747754, EBI-5461838; CC P28799; Q8IZU1: FAM9A; NbExp=3; IntAct=EBI-747754, EBI-8468186; CC P28799; Q9NW38: FANCL; NbExp=3; IntAct=EBI-747754, EBI-2339898; CC P28799; Q53R41: FASTKD1; NbExp=3; IntAct=EBI-747754, EBI-3957005; CC P28799; Q8NFZ0: FBH1; NbExp=3; IntAct=EBI-747754, EBI-724767; CC P28799; Q9UBX5: FBLN5; NbExp=3; IntAct=EBI-747754, EBI-947897; CC P28799; P15976-2: GATA1; NbExp=3; IntAct=EBI-747754, EBI-9090198; CC P28799; P23769-2: GATA2; NbExp=3; IntAct=EBI-747754, EBI-21856389; CC P28799; Q9NXC2: GFOD1; NbExp=3; IntAct=EBI-747754, EBI-8799578; CC P28799; P10075: GLI4; NbExp=3; IntAct=EBI-747754, EBI-14061927; CC P28799; O76003: GLRX3; NbExp=9; IntAct=EBI-747754, EBI-374781; CC P28799; Q9Y223-2: GNE; NbExp=6; IntAct=EBI-747754, EBI-11975289; CC P28799; Q9HBQ8: GOLGA2P5; NbExp=3; IntAct=EBI-747754, EBI-22000587; CC P28799; Q7Z602: GPR141; NbExp=3; IntAct=EBI-747754, EBI-21649723; CC P28799; Q9Y4H4: GPSM3; NbExp=3; IntAct=EBI-747754, EBI-347538; CC P28799; O75409: H2AP; NbExp=3; IntAct=EBI-747754, EBI-6447217; CC P28799; Q6NXT2: H3-5; NbExp=3; IntAct=EBI-747754, EBI-2868501; CC P28799; P68431: H3C12; NbExp=3; IntAct=EBI-747754, EBI-79722; CC P28799; A8K0U2: hCG_2001421; NbExp=3; IntAct=EBI-747754, EBI-25843825; CC P28799; Q03014: HHEX; NbExp=3; IntAct=EBI-747754, EBI-747421; CC P28799; P49639: HOXA1; NbExp=18; IntAct=EBI-747754, EBI-740785; CC P28799; P09017: HOXC4; NbExp=3; IntAct=EBI-747754, EBI-3923226; CC P28799; P98160: HSPG2; NbExp=3; IntAct=EBI-747754, EBI-947664; CC P28799; P22692: IGFBP4; NbExp=3; IntAct=EBI-747754, EBI-2831948; CC P28799; Q14005-2: IL16; NbExp=3; IntAct=EBI-747754, EBI-17178971; CC P28799; Q9NXX0: ILF3; NbExp=3; IntAct=EBI-747754, EBI-743980; CC P28799; Q9UNL4: ING4; NbExp=3; IntAct=EBI-747754, EBI-2866661; CC P28799; Q8IXL9: IQCF2; NbExp=3; IntAct=EBI-747754, EBI-10238842; CC P28799; Q9Y6F6-3: IRAG1; NbExp=3; IntAct=EBI-747754, EBI-25840037; CC P28799; Q86U28: ISCA2; NbExp=3; IntAct=EBI-747754, EBI-10258659; CC P28799; Q14145: KEAP1; NbExp=3; IntAct=EBI-747754, EBI-751001; CC P28799; Q12756: KIF1A; NbExp=3; IntAct=EBI-747754, EBI-2679809; CC P28799; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-747754, EBI-2796400; CC P28799; P57682: KLF3; NbExp=4; IntAct=EBI-747754, EBI-8472267; CC P28799; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-747754, EBI-714379; CC P28799; O76011: KRT34; NbExp=3; IntAct=EBI-747754, EBI-1047093; CC P28799; Q07627: KRTAP1-1; NbExp=3; IntAct=EBI-747754, EBI-11959885; CC P28799; Q9BYS1: KRTAP1-5; NbExp=3; IntAct=EBI-747754, EBI-11741292; CC P28799; P60409: KRTAP10-7; NbExp=3; IntAct=EBI-747754, EBI-10172290; CC P28799; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-747754, EBI-10171774; CC P28799; Q8IUC1: KRTAP11-1; NbExp=3; IntAct=EBI-747754, EBI-1052037; CC P28799; P59990: KRTAP12-1; NbExp=3; IntAct=EBI-747754, EBI-10210845; CC P28799; Q52LG2: KRTAP13-2; NbExp=3; IntAct=EBI-747754, EBI-11953846; CC P28799; Q3SY46: KRTAP13-3; NbExp=3; IntAct=EBI-747754, EBI-10241252; CC P28799; Q3LI76: KRTAP15-1; NbExp=3; IntAct=EBI-747754, EBI-11992140; CC P28799; Q3SYF9: KRTAP19-7; NbExp=3; IntAct=EBI-747754, EBI-10241353; CC P28799; Q6PEX3: KRTAP26-1; NbExp=8; IntAct=EBI-747754, EBI-3957672; CC P28799; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-747754, EBI-3958099; CC P28799; Q3LI64: KRTAP6-1; NbExp=3; IntAct=EBI-747754, EBI-12111050; CC P28799; Q3LI66: KRTAP6-2; NbExp=3; IntAct=EBI-747754, EBI-11962084; CC P28799; Q8IUC2: KRTAP8-1; NbExp=3; IntAct=EBI-747754, EBI-10261141; CC P28799; Q14847-2: LASP1; NbExp=3; IntAct=EBI-747754, EBI-9088686; CC P28799; O95447: LCA5L; NbExp=3; IntAct=EBI-747754, EBI-8473670; CC P28799; Q5T7P2: LCE1A; NbExp=3; IntAct=EBI-747754, EBI-11962058; CC P28799; Q5T7P3: LCE1B; NbExp=3; IntAct=EBI-747754, EBI-10245913; CC P28799; Q5T752: LCE1D; NbExp=3; IntAct=EBI-747754, EBI-11741311; CC P28799; Q5T753: LCE1E; NbExp=3; IntAct=EBI-747754, EBI-11955335; CC P28799; Q5TA79: LCE2A; NbExp=3; IntAct=EBI-747754, EBI-10246607; CC P28799; O14633: LCE2B; NbExp=3; IntAct=EBI-747754, EBI-11478468; CC P28799; Q5TA82: LCE2D; NbExp=3; IntAct=EBI-747754, EBI-10246750; CC P28799; Q5T5A8: LCE3C; NbExp=3; IntAct=EBI-747754, EBI-10245291; CC P28799; Q5T5B0: LCE3E; NbExp=3; IntAct=EBI-747754, EBI-10245456; CC P28799; Q5TA78: LCE4A; NbExp=4; IntAct=EBI-747754, EBI-10246358; CC P28799; Q9UPM6: LHX6; NbExp=3; IntAct=EBI-747754, EBI-10258746; CC P28799; Q68G74: LHX8; NbExp=3; IntAct=EBI-747754, EBI-8474075; CC P28799; A2RU56: LOC401296; NbExp=3; IntAct=EBI-747754, EBI-9088215; CC P28799; Q96JB6: LOXL4; NbExp=3; IntAct=EBI-747754, EBI-749562; CC P28799; Q14693: LPIN1; NbExp=3; IntAct=EBI-747754, EBI-5278370; CC P28799; Q6Q4G3-4: LVRN; NbExp=3; IntAct=EBI-747754, EBI-25862057; CC P28799; Q9UDY8-2: MALT1; NbExp=3; IntAct=EBI-747754, EBI-12056869; CC P28799; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-747754, EBI-373144; CC P28799; Q99683: MAP3K5; NbExp=3; IntAct=EBI-747754, EBI-476263; CC P28799; P61244-4: MAX; NbExp=3; IntAct=EBI-747754, EBI-25848049; CC P28799; O95243-2: MBD4; NbExp=3; IntAct=EBI-747754, EBI-6448717; CC P28799; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-747754, EBI-16439278; CC P28799; P41218: MNDA; NbExp=3; IntAct=EBI-747754, EBI-2829677; CC P28799; Q86VF5-3: MOGAT3; NbExp=3; IntAct=EBI-747754, EBI-25840143; CC P28799; Q9Y2R5: MRPS17; NbExp=3; IntAct=EBI-747754, EBI-1046443; CC P28799; O43196-4: MSH5; NbExp=3; IntAct=EBI-747754, EBI-25860238; CC P28799; Q8IXL7-2: MSRB3; NbExp=3; IntAct=EBI-747754, EBI-10699187; CC P28799; Q96A32: MYL11; NbExp=3; IntAct=EBI-747754, EBI-1390771; CC P28799; Q9NPC7: MYNN; NbExp=3; IntAct=EBI-747754, EBI-3446748; CC P28799; O15069: NACAD; NbExp=3; IntAct=EBI-747754, EBI-7108375; CC P28799; Q99608: NDN; NbExp=3; IntAct=EBI-747754, EBI-718177; CC P28799; Q9P032: NDUFAF4; NbExp=3; IntAct=EBI-747754, EBI-2606839; CC P28799; Q12986: NFX1; NbExp=3; IntAct=EBI-747754, EBI-2130062; CC P28799; Q8N5V2: NGEF; NbExp=3; IntAct=EBI-747754, EBI-718372; CC P28799; Q9UBE8: NLK; NbExp=7; IntAct=EBI-747754, EBI-366978; CC P28799; Q96AM0: NLRP1; NbExp=3; IntAct=EBI-747754, EBI-25860999; CC P28799; Q6IAD4: NOTCH1; NbExp=3; IntAct=EBI-747754, EBI-25860267; CC P28799; Q14995: NR1D2; NbExp=3; IntAct=EBI-747754, EBI-6144053; CC P28799; Q7Z417: NUFIP2; NbExp=10; IntAct=EBI-747754, EBI-1210753; CC P28799; O43482: OIP5; NbExp=3; IntAct=EBI-747754, EBI-536879; CC P28799; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-747754, EBI-1058491; CC P28799; P32242: OTX1; NbExp=10; IntAct=EBI-747754, EBI-740446; CC P28799; Q15077: P2RY6; NbExp=3; IntAct=EBI-747754, EBI-10235794; CC P28799; P07237: P4HB; NbExp=4; IntAct=EBI-747754, EBI-395883; CC P28799; O75781-2: PALM; NbExp=3; IntAct=EBI-747754, EBI-16399860; CC P28799; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-747754, EBI-17159452; CC P28799; Q86SE9-2: PCGF5; NbExp=3; IntAct=EBI-747754, EBI-25861637; CC P28799; O15534: PER1; NbExp=3; IntAct=EBI-747754, EBI-2557276; CC P28799; Q96FX8: PERP; NbExp=3; IntAct=EBI-747754, EBI-17183069; CC P28799; Q96LB9: PGLYRP3; NbExp=3; IntAct=EBI-747754, EBI-12339509; CC P28799; Q9BWX1: PHF7; NbExp=3; IntAct=EBI-747754, EBI-4307517; CC P28799; A2BDE7: PHLDA1; NbExp=3; IntAct=EBI-747754, EBI-14084211; CC P28799; O75925: PIAS1; NbExp=3; IntAct=EBI-747754, EBI-629434; CC P28799; Q9BZM1: PLA2G12A; NbExp=3; IntAct=EBI-747754, EBI-3916751; CC P28799; Q58EX7-2: PLEKHG4; NbExp=3; IntAct=EBI-747754, EBI-21503705; CC P28799; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-747754, EBI-12891828; CC P28799; Q9Y342: PLLP; NbExp=3; IntAct=EBI-747754, EBI-3919291; CC P28799; Q8TBJ4: PLPPR1; NbExp=3; IntAct=EBI-747754, EBI-18063495; CC P28799; Q9H1D9: POLR3F; NbExp=3; IntAct=EBI-747754, EBI-710067; CC P28799; Q12837: POU4F2; NbExp=6; IntAct=EBI-747754, EBI-17236143; CC P28799; P09565: PP9974; NbExp=3; IntAct=EBI-747754, EBI-10196507; CC P28799; P54646: PRKAA2; NbExp=3; IntAct=EBI-747754, EBI-1383852; CC P28799; O43741: PRKAB2; NbExp=4; IntAct=EBI-747754, EBI-1053424; CC P28799; P11908: PRPS2; NbExp=3; IntAct=EBI-747754, EBI-4290895; CC P28799; P07602: PSAP; NbExp=6; IntAct=EBI-747754, EBI-716699; CC P28799; P40306: PSMB10; NbExp=3; IntAct=EBI-747754, EBI-603329; CC P28799; P28062-2: PSMB8; NbExp=3; IntAct=EBI-747754, EBI-372312; CC P28799; Q8TBK9: PTMA; NbExp=3; IntAct=EBI-747754, EBI-1056327; CC P28799; Q8WUK0: PTPMT1; NbExp=3; IntAct=EBI-747754, EBI-7199479; CC P28799; Q14671: PUM1; NbExp=3; IntAct=EBI-747754, EBI-948453; CC P28799; Q7Z7K5: PXN; NbExp=3; IntAct=EBI-747754, EBI-25841978; CC P28799; P47897: QARS1; NbExp=3; IntAct=EBI-747754, EBI-347462; CC P28799; Q96PK6: RBM14; NbExp=3; IntAct=EBI-747754, EBI-954272; CC P28799; Q96PM5-4: RCHY1; NbExp=3; IntAct=EBI-747754, EBI-21252376; CC P28799; Q8TCX5: RHPN1; NbExp=3; IntAct=EBI-747754, EBI-746325; CC P28799; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-747754, EBI-25829984; CC P28799; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-747754, EBI-749039; CC P28799; Q9UBS8: RNF14; NbExp=3; IntAct=EBI-747754, EBI-2130308; CC P28799; Q9H0X6: RNF208; NbExp=3; IntAct=EBI-747754, EBI-751555; CC P28799; P62244: RPS15A; NbExp=3; IntAct=EBI-747754, EBI-347895; CC P28799; Q66K80: RUSC1-AS1; NbExp=3; IntAct=EBI-747754, EBI-10248967; CC P28799; Q8N488: RYBP; NbExp=3; IntAct=EBI-747754, EBI-752324; CC P28799; Q969E2: SCAMP4; NbExp=3; IntAct=EBI-747754, EBI-4403649; CC P28799; P34741: SDC2; NbExp=3; IntAct=EBI-747754, EBI-1172957; CC P28799; P60896: SEM1; NbExp=3; IntAct=EBI-747754, EBI-79819; CC P28799; Q9NTN9-3: SEMA4G; NbExp=3; IntAct=EBI-747754, EBI-9089805; CC P28799; Q14141: SEPTIN6; NbExp=3; IntAct=EBI-747754, EBI-745901; CC P28799; Q13530: SERINC3; NbExp=3; IntAct=EBI-747754, EBI-1045571; CC P28799; O43765: SGTA; NbExp=7; IntAct=EBI-747754, EBI-347996; CC P28799; Q9NUL5-3: SHFL; NbExp=3; IntAct=EBI-747754, EBI-22000547; CC P28799; O60902-3: SHOX2; NbExp=3; IntAct=EBI-747754, EBI-9092164; CC P28799; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-747754, EBI-358545; CC P28799; O15198-2: SMAD9; NbExp=3; IntAct=EBI-747754, EBI-12273450; CC P28799; P49901: SMCP; NbExp=3; IntAct=EBI-747754, EBI-750494; CC P28799; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-747754, EBI-9845742; CC P28799; Q96DI7: SNRNP40; NbExp=3; IntAct=EBI-747754, EBI-538492; CC P28799; Q99523: SORT1; NbExp=3; IntAct=EBI-747754, EBI-1057058; CC P28799; Q6RVD6: SPATA8; NbExp=3; IntAct=EBI-747754, EBI-8635958; CC P28799; P20155: SPINK2; NbExp=3; IntAct=EBI-747754, EBI-10200479; CC P28799; Q8N865: SPMIP4; NbExp=3; IntAct=EBI-747754, EBI-10174456; CC P28799; Q7Z698: SPRED2; NbExp=3; IntAct=EBI-747754, EBI-7082156; CC P28799; O43597: SPRY2; NbExp=3; IntAct=EBI-747754, EBI-742487; CC P28799; Q9C004: SPRY4; NbExp=3; IntAct=EBI-747754, EBI-354861; CC P28799; Q6PJ21: SPSB3; NbExp=3; IntAct=EBI-747754, EBI-3937206; CC P28799; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-747754, EBI-357085; CC P28799; Q8NBJ7: SUMF2; NbExp=3; IntAct=EBI-747754, EBI-723091; CC P28799; Q17RD7-3: SYT16; NbExp=3; IntAct=EBI-747754, EBI-25861603; CC P28799; Q5VWN6: TASOR2; NbExp=3; IntAct=EBI-747754, EBI-745958; CC P28799; P17735: TAT; NbExp=3; IntAct=EBI-747754, EBI-12046643; CC P28799; Q86VP1: TAX1BP1; NbExp=3; IntAct=EBI-747754, EBI-529518; CC P28799; P62380: TBPL1; NbExp=3; IntAct=EBI-747754, EBI-716225; CC P28799; Q8IYN2: TCEAL8; NbExp=3; IntAct=EBI-747754, EBI-2116184; CC P28799; Q13569: TDG; NbExp=3; IntAct=EBI-747754, EBI-348333; CC P28799; P28347-2: TEAD1; NbExp=3; IntAct=EBI-747754, EBI-12151837; CC P28799; Q8NA77: TEX19; NbExp=3; IntAct=EBI-747754, EBI-13323487; CC P28799; O60830: TIMM17B; NbExp=3; IntAct=EBI-747754, EBI-2372529; CC P28799; Q04724: TLE1; NbExp=3; IntAct=EBI-747754, EBI-711424; CC P28799; Q08117-2: TLE5; NbExp=3; IntAct=EBI-747754, EBI-11741437; CC P28799; Q8N0U2: TMEM61; NbExp=3; IntAct=EBI-747754, EBI-25830583; CC P28799; Q53NU3: tmp_locus_54; NbExp=3; IntAct=EBI-747754, EBI-10242677; CC P28799; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-747754, EBI-25831574; CC P28799; P19438: TNFRSF1A; NbExp=4; IntAct=EBI-747754, EBI-299451; CC P28799; P20333: TNFRSF1B; NbExp=5; IntAct=EBI-747754, EBI-358983; CC P28799; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-747754, EBI-17716262; CC P28799; Q9BVS5: TRMT61B; NbExp=3; IntAct=EBI-747754, EBI-3197877; CC P28799; Q96Q11-3: TRNT1; NbExp=3; IntAct=EBI-747754, EBI-25861172; CC P28799; Q9Y3Q8: TSC22D4; NbExp=3; IntAct=EBI-747754, EBI-739485; CC P28799; O14817: TSPAN4; NbExp=3; IntAct=EBI-747754, EBI-8652667; CC P28799; Q9Y5U2: TSSC4; NbExp=3; IntAct=EBI-747754, EBI-717229; CC P28799; Q99614: TTC1; NbExp=3; IntAct=EBI-747754, EBI-742074; CC P28799; Q5W5X9-3: TTC23; NbExp=3; IntAct=EBI-747754, EBI-9090990; CC P28799; Q5VYS8-5: TUT7; NbExp=3; IntAct=EBI-747754, EBI-9088812; CC P28799; Q9BRU9: UTP23; NbExp=3; IntAct=EBI-747754, EBI-5457544; CC P28799; Q6EMK4: VASN; NbExp=3; IntAct=EBI-747754, EBI-10249550; CC P28799; P45880: VDAC2; NbExp=3; IntAct=EBI-747754, EBI-354022; CC P28799; Q8NEZ2: VPS37A; NbExp=3; IntAct=EBI-747754, EBI-2850578; CC P28799; Q8NEZ2-2: VPS37A; NbExp=3; IntAct=EBI-747754, EBI-10270911; CC P28799; P58304: VSX2; NbExp=3; IntAct=EBI-747754, EBI-6427899; CC P28799; Q9NZC7-5: WWOX; NbExp=3; IntAct=EBI-747754, EBI-12040603; CC P28799; Q8IY57-5: YAF2; NbExp=3; IntAct=EBI-747754, EBI-12111538; CC P28799; O95070: YIF1A; NbExp=3; IntAct=EBI-747754, EBI-2799703; CC P28799; P25490: YY1; NbExp=4; IntAct=EBI-747754, EBI-765538; CC P28799; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-747754, EBI-25842419; CC P28799; Q9NTW7: ZFP64; NbExp=3; IntAct=EBI-747754, EBI-711679; CC P28799; Q15776: ZKSCAN8; NbExp=3; IntAct=EBI-747754, EBI-2602314; CC P28799; Q15973: ZNF124; NbExp=3; IntAct=EBI-747754, EBI-2555767; CC P28799; P52744: ZNF138; NbExp=3; IntAct=EBI-747754, EBI-10746567; CC P28799; Q9UJW8-4: ZNF180; NbExp=3; IntAct=EBI-747754, EBI-12055755; CC P28799; Q16600: ZNF239; NbExp=3; IntAct=EBI-747754, EBI-8787052; CC P28799; Q8WUU4: ZNF296; NbExp=3; IntAct=EBI-747754, EBI-8834821; CC P28799; Q8N895: ZNF366; NbExp=3; IntAct=EBI-747754, EBI-2813661; CC P28799; Q8N0Y2-2: ZNF444; NbExp=3; IntAct=EBI-747754, EBI-12010736; CC P28799; Q96MN9-2: ZNF488; NbExp=3; IntAct=EBI-747754, EBI-25831733; CC P28799; Q6ZNH5: ZNF497; NbExp=3; IntAct=EBI-747754, EBI-10486136; CC P28799; Q96C55: ZNF524; NbExp=3; IntAct=EBI-747754, EBI-10283126; CC P28799; Q68EA5: ZNF57; NbExp=3; IntAct=EBI-747754, EBI-8490788; CC P28799; Q7Z3I7: ZNF572; NbExp=3; IntAct=EBI-747754, EBI-10172590; CC P28799; Q96I27-2: ZNF625; NbExp=3; IntAct=EBI-747754, EBI-12038525; CC P28799; Q96N77-2: ZNF641; NbExp=3; IntAct=EBI-747754, EBI-12939666; CC P28799; Q9BS34: ZNF670; NbExp=3; IntAct=EBI-747754, EBI-745276; CC P28799; Q9H7X3: ZNF696; NbExp=3; IntAct=EBI-747754, EBI-11090299; CC P28799; Q5TEC3: ZNF697; NbExp=3; IntAct=EBI-747754, EBI-25845217; CC P28799; Q6NX45: ZNF774; NbExp=3; IntAct=EBI-747754, EBI-10251462; CC P28799; Q3KP31: ZNF791; NbExp=3; IntAct=EBI-747754, EBI-2849119; CC P28799; Q16670: ZSCAN26; NbExp=3; IntAct=EBI-747754, EBI-3920053; CC P28799; O15535: ZSCAN9; NbExp=3; IntAct=EBI-747754, EBI-751531; CC P28799; A0A384ME25; NbExp=3; IntAct=EBI-747754, EBI-10211777; CC P28799; Q7L8T7; NbExp=3; IntAct=EBI-747754, EBI-25831943; CC P28799; Q7Z783; NbExp=3; IntAct=EBI-747754, EBI-9088990; CC P28799; P09022: Hoxa1; Xeno; NbExp=2; IntAct=EBI-747754, EBI-3957603; CC P28799-2; Q9UII2: ATP5IF1; NbExp=3; IntAct=EBI-25860013, EBI-718459; CC P28799-2; P50750-2: CDK9; NbExp=3; IntAct=EBI-25860013, EBI-12029902; CC P28799-2; Q02930-3: CREB5; NbExp=3; IntAct=EBI-25860013, EBI-10192698; CC P28799-2; P80370: DLK1; NbExp=3; IntAct=EBI-25860013, EBI-21555397; CC P28799-2; O14531: DPYSL4; NbExp=3; IntAct=EBI-25860013, EBI-719542; CC P28799-2; Q92997: DVL3; NbExp=3; IntAct=EBI-25860013, EBI-739789; CC P28799-2; O15540: FABP7; NbExp=3; IntAct=EBI-25860013, EBI-10697159; CC P28799-2; Q96AQ9: FAM131C; NbExp=3; IntAct=EBI-25860013, EBI-741921; CC P28799-2; Q5HYJ3-3: FAM76B; NbExp=3; IntAct=EBI-25860013, EBI-11956087; CC P28799-2; Q8N7T0: hCG_1820408; NbExp=3; IntAct=EBI-25860013, EBI-25858908; CC P28799-2; P49639: HOXA1; NbExp=3; IntAct=EBI-25860013, EBI-740785; CC P28799-2; Q5TA79: LCE2A; NbExp=3; IntAct=EBI-25860013, EBI-10246607; CC P28799-2; Q8IXL7-2: MSRB3; NbExp=3; IntAct=EBI-25860013, EBI-10699187; CC P28799-2; Q14995: NR1D2; NbExp=3; IntAct=EBI-25860013, EBI-6144053; CC P28799-2; P09565: PP9974; NbExp=3; IntAct=EBI-25860013, EBI-10196507; CC P28799-2; Q14671: PUM1; NbExp=3; IntAct=EBI-25860013, EBI-948453; CC P28799-2; Q7Z7K5: PXN; NbExp=3; IntAct=EBI-25860013, EBI-25841978; CC P28799-2; Q969E2: SCAMP4; NbExp=3; IntAct=EBI-25860013, EBI-4403649; CC P28799-2; P34741: SDC2; NbExp=3; IntAct=EBI-25860013, EBI-1172957; CC P28799-2; Q9NTG7: SIRT3; NbExp=3; IntAct=EBI-25860013, EBI-724621; CC P28799-2; O95416: SOX14; NbExp=3; IntAct=EBI-25860013, EBI-9087806; CC P28799-2; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-25860013, EBI-5235340; CC P28799-2; P17735: TAT; NbExp=3; IntAct=EBI-25860013, EBI-12046643; CC P28799-2; Q8TDR4: TCP10L; NbExp=3; IntAct=EBI-25860013, EBI-3923210; CC P28799-2; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-25860013, EBI-25831574; CC P28799-2; Q9Y2B4: TP53TG5; NbExp=3; IntAct=EBI-25860013, EBI-21870909; CC P28799-2; P25490: YY1; NbExp=3; IntAct=EBI-25860013, EBI-765538; CC P28799-2; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-25860013, EBI-25850811; CC P28799-2; Q9UJW8-4: ZNF180; NbExp=3; IntAct=EBI-25860013, EBI-12055755; CC P28799-2; Q8N895: ZNF366; NbExp=3; IntAct=EBI-25860013, EBI-2813661; CC P28799-2; A0A087WZY1; NbExp=3; IntAct=EBI-25860013, EBI-13387614; CC P28799-2; Q7L8T7; NbExp=3; IntAct=EBI-25860013, EBI-25831943; CC PRO_0000012695; P07339: CTSD; NbExp=2; IntAct=EBI-21335602, EBI-2115097; CC PRO_0000012696; P07339: CTSD; NbExp=2; IntAct=EBI-21335615, EBI-2115097; CC PRO_0000012697; P07339: CTSD; NbExp=2; IntAct=EBI-21335629, EBI-2115097; CC PRO_0000012698; P07339: CTSD; NbExp=2; IntAct=EBI-21335642, EBI-2115097; CC PRO_0000012699; P07339: CTSD; NbExp=2; IntAct=EBI-21335656, EBI-2115097; CC PRO_0000012700; P07339: CTSD; NbExp=2; IntAct=EBI-21335669, EBI-2115097; CC PRO_0000012701; P07339: CTSD; NbExp=2; IntAct=EBI-21335682, EBI-2115097; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:21092856, CC ECO:0000269|PubMed:26370502}. Lysosome {ECO:0000269|PubMed:21092856, CC ECO:0000269|PubMed:26370502, ECO:0000269|PubMed:28073925, CC ECO:0000269|PubMed:28541286, ECO:0000269|PubMed:28743268}. CC Note=Endocytosed by SORT1 and delivred to lysosomes (PubMed:21092856, CC PubMed:28073925). Targeted to lysosome by PSAP via M6PR and LRP1, in CC both biosynthetic and endocytic pathways (PubMed:26370502, CC PubMed:28073925). Co-localized with GBA1 in the intracellular CC trafficking compartments until to lysosome (By similarity). CC {ECO:0000250|UniProtKB:P28798, ECO:0000269|PubMed:21092856, CC ECO:0000269|PubMed:26370502, ECO:0000269|PubMed:28073925}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P28799-1; Sequence=Displayed; CC Name=2; CC IsoId=P28799-2; Sequence=VSP_001837; CC Name=3; CC IsoId=P28799-3; Sequence=VSP_053472, VSP_053473; CC -!- TISSUE SPECIFICITY: In myelogenous leukemic cell lines of promonocytic, CC promyelocytic, and proerythroid lineage, in fibroblasts, and very CC strongly in epithelial cell lines. Present in inflammatory cells and CC bone marrow. Highest levels in kidney. CC -!- INDUCTION: Increased in response to lysosome alkalization. CC {ECO:0000269|PubMed:28073925}. CC -!- PTM: Cleaved by ELANE; proteolysis is blocked by SLPI and is CC concentration- and time-dependent and induces CXCL8/IL-8 production; CC granulin-3 and granulin-4 are resistant to ELANE (PubMed:12526812, CC PubMed:28743268). Cleaved by CTSL in lysosome thus regulating the CC maturation and turnover of progranulin within the lysosome CC (PubMed:28743268). {ECO:0000269|PubMed:12526812, CC ECO:0000269|PubMed:28743268}. CC -!- DISEASE: Frontotemporal dementia 2 (FTD2) [MIM:607485]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. Gestural apraxia, CC parkinsonism, visual loss, and visual hallucinations are present in 25 CC to 40% of patients. {ECO:0000269|PubMed:16862116, CC ECO:0000269|PubMed:16983685, ECO:0000269|PubMed:18183624}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 11 (CLN11) [MIM:614706]: A CC form of neuronal ceroid lipofuscinosis characterized by rapidly CC progressive visual loss due to retinal dystrophy, seizures, cerebellar CC ataxia, and cerebellar atrophy. Cognitive decline may also occur. CC Neuronal ceroid lipofuscinoses are progressive neurodegenerative, CC lysosomal storage diseases characterized by intracellular accumulation CC of autofluorescent liposomal material. {ECO:0000269|PubMed:22608501}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the granulin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/40757/GRN"; 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; X62320; CAA44196.1; -; mRNA. DR EMBL; AF055008; AAC09359.1; -; mRNA. DR EMBL; M75161; AAA58617.1; -; mRNA. DR EMBL; AY124489; AAM94026.1; -; mRNA. DR EMBL; BT006844; AAP35490.1; -; mRNA. DR EMBL; AK023348; BAB14535.1; -; mRNA. DR EMBL; AK222522; BAD96242.1; -; mRNA. DR EMBL; CH471178; EAW51599.1; -; Genomic_DNA. DR EMBL; CH471178; EAW51600.1; -; Genomic_DNA. DR EMBL; BC000324; AAH00324.1; -; mRNA. DR EMBL; BC010577; AAH10577.1; -; mRNA. DR CCDS; CCDS11483.1; -. [P28799-1] DR PIR; JC1284; GYHU. DR RefSeq; NP_002078.1; NM_002087.4. [P28799-1] DR PDB; 1G26; NMR; -; A=281-311. DR PDB; 2JYE; NMR; -; A=281-337. DR PDB; 2JYT; NMR; -; A=364-417. DR PDB; 2JYU; NMR; -; A=364-417. DR PDB; 2JYV; NMR; -; A=123-179. DR PDB; 6NUG; NMR; -; A=284-307. DR PDB; 8T8R; X-ray; 2.87 A; B=578-593. DR PDB; 8T8S; X-ray; 2.99 A; C/D=578-593. DR PDBsum; 1G26; -. DR PDBsum; 2JYE; -. DR PDBsum; 2JYT; -. DR PDBsum; 2JYU; -. DR PDBsum; 2JYV; -. DR PDBsum; 6NUG; -. DR PDBsum; 8T8R; -. DR PDBsum; 8T8S; -. DR AlphaFoldDB; P28799; -. DR SMR; P28799; -. DR BioGRID; 109153; 249. DR CORUM; P28799; -. DR DIP; DIP-41742N; -. DR FunCoup; P28799; 1096. DR IntAct; P28799; 468. DR MINT; P28799; -. DR STRING; 9606.ENSP00000053867; -. DR GlyConnect; 1290; 5 N-Linked glycans (1 site), 3 O-Linked glycans (1 site). DR GlyCosmos; P28799; 6 sites, 5 glycans. DR GlyGen; P28799; 10 sites, 29 N-linked glycans (3 sites), 5 O-linked glycans (4 sites). DR iPTMnet; P28799; -. DR MetOSite; P28799; -. DR PhosphoSitePlus; P28799; -. DR SwissPalm; P28799; -. DR BioMuta; GRN; -. DR DMDM; 77416865; -. DR jPOST; P28799; -. DR MassIVE; P28799; -. DR PaxDb; 9606-ENSP00000053867; -. DR PeptideAtlas; P28799; -. DR ProteomicsDB; 54499; -. [P28799-1] DR ProteomicsDB; 54500; -. [P28799-2] DR ProteomicsDB; 81234; -. DR Pumba; P28799; -. DR TopDownProteomics; P28799-2; -. [P28799-2] DR TopDownProteomics; P28799-3; -. [P28799-3] DR Antibodypedia; 1406; 664 antibodies from 38 providers. DR DNASU; 2896; -. DR Ensembl; ENST00000053867.8; ENSP00000053867.2; ENSG00000030582.20. [P28799-1] DR GeneID; 2896; -. DR KEGG; hsa:2896; -. DR MANE-Select; ENST00000053867.8; ENSP00000053867.2; NM_002087.4; NP_002078.1. DR UCSC; uc002igp.2; human. [P28799-1] DR AGR; HGNC:4601; -. DR ClinPGx; PA28998; -. DR CTD; 2896; -. DR DisGeNET; 2896; -. DR GeneCards; GRN; -. DR GeneReviews; GRN; -. DR HGNC; HGNC:4601; GRN. DR HPA; ENSG00000030582; Low tissue specificity. DR MalaCards; GRN; -. DR MIM; 138945; gene. DR MIM; 607485; phenotype. DR MIM; 614706; phenotype. DR NIAGADS; ENSG00000030582; -. DR OpenTargets; ENSG00000030582; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 314629; CLN11 disease. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000030582; -. DR eggNOG; KOG4296; Eukaryota. DR GeneTree; ENSGT00470000042293; -. DR HOGENOM; CLU_026274_0_0_1; -. DR InParanoid; P28799; -. DR OMA; CCPYSSA; -. DR OrthoDB; 5854875at2759; -. DR PAN-GO; P28799; 2 GO annotations based on evolutionary models. DR PhylomeDB; P28799; -. DR PathwayCommons; P28799; -. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR SignaLink; P28799; -. DR SIGNOR; P28799; -. DR Agora; ENSG00000030582; -. DR BioGRID-ORCS; 2896; 18 hits in 1158 CRISPR screens. DR ChiTaRS; GRN; human. DR EvolutionaryTrace; P28799; -. DR GeneWiki; Granulin; -. DR GenomeRNAi; 2896; -. DR Pharos; P28799; Tbio. DR PRO; PR:P28799; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P28799; protein. DR Bgee; ENSG00000030582; Expressed in monocyte and 210 other cell types or tissues. DR ExpressionAtlas; P28799; baseline and differential. DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome. DR GO; GO:0150053; C:cerebellar climbing fiber to Purkinje cell synapse; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005768; C:endosome; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:ARUK-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:HPA. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW. DR GO; GO:0008083; F:growth factor activity; TAS:ProtInc. DR GO; GO:0051087; F:protein-folding chaperone binding; IDA:UniProtKB. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0002265; P:astrocyte activation involved in immune response; ISS:UniProtKB. DR GO; GO:0001835; P:blastocyst hatching; IEA:Ensembl. DR GO; GO:0007566; P:embryo implantation; IEA:Ensembl. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl. DR GO; GO:0007042; P:lysosomal lumen acidification; IMP:UniProtKB. DR GO; GO:1905146; P:lysosomal protein catabolic process; IEA:Ensembl. DR GO; GO:0007041; P:lysosomal transport; IMP:UniProtKB. DR GO; GO:0007040; P:lysosome organization; ISS:UniProtKB. DR GO; GO:0099558; P:maintenance of synapse structure; IEA:Ensembl. DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:UniProtKB. DR GO; GO:1903979; P:negative regulation of microglial cell activation; ISS:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:UniProtKB. DR GO; GO:1902564; P:negative regulation of neutrophil activation; IDA:UniProtKB. DR GO; GO:0060266; P:negative regulation of respiratory burst involved in inflammatory response; IDA:UniProtKB. DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB. DR GO; GO:1905247; P:positive regulation of aspartic-type peptidase activity; IMP:UniProtKB. DR GO; GO:0048680; P:positive regulation of axon regeneration; ISS:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:ARUK-UCL. DR GO; GO:1900426; P:positive regulation of defense response to bacterium; ISS:UniProtKB. DR GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IDA:UniProtKB. DR GO; GO:0106016; P:positive regulation of inflammatory response to wounding; ISS:UniProtKB. DR GO; GO:1905673; P:positive regulation of lysosome organization; IDA:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB. DR GO; GO:1903334; P:positive regulation of protein folding; ISS:UniProtKB. DR GO; GO:1904075; P:positive regulation of trophectodermal cell proliferation; IEA:Ensembl. DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB. DR GO; GO:0050727; P:regulation of inflammatory response; IBA:GO_Central. DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; NAS:ProtInc. DR GO; GO:0001834; P:trophectodermal cell proliferation; IEA:Ensembl. DR FunFam; 2.10.25.160:FF:000001; Granulin precursor; 5. DR FunFam; 2.10.25.160:FF:000004; Granulin precursor; 1. DR FunFam; 2.10.25.160:FF:000003; Progranulin; 1. DR Gene3D; 2.10.25.160; Granulin; 7. DR InterPro; IPR000118; Granulin. DR InterPro; IPR039036; Granulin_fam. DR InterPro; IPR037277; Granulin_sf. DR PANTHER; PTHR12274; GRANULIN; 1. DR PANTHER; PTHR12274:SF3; PROGRANULIN; 1. DR Pfam; PF00396; Granulin; 7. DR SMART; SM00277; GRAN; 7. DR SUPFAM; SSF57277; Granulin repeat; 6. DR PROSITE; PS00799; GRANULINS; 7. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytokine; Direct protein sequencing; KW Disulfide bond; Glycoprotein; Lysosome; Neurodegeneration; KW Neuronal ceroid lipofuscinosis; Proteomics identification; KW Reference proteome; Repeat; Secreted; Signal. FT SIGNAL 1..17 FT /evidence="ECO:0000255" FT CHAIN 18..593 FT /note="Progranulin" FT /id="PRO_0000012693" FT PEPTIDE 18..?47 FT /note="Paragranulin" FT /id="PRO_0000012694" FT PEPTIDE ?58..?113 FT /note="Granulin-1" FT /id="PRO_0000012695" FT PEPTIDE 123..179 FT /note="Granulin-2" FT /id="PRO_0000012696" FT PEPTIDE 206..261 FT /note="Granulin-3" FT /id="PRO_0000012697" FT PEPTIDE 281..336 FT /note="Granulin-4" FT /id="PRO_0000012698" FT PEPTIDE 364..417 FT /note="Granulin-5" FT /id="PRO_0000012699" FT PEPTIDE 442..?496 FT /note="Granulin-6" FT /id="PRO_0000012700" FT PEPTIDE ?518..?573 FT /note="Granulin-7" FT /id="PRO_0000012701" FT CARBOHYD 118 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20188224" FT CARBOHYD 236 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 265 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:20188224" FT CARBOHYD 368 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20188224" FT CARBOHYD 530 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:20188224" FT DISULFID 126..139 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 133..149 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 284..296 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 290..306 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 297..314 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 307..321 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 315..328 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 322..335 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 366..378 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 372..388 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 397..410 FT /evidence="ECO:0000269|PubMed:18359860" FT DISULFID 404..416 FT /evidence="ECO:0000269|PubMed:18359860" FT VAR_SEQ 1..71 FT /note="MWTLVSWVALTAGLVAGTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTT FT LSRHLGGPCQVDAHCSAGH -> MAITAAHGASTAVQTGDPASKDQVTTPWVPSSALIV FT SSNARTSPRAVLWSMAPGGAAPCPRLPAVKTGCTA (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053472" FT VAR_SEQ 72..251 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053473" FT VAR_SEQ 377..531 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.6" FT /id="VSP_001837" FT VARIANT 9 FT /note="A -> D (in FTD2; no significant difference in the FT total mRNA between cases and controls; although the mutant FT protein is expressed it is not secreted and appears to be FT trapped within an intracellular compartment; FT dbSNP:rs63751243)" FT /evidence="ECO:0000269|PubMed:16983685, FT ECO:0000269|PubMed:18183624" FT /id="VAR_044451" FT VARIANT 19 FT /note="R -> W (in dbSNP:rs63750723)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064625" FT VARIANT 55 FT /note="R -> W (in dbSNP:rs1555610922)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064626" FT VARIANT 69 FT /note="A -> T (in dbSNP:rs199944486)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064627" FT VARIANT 119 FT /note="Missing (in dbSNP:rs758168578)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064628" FT VARIANT 120 FT /note="S -> Y (in dbSNP:rs63750043)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064629" FT VARIANT 182 FT /note="T -> M (in dbSNP:rs63750479)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064630" FT VARIANT 221 FT /note="C -> S (in dbSNP:rs758322775)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064631" FT VARIANT 275 FT /note="P -> L (in dbSNP:rs529849967)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064632" FT VARIANT 376 FT /note="D -> N (in dbSNP:rs143030899)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064633" FT VARIANT 398 FT /note="S -> L (in dbSNP:rs148213321)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064634" FT VARIANT 433 FT /note="R -> Q (in dbSNP:rs114248177)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064635" FT VARIANT 515 FT /note="G -> A (in dbSNP:rs25647)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_014830" FT VARIANT 564 FT /note="R -> H (in dbSNP:rs971443926)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064636" FT CONFLICT 219 FT /note="S -> H (in Ref. 12; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 290 FT /note="C -> S (in Ref. 13; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 386 FT /note="W -> H (in Ref. 12; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 407 FT /note="G -> R (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 428 FT /note="K -> E (in Ref. 8; BAD96242)" FT /evidence="ECO:0000305" FT CONFLICT 434 FT /note="A -> G (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 454 FT /note="Q -> G (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 460 FT /note="L -> Q (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 547 FT /note="R -> A (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT CONFLICT 567 FT /note="A -> R (in Ref. 3; AAA58617)" FT /evidence="ECO:0000305" FT STRAND 137..141 FT /evidence="ECO:0007829|PDB:2JYV" FT STRAND 143..145 FT /evidence="ECO:0007829|PDB:2JYV" FT STRAND 147..151 FT /evidence="ECO:0007829|PDB:2JYV" FT STRAND 282..285 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 288..290 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 294..298 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 304..308 FT /evidence="ECO:0007829|PDB:1G26" FT STRAND 315..319 FT /evidence="ECO:0007829|PDB:2JYE" FT TURN 330..333 FT /evidence="ECO:0007829|PDB:2JYE" FT TURN 367..369 FT /evidence="ECO:0007829|PDB:2JYU" FT STRAND 377..380 FT /evidence="ECO:0007829|PDB:2JYT" FT STRAND 382..384 FT /evidence="ECO:0007829|PDB:2JYT" FT STRAND 386..389 FT /evidence="ECO:0007829|PDB:2JYT" FT TURN 399..402 FT /evidence="ECO:0007829|PDB:2JYU" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:2JYT" FT TURN 412..414 FT /evidence="ECO:0007829|PDB:2JYT" FT STRAND 415..417 FT /evidence="ECO:0007829|PDB:2JYT" SQ SEQUENCE 593 AA; 63544 MW; 4E5947F1B4EDE619 CRC64; MWTLVSWVAL TAGLVAGTRC PDGQFCPVAC CLDPGGASYS CCRPLLDKWP TTLSRHLGGP CQVDAHCSAG HSCIFTVSGT SSCCPFPEAV ACGDGHHCCP RGFHCSADGR SCFQRSGNNS VGAIQCPDSQ FECPDFSTCC VMVDGSWGCC PMPQASCCED RVHCCPHGAF CDLVHTRCIT PTGTHPLAKK LPAQRTNRAV ALSSSVMCPD ARSRCPDGST CCELPSGKYG CCPMPNATCC SDHLHCCPQD TVCDLIQSKC LSKENATTDL LTKLPAHTVG DVKCDMEVSC PDGYTCCRLQ SGAWGCCPFT QAVCCEDHIH CCPAGFTCDT QKGTCEQGPH QVPWMEKAPA HLSLPDPQAL KRDVPCDNVS SCPSSDTCCQ LTSGEWGCCP IPEAVCCSDH QHCCPQGYTC VAEGQCQRGS EIVAGLEKMP ARRASLSHPR DIGCDQHTSC PVGQTCCPSL GGSWACCQLP HAVCCEDRQH CCPAGYTCNV KARSCEKEVV SAQPATFLAR SPHVGVKDVE CGEGHFCHDN QTCCRDNRQG WACCPYRQGV CCADRRHCCP AGFRCAARGT KCLRREAPRW DAPLRDPALR QLL // 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 PRIO_HUMAN Reviewed; 253 AA. AC P04156; O60489; P78446; Q15216; Q15221; Q27H91; Q5QPB4; Q8TBG0; Q96E70; AC Q9UP19; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1986, sequence version 1. DT 28-JAN-2026, entry version 280. DE RecName: Full=Major prion protein; DE Short=PrP; DE AltName: Full=ASCR; DE AltName: Full=PrP27-30; DE AltName: Full=PrP33-35C; DE AltName: CD_antigen=CD230; DE Flags: Precursor; GN Name=PRNP; Synonyms=ALTPRP, PRIP, PRP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3755672; DOI=10.1089/dna.1986.5.315; RA Kretzschmar H.A., Stowring L.E., Westaway D., Stubblebine W.H., RA Prusiner S.B., Dearmond S.J.; RT "Molecular cloning of a human prion protein cDNA."; RL DNA 5:315-324(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT 56-GLY--GLY-63 DEL. RC TISSUE=Brain; RX PubMed=1678248; RA Puckett C., Concannon P., Casey C., Hood L.E.; RT "Genomic structure of the human prion protein gene."; RL Am. J. Hum. Genet. 49:320-329(1991). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9799790; DOI=10.1101/gr.8.10.1022; RA Lee I.Y., Westaway D., Smit A.F.A., Wang K., Seto J., Chen L., Acharya C., RA Ankener M., Baskin D., Cooper C., Yao H., Prusiner S.B., Hood L.E.; RT "Complete genomic sequence and analysis of the prion protein gene region RT from three mammalian species."; RL Genome Res. 8:1022-1037(1998). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GSD ARG-187. RC TISSUE=Blood; RX PubMed=10581485; RX DOI=10.1002/(sici)1096-8628(19991215)88:6<653::aid-ajmg14>3.0.co;2-e; RA Cervenakova L., Buetefisch C., Lee H.S., Taller I., Stone G., RA Gibbs C.J. Jr., Brown P., Hallett M., Goldfarb L.G.; RT "Novel PRNP sequence variant associated with familial encephalopathy."; RL Am. J. Med. Genet. 88:653-656(1999). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Prostate; RA Hryb D.J., Reynolds T.A., Nakhla A.M., Kahn S.M., Khan S.M., Romas N.A., RA Rosner W.; RT "Cloning of human prostate prion protein cDNA."; RL Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Zhang J., Liu Y., Chen H., Jiang H., Lu W., Zhu X., Xie Q., Cai X., Liu X.; RT "Analysis and comparison of several mammalian prion protein genes Prnp."; RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 8-253. RX PubMed=3014653; DOI=10.1126/science.3014653; RA Liao Y.-C.J., Lebo R.V., Clawson G.A., Smuckler E.A.; RT "Human prion protein cDNA: molecular cloning, chromosomal mapping, and RT biological implications."; RL Science 233:364-367(1986). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 9-232, AND VARIANT 56-GLY--GLY-63 DEL. RC TISSUE=Brain; RX PubMed=1363802; DOI=10.1093/hmg/1.6.443; RA Diedrich J.F., Knopman D.S., List J.F., Olson K., Frey W.H., Emory C.R., RA Sung J.H., Haase A.T.; RT "Deletion in the prion protein gene in a demented patient."; RL Hum. Mol. Genet. 1:443-444(1992). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 8-253, AND VARIANT SCHIZOAFFECTIVE RP DISORDER SER-171. RX PubMed=9384372; DOI=10.1038/36757; RA Samaia H.B., Mari J.J., Vallada H.P., Moura R.P., Simpson A.J.G., RA Brentani R.R.; RT "A prion-linked psychiatric disorder."; RL Nature 390:241-241(1997). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 41-85, AND VARIANT 56-GLY--GLY-63 DEL. RX PubMed=7485229; DOI=10.1002/ajmg.1320600104; RA Perry R.T., Go R.C., Harrell L.E., Acton R.T.; RT "SSCP analysis and sequencing of the human prion protein gene (PRNP) RT detects two different 24 bp deletions in an atypical Alzheimer's disease RT family."; RL Am. J. Med. Genet. 60:12-18(1995). RN [13] RP PROTEIN SEQUENCE OF 58-85 AND 111-150. RX PubMed=1672107; DOI=10.1002/j.1460-2075.1991.tb07977.x; RA Tagliavini F., Prelli F., Ghiso J., Bugiani O., Serban D., Prusiner S.B., RA Farlow M.R., Ghetti B., Frangione B.; RT "Amyloid protein of Gerstmann-Straussler-Scheinker disease (Indiana RT kindred) is an 11 kd fragment of prion protein with an N-terminal glycine RT at codon 58."; RL EMBO J. 10:513-519(1991). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 84-91. RX PubMed=1683708; DOI=10.1073/pnas.88.23.10926; RA Goldfarb L.G., Brown P., McCombie W.R., Goldgaber D., Swergold G.D., RA Wills P.R., Cervenakova L., Baron H., Gibbs C.J. Jr., Gajdusek D.C.; RT "Transmissible familial Creutzfeldt-Jakob disease associated with five, RT seven, and eight extra octapeptide coding repeats in the PRNP gene."; RL Proc. Natl. Acad. Sci. U.S.A. 88:10926-10930(1991). RN [15] RP INVOLVEMENT IN HDL1. RX PubMed=9792871; DOI=10.1086/302093; RA Xiang F., Almqvist E.W., Huq M., Lundin A., Hayden M.R., Edstroem L., RA Anvret M., Zhang Z.; RT "A Huntington disease-like neurodegenerative disorder maps to chromosome RT 20p."; RL Am. J. Hum. Genet. 63:1431-1438(1998). RN [16] RP COPPER-BINDING, AND FUNCTION. RX PubMed=12732622; DOI=10.1074/jbc.m300394200; RA Mani K., Cheng F., Havsmark B., Jonsson M., Belting M., Fransson L.A.; RT "Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S- RT nitroso-dependent autocleavage of glypican-1 heparan sulfate."; RL J. Biol. Chem. 278:38956-38965(2003). RN [17] RP GLYCOSYLATION AT ASN-181, VARIANT SENF ALA-183, AND CHARACTERIZATION OF RP VARIANT SENF ALA-183. RX PubMed=12214108; DOI=10.3233/jad-2000-2104; RA Capellari S., Zaidi S.I., Long A.C., Kwon E.E., Petersen R.B.; RT "The Thr183Ala mutation, not the loss of the first glycosylation site, RT alters the physical properties of the prion protein."; RL J. Alzheimers Dis. 2:27-35(2000). RN [18] RP COPPER-BINDING. RX PubMed=16144413; DOI=10.1021/ja053254z; RA Chattopadhyay M., Walter E.D., Newell D.J., Jackson P.J., RA Aronoff-Spencer E., Peisach J., Gerfen G.J., Bennett B., Antholine W.E., RA Millhauser G.L.; RT "The octarepeat domain of the prion protein binds Cu(II) with three RT distinct coordination modes at pH 7.4."; RL J. Am. Chem. Soc. 127:12647-12656(2005). RN [19] RP COPPER-BINDING, AND ZINC-BINDING. RX PubMed=18034490; DOI=10.1021/ja077146j; RA Walter E.D., Stevens D.J., Visconte M.P., Millhauser G.L.; RT "The prion protein is a combined zinc and copper binding protein: Zn2+ RT alters the distribution of Cu2+ coordination modes."; RL J. Am. Chem. Soc. 129:15440-15441(2007). RN [20] RP RETRACTED PAPER. RX PubMed=19059915; DOI=10.1074/jbc.m804051200; RA Juanes M.E., Elvira G., Garcia-Grande A., Calero M., Gasset M.; RT "Biosynthesis of prion protein nucleocytoplasmic isoforms by alternative RT initiation of translation."; RL J. Biol. Chem. 284:2787-2794(2009). RN [21] RP RETRACTION NOTICE OF PUBMED:19059915. RX PubMed=29222195; DOI=10.1074/jbc.w117.000658; RA Juanes M.E., Elvira G., Garcia-Grande A., Calero M., Gasset M.; RT "Biosynthesis of prion protein nucleocytoplasmic isoforms by alternative RT initiation of translation."; RL J. Biol. Chem. 292:20044-20044(2017). RN [22] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-197. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [23] RP FUNCTION, SUBCELLULAR LOCATION, AND DISEASE ASSOCIATION. RX PubMed=19936054; DOI=10.1371/journal.ppat.1000666; RA Taylor D.R., Whitehouse I.J., Hooper N.M.; RT "Glypican-1 mediates both prion protein lipid raft association and disease RT isoform formation."; RL PLoS Pathog. 5:E1000666-E1000666(2009). RN [24] RP COPPER-BINDING. RX PubMed=19381258; DOI=10.1371/journal.ppat.1000390; RA Stevens D.J., Walter E.D., Rodriguez A., Draper D., Davies P., Brown D.R., RA Millhauser G.L.; RT "Early onset prion disease from octarepeat expansion correlates with copper RT or zinc binding properties."; RL PLoS Pathog. 5:E1000390-E1000390(2009). RN [25] RP SUBUNIT, AND DOMAIN. RX PubMed=20375014; DOI=10.1074/jbc.m110.111815; RA Adrover M., Pauwels K., Prigent S., de Chiara C., Xu Z., Chapuis C., RA Pastore A., Rezaei H.; RT "Prion fibrillization is mediated by a native structural element that RT comprises helices H2 and H3."; RL J. Biol. Chem. 285:21004-21012(2010). RN [26] RP COPPER-BINDING, CIRCULAR DICHROISM, DOMAIN, FUNCTION, AND SUBUNIT. RX PubMed=20564047; DOI=10.1002/jcb.22743; RA Wu D., Zhang W., Luo Q., Luo K., Huang L., Wang W., Huang T., Chen R., RA Lin Y., Pang D., Xiao G.; RT "Copper (II) promotes the formation of soluble neurotoxic PrP oligomers in RT acidic environment."; RL J. Cell. Biochem. 111:627-633(2010). RN [27] RP BICISTRONIC GENE. RX PubMed=21478263; DOI=10.1096/fj.10-173815; RA Vanderperre B., Staskevicius A.B., Tremblay G., McCoy M., O'Neill M.A., RA Cashman N.R., Roucou X.; RT "An overlapping reading frame in the PRNP gene encodes a novel polypeptide RT distinct from the prion protein."; RL FASEB J. 25:2373-2386(2011). RN [28] RP INTERACTION WITH KIAA1191. RX PubMed=21153684; DOI=10.1007/s11010-010-0690-4; RA Mishra M., Inoue N., Heese K.; RT "Characterizing the novel protein p33MONOX."; RL Mol. Cell. Biochem. 350:127-134(2011). RN [29] RP STRUCTURE BY NMR OF 90-231 OF MUTANT LYS-200. RX PubMed=10954699; DOI=10.1074/jbc.c000483200; RA Zhang Y., Swietnicki W., Zagorski M.G., Surewicz W.K., Soennichsen F.D.; RT "Solution structure of the E200K variant of human prion protein. RT Implications for the mechanism of pathogenesis in familial prion RT diseases."; RL J. Biol. Chem. 275:33650-33654(2000). RN [30] RP STRUCTURE BY NMR OF 23-230. RX PubMed=10618385; DOI=10.1073/pnas.97.1.145; RA Zahn R., Liu A., Luhrs T., Riek R., von Schroetter C., Lopez Garcia F., RA Billeter M., Calzolai L., Wider G., Wuethrich K.; RT "NMR solution structure of the human prion protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:145-150(2000). RN [31] RP STRUCTURE BY NMR OF 118-221. RX PubMed=10900000; DOI=10.1073/pnas.97.15.8340; RA Calzolai L., Lysek D.A., Guntert P., von Schroetter C., Riek R., Zahn R., RA Wuethrich K.; RT "NMR structures of three single-residue variants of the human prion RT protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:8340-8345(2000). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 119-226, DOMAIN, AND SUBUNIT. RX PubMed=11524679; DOI=10.1038/nsb0901-770; RA Knaus K.J., Morillas M., Swietnicki W., Malone M., Surewicz W.K., Yee V.C.; RT "Crystal structure of the human prion protein reveals a mechanism for RT oligomerization."; RL Nat. Struct. Biol. 8:770-774(2001). RN [33] RP X-RAY CRYSTALLOGRAPHY (0.75 ANGSTROMS) OF 61-65 IN COMPLEX WITH COPPER ION, RP DOMAIN, AND SUBUNIT. RX PubMed=11900542; DOI=10.1021/bi011922x; RA Burns C.S., Aronoff-Spencer E., Dunham C.M., Lario P., Avdievich N.I., RA Antholine W.E., Olmstead M.M., Vrielink A., Gerfen G.J., Peisach J., RA Scott W.G., Millhauser G.L.; RT "Molecular features of the copper binding sites in the octarepeat domain of RT the prion protein."; RL Biochemistry 41:3991-4001(2002). RN [34] RP STRUCTURE BY NMR OF 61-68, DISULFIDE BOND, AND SUBUNIT. RX PubMed=14623188; DOI=10.1016/j.jmb.2003.09.048; RA Zahn R.; RT "The octapeptide repeats in mammalian prion protein constitute a pH- RT dependent folding and aggregation site."; RL J. Mol. Biol. 334:477-488(2003). RN [35] RP REVIEW ON VARIANTS. RX PubMed=8364585; DOI=10.1002/humu.1380020303; RA Palmer M.S., Collinge J.; RT "Mutations and polymorphisms in the prion protein gene."; RL Hum. Mutat. 2:168-173(1993). RN [36] RP REVIEW ON VARIANTS, AND INVOLVEMENT IN PRION DISEASES. RX PubMed=8105771; DOI=10.1001/archneur.1993.00540110011002; RA Prusiner S.B.; RT "Genetic and infectious prion diseases."; RL Arch. Neurol. 50:1129-1153(1993). RN [37] RP X-RAY CRYSTALLOGRAPHY (0.85 ANGSTROMS) OF 170-175, SUBUNIT, AND DOMAIN. RX PubMed=17468747; DOI=10.1038/nature05695; RA Sawaya M.R., Sambashivan S., Nelson R., Ivanova M.I., Sievers S.A., RA Apostol M.I., Thompson M.J., Balbirnie M., Wiltzius J.J., McFarlane H.T., RA Madsen A.O., Riekel C., Eisenberg D.; RT "Atomic structures of amyloid cross-beta spines reveal varied steric RT zippers."; RL Nature 447:453-457(2007). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 119-231 IN COMPLEX WITH FAB RP FRAGMENT OF MONOCLONAL ANTIBODY ICSM 18, AND SUBUNIT. RX PubMed=19204296; DOI=10.1073/pnas.0809170106; RA Antonyuk S.V., Trevitt C.R., Strange R.W., Jackson G.S., Sangar D., RA Batchelor M., Cooper S., Fraser C., Jones S., Georgiou T., RA Khalili-Shirazi A., Clarke A.R., Hasnain S.S., Collinge J.; RT "Crystal structure of human prion protein bound to a therapeutic RT antibody."; RL Proc. Natl. Acad. Sci. U.S.A. 106:2554-2558(2009). RN [39] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 125-227 OF VARIANT VAL-129, RP VARIANT VAL-129, VARIANT CJD ASN-178, VARIANT FFI ASN-178, VARIANT GSD RP SER-198, SUBUNIT, AND DOMAIN. RX PubMed=19927125; DOI=10.1038/emboj.2009.333; RA Lee S., Antony L., Hartmann R., Knaus K.J., Surewicz K., Surewicz W.K., RA Yee V.C.; RT "Conformational diversity in prion protein variants influences RT intermolecular beta-sheet formation."; RL EMBO J. 29:251-262(2010). RN [40] RP VARIANT GSD LEU-102. RX PubMed=2564168; DOI=10.1038/338342a0; RA Hsiao K., Baker H.F., Crow T.J., Poulter M., Owen F., Terwilliger J.D., RA Westaway D., Ott J., Pursiner S.B.; RT "Linkage of a prion protein missense variant to Gerstmann-Straussler RT syndrome."; RL Nature 338:342-345(1989). RN [41] RP VARIANTS LEU-102; VAL-117 AND VAL-129. RX PubMed=2783132; DOI=10.1016/0006-291x(89)92317-6; RA Doh-Ura K., Tateishi J., Sasaki H., Kitamoto T., Sakaki Y.; RT "Pro-->Leu change at position 102 of prion protein is the most common but RT not the sole mutation related to Gerstmann-Straussler syndrome."; RL Biochem. Biophys. Res. Commun. 163:974-979(1989). RN [42] RP VARIANT FFI ASN-178. RX PubMed=1347910; DOI=10.1212/wnl.42.3.669; RA Medori R., Montagna P., Tritschler H.J., Leblanc A., Cortelli P., RA Tinuper P., Lugaresi E., Gambetti P.; RT "Fatal familial insomnia: a second kindred with mutation of prion protein RT gene at codon 178."; RL Neurology 42:669-670(1992). RN [43] RP VARIANT CJD ASN-178. RX PubMed=1671440; DOI=10.1016/0140-6736(91)91198-4; RA Goldfarb L.G., Haltia M., Brown P., Nieto A., Kovanen J., McCombie W.R., RA Trapp S., Gajdusek D.C.; RT "New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish RT Creutzfeldt-Jakob kindred."; RL Lancet 337:425-425(1991). RN [44] RP VARIANT CJD LYS-200. RX PubMed=1975028; DOI=10.1016/0140-6736(90)92073-q; RA Goldfarb L., Mitrova E., Brown P., Toh B.K., Gajdusek D.C.; RT "Mutation in codon 200 of scrapie amyloid protein gene in two clusters of RT Creutzfeldt-Jakob disease in Slovakia."; RL Lancet 336:514-515(1990). RN [45] RP VARIANT GSD ARG-217. RX PubMed=1363810; DOI=10.1038/ng0492-68; RA Hsiao K., Dlouhy S.R., Farlow M.R., Cass C., da Costa M., Conneally P.M., RA Hodes M.E., Ghetti B., Prusiner S.B.; RT "Mutant prion proteins in Gerstmann-Straussler-Scheinker disease with RT neurofibrillary tangles."; RL Nat. Genet. 1:68-71(1992). RN [46] RP VARIANT VAL-129, VARIANT CJD ASN-178, VARIANT FFI ASN-178, CHARACTERIZATION RP OF VARIANT VAL-129, CHARACTERIZATION OF VARIANT CJD ASN-178, RP CHARACTERIZATION OF VARIANT FFI ASN-178, AND POLYMORPHISM. RX PubMed=1439789; DOI=10.1126/science.1439789; RA Goldfarb L.G., Petersen R.B., Tabaton M., Brown P., LeBlanc A.C., RA Montagna P., Cortelli P., Julien J., Vital C., Pendelbury W.W.; RT "Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease RT phenotype determined by a DNA polymorphism."; RL Science 258:806-808(1992). RN [47] RP VARIANTS CJD ILE-180 AND ARG-232. RX PubMed=8461023; DOI=10.1006/bbrc.1993.1275; RA Kitamoto T., Ohta M., Doh-Ura K., Hitoshi S., Terao Y., Tateishi J.; RT "Novel missense variants of prion protein in Creutzfeldt-Jakob disease or RT Gerstmann-Straussler syndrome."; RL Biochem. Biophys. Res. Commun. 191:709-714(1993). RN [48] RP VARIANT CJD ILE-210. RX PubMed=7902693; DOI=10.1002/ana.410340608; RA Pocchiari M., Salvatore M., Cutruzzola F., Genuardi M., Allcatelli C.T., RA Masullo C., Macchi G., Alema G., Galgani S., Xi Y.G., Petraroli R., RA Silvestrini M.C., Brunori M.; RT "A new point mutation of the prion protein gene in Creutzfeldt-Jakob RT disease."; RL Ann. Neurol. 34:802-807(1993). RN [49] RP VARIANT GSD LEU-105. RX PubMed=7902972; DOI=10.1212/wnl.43.12.2723-a; RA Yamada M., Itoh Y., Fujigasaki H., Naruse S., Kaneko K., Kitamoto T., RA Tateishi J., Otomo E., Hayakawa M., Tanaka J., Matsushita M., Miyatake T.; RT "A missense mutation at codon 105 with codon 129 polymorphism of the prion RT protein gene in a new variant of Gerstmann-Straussler-Scheinker disease."; RL Neurology 43:2723-2724(1993). RN [50] RP VARIANT GSD LEU-105. RX PubMed=7699395; DOI=10.1016/0022-510x(94)90138-4; RA Itoh Y., Yamada M., Hayakawa M., Shozawa T., Tanaka J., Matsushita M., RA Kitamoto T., Tateishi J., Otomo E.; RT "A variant of Gerstmann-Straussler-Scheinker disease carrying codon 105 RT mutation with codon 129 polymorphism of the prion protein gene: a RT clinicopathological study."; RL J. Neurol. Sci. 127:77-86(1994). RN [51] RP VARIANT CJD LYS-200. RX PubMed=7906019; DOI=10.1212/wnl.44.2.299; RA Inoue I., Kitamoto T., Doh-Ura K., Shii H., Goto I., Tateishi J.; RT "Japanese family with Creutzfeldt-Jakob disease with codon 200 point RT mutation of the prion protein gene."; RL Neurology 44:299-301(1994). RN [52] RP VARIANT CJD LYS-200. RX PubMed=7913755; DOI=10.1098/rstb.1994.0033; RA Gabizon R., Rosenman H., Meiner Z., Kahana I., Kahana E., Shugart Y., RA Ott J., Prusiner S.B.; RT "Mutation in codon 200 and polymorphism in codon 129 of the prion protein RT gene in Libyan Jews with Creutzfeldt-Jakob disease."; RL Philos. Trans. R. Soc. Lond., B, Biol. Sci. 343:385-390(1994). RN [53] RP VARIANT GSD LEU-102. RX PubMed=7783876; DOI=10.1212/wnl.45.6.1127; RA Young K., Jones C.K., Piccardo P., Lazzarini A., Golbe L.I., RA Zimmerman T.R., Dickson D.W., McLachlan D.C., St George-Hyslop P.H., RA Lennox A.; RT "Gerstmann-Straussler-Scheinker disease with mutation at codon 102 and RT methionine at codon 129 of PRNP in previously unreported patients."; RL Neurology 45:1127-1134(1995). RN [54] RP VARIANT GSD LEU-102, AND VARIANT LYS-219. RX PubMed=8797472; DOI=10.1212/wnl.47.3.734; RA Barbanti P., Fabbrini G., Salvatore M., Petraroli R., Cardone F., Maras B., RA Equestre M., Macchi G., Lenzi G.L., Pocchiari M.; RT "Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity RT in a previously unreported family with Gerstmann-Straussler-Scheinker RT disease (PrP-P102L mutation)."; RL Neurology 47:734-741(1996). RN [55] RP VARIANT CJD HIS-208. RX PubMed=8909447; DOI=10.1212/wnl.47.5.1305; RA Mastrianni J.A., Iannicola C., Myers R.M., Dearmond S., Prusiner S.B.; RT "Mutation of the prion protein gene at codon 208 in familial Creutzfeldt- RT Jakob disease."; RL Neurology 47:1305-1312(1996). RN [56] RP VARIANT SENF ALA-183. RX PubMed=9266722; DOI=10.1002/ana.410420203; RA Nitrini R., Rosemberg S., Passos-Bueno M.R., da Silva L.S., Iughetti P., RA Papadopoulos M., Carrilho P.M., Caramelli P., Albrecht S., Zatz M., RA Leblanc A.; RT "Familial spongiform encephalopathy associated with a novel prion protein RT gene mutation."; RL Ann. Neurol. 42:138-146(1997). RN [57] RP VARIANTS GSD ASN-202 AND PRO-212. RX PubMed=9786248; DOI=10.1097/00005072-199810000-00010; RA Piccardo P., Dlouhy S.R., Lievens P.M., Young K., Bird T.D., Nochlin D., RA Dickson D.W., Vinters H.V., Zimmerman T.R., Mackenzie I.R., Kish S.J., RA Ang L.C., De Carli C., Pocchiari M., Brown P., Gibbs C.J. Jr., RA Gajdusek D.C., Bugiani O., Ironside J., Tagliavini F., Ghetti B.; RT "Phenotypic variability of Gerstmann-Straussler-Scheinker disease is RT associated with prion protein heterogeneity."; RL J. Neuropathol. Exp. Neurol. 57:979-988(1998). RN [58] RP VARIANT LYS-219, CHARACTERIZATION OF VARIANT LYS-219, AND POLYMORPHISM. RX PubMed=9482303; DOI=10.1016/s0140-6736(05)78358-6; RA Shibuya S., Higuchi J., Shin R.W., Tateishi J., Kitamoto T.; RT "Protective prion protein polymorphisms against sporadic Creutzfeldt-Jakob RT disease."; RL Lancet 351:419-419(1998). RN [59] RP VARIANTS ARG-188 AND SER-238. RX PubMed=10987652; DOI=10.1007/s004399900124; RA Windl O., Giese A., Schulz-Schaeffer W., Zerr I., Skworc K., Arendt S., RA Oberdieck C., Bodemer M., Poser S., Kretzschmar H.A.; RT "Molecular genetics of human prion diseases in Germany."; RL Hum. Genet. 105:244-252(1999). RN [60] RP VARIANTS EARLY-ONSET DEMENTIA LEU-102; ALA-183 AND LYS-188. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [61] RP VARIANTS CJD LYS-196; ILE-203 AND GLN-211. RX PubMed=10790216; RX DOI=10.1002/(sici)1098-1004(200005)15:5<482::aid-humu16>3.0.co;2-1; RA Peoc'h K., Manivet P., Beaudry P., Attane F., Besson G., Didier H., RA Delasnerie-Laupretre N., Laplanche J.-L.; RT "Identification of three novel mutations (E196K, V203I, E211Q) in the prion RT protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob RT disease phenotype."; RL Hum. Mutat. 15:482-482(2000). RN [62] RP VARIANT GSD VAL-131. RX PubMed=11709001; DOI=10.1001/archneur.58.11.1899; RA Panegyres P.K., Toufexis K., Kakulas B.A., Cernevakova L., Brown P., RA Ghetti B., Piccardo P., Dlouhy S.R.; RT "A new PRNP mutation (G131V) associated with Gerstmann-Straussler-Scheinker RT disease."; RL Arch. Neurol. 58:1899-1902(2001). RN [63] RP VARIANT VAL-129, AND CHARACTERIZATION OF VARIANT VAL-129. RX PubMed=12690204; DOI=10.1126/science.1083320; RA Mead S., Stumpf M.P., Whitfield J., Beck J.A., Poulter M., Campbell T., RA Uphill J.B., Goldstein D., Alpers M., Fisher E.M., Collinge J.; RT "Balancing selection at the prion protein gene consistent with prehistoric RT kurulike epidemics."; RL Science 300:640-643(2003). RN [64] RP VARIANT VAL-127, AND INVOLVEMENT IN KURU. RX PubMed=19923577; DOI=10.1056/nejmoa0809716; RA Mead S., Whitfield J., Poulter M., Shah P., Uphill J., Campbell T., RA Al-Dujaily H., Hummerich H., Beck J., Mein C.A., Verzilli C., Whittaker J., RA Alpers M.P., Collinge J.; RT "A novel protective prion protein variant that colocalizes with kuru RT exposure."; RL N. Engl. J. Med. 361:2056-2065(2009). RN [65] RP VARIANT VAL-127, CHARACTERIZATION OF VARIANT VAL-127, INVOLVEMENT IN KURU, RP AND POLYMORPHISM. RX PubMed=26061765; DOI=10.1038/nature14510; RA Asante E.A., Smidak M., Grimshaw A., Houghton R., Tomlinson A., Jeelani A., RA Jakubcova T., Hamdan S., Richard-Londt A., Linehan J.M., Brandner S., RA Alpers M., Whitfield J., Mead S., Wadsworth J.D., Collinge J.; RT "A naturally occurring variant of the human prion protein completely RT prevents prion disease."; RL Nature 522:478-481(2015). CC -!- FUNCTION: Its primary physiological function is unclear. May play a CC role in neuronal development and synaptic plasticity. May be required CC for neuronal myelin sheath maintenance. May promote myelin homeostasis CC through acting as an agonist for ADGRG6 receptor. May play a role in CC iron uptake and iron homeostasis. Soluble oligomers are toxic to CC cultured neuroblastoma cells and induce apoptosis (in vitro) (By CC similarity). Association with GPC1 (via its heparan sulfate chains) CC targets PRNP to lipid rafts. Also provides Cu(2+) or Zn(2+) for the CC ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate CC side chains (By similarity). {ECO:0000250|UniProtKB:P04925, CC ECO:0000269|PubMed:12732622, ECO:0000269|PubMed:19936054, CC ECO:0000269|PubMed:20564047, ECO:0000305}. CC -!- SUBUNIT: Monomer and homodimer. Has a tendency to aggregate into CC amyloid fibrils containing a cross-beta spine, formed by a steric CC zipper of superposed beta-strands. Soluble oligomers may represent an CC intermediate stage on the path to fibril formation. Copper binding may CC promote oligomerization (PubMed:11524679, PubMed:11900542, CC PubMed:14623188, PubMed:17468747, PubMed:19204296, PubMed:19927125, CC PubMed:20375014, PubMed:20564047). Interacts with GRB2, APP, CC ERI3/PRNPIP and SYN1. Mislocalized cytosolically exposed PrP interacts CC with MGRN1; this interaction alters MGRN1 subcellular location and CC causes lysosomal enlargement (By similarity). Interacts with KIAA1191 CC (PubMed:21153684). Interacts with ADGRG6 (By similarity). CC {ECO:0000250|UniProtKB:P04925, ECO:0000269|PubMed:11524679, CC ECO:0000269|PubMed:11900542, ECO:0000269|PubMed:14623188, CC ECO:0000269|PubMed:17468747, ECO:0000269|PubMed:19204296, CC ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:20375014, CC ECO:0000269|PubMed:20564047, ECO:0000269|PubMed:21153684}. CC -!- INTERACTION: CC P04156; Q9UL18: AGO1; NbExp=2; IntAct=EBI-977302, EBI-527363; CC P04156; Q9UKV8: AGO2; NbExp=4; IntAct=EBI-977302, EBI-528269; CC P04156; P05067: APP; NbExp=6; IntAct=EBI-977302, EBI-77613; CC P04156; P05067-4: APP; NbExp=2; IntAct=EBI-977302, EBI-302641; CC P04156; PRO_0000000092 [P05067]: APP; NbExp=3; IntAct=EBI-977302, EBI-821758; CC P04156; Q8WXF7: ATL1; NbExp=3; IntAct=EBI-977302, EBI-2410266; CC P04156; P25311: AZGP1; NbExp=4; IntAct=EBI-977302, EBI-2513837; CC P04156; P55085: F2RL1; NbExp=3; IntAct=EBI-977302, EBI-4303189; CC P04156; Q13642: FHL1; NbExp=3; IntAct=EBI-977302, EBI-912547; CC P04156; O75084: FZD7; NbExp=3; IntAct=EBI-977302, EBI-746917; CC P04156; P49639: HOXA1; NbExp=4; IntAct=EBI-977302, EBI-740785; CC P04156; P42858: HTT; NbExp=13; IntAct=EBI-977302, EBI-466029; CC P04156; P10636: MAPT; NbExp=2; IntAct=EBI-977302, EBI-366182; CC P04156; P29372: MPG; NbExp=4; IntAct=EBI-977302, EBI-1043398; CC P04156; Q9BSJ6: PIMREG; NbExp=5; IntAct=EBI-977302, EBI-2568609; CC P04156; Q9H4B4: PLK3; NbExp=4; IntAct=EBI-977302, EBI-751877; CC P04156; Q06830: PRDX1; NbExp=4; IntAct=EBI-977302, EBI-353193; CC P04156; P04156: PRNP; NbExp=33; IntAct=EBI-977302, EBI-977302; CC P04156; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-977302, EBI-11528848; CC P04156; Q8CJG0: Ago2; Xeno; NbExp=2; IntAct=EBI-977302, EBI-528299; CC P04156; P04925: Prnp; Xeno; NbExp=3; IntAct=EBI-977302, EBI-768613; CC P04156; P10279: PRNP; Xeno; NbExp=5; IntAct=EBI-977302, EBI-7430632; CC P04156; P23907: PRNP; Xeno; NbExp=3; IntAct=EBI-977302, EBI-7670302; CC PRO_0000025675; P31424-2: Grm5; Xeno; NbExp=4; IntAct=EBI-8830282, EBI-8830305; CC PRO_0000025675; P52480: Pkm; Xeno; NbExp=5; IntAct=EBI-8830282, EBI-647785; CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor CC {ECO:0000269|PubMed:19936054}. Golgi apparatus CC {ECO:0000250|UniProtKB:P04925}. Note=Targeted to lipid rafts via CC association with the heparan sulfate chains of GPC1. Colocates, in the CC presence of Cu(2+), to vesicles in para- and perinuclear regions, where CC both proteins undergo internalization. Heparin displaces PRNP from CC lipid rafts and promotes endocytosis. {ECO:0000269|PubMed:19936054}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=2; CC Name=1; Synonyms=PrP; CC IsoId=P04156-1; Sequence=Displayed; CC Name=3; Synonyms=AltPrP; CC IsoId=F7VJQ1-1; Sequence=External; CC -!- DOMAIN: The normal, monomeric form, PRPN(C), has a mainly alpha-helical CC structure. Misfolding of this form produces a disease-associated, CC protease-resistant form, PRPN (Sc), accompanied by a large increase of CC the beta-sheet content and formation of amyloid fibrils. These fibrils CC consist of a cross-beta spine, formed by a steric zipper of superposed CC beta-strands. Disease mutations may favor intermolecular contacts via CC short beta strands, and may thereby trigger oligomerization. In CC addition, the heparan-sulfate proteoglycan, GPC1, promotes the CC association of PRPN (C) to lipid rafts and appears to facilitate the CC conversion to PRPN (Sc). {ECO:0000269|PubMed:17468747, CC ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:20564047}. CC -!- DOMAIN: Contains an N-terminal region composed of octamer repeats. At CC low copper concentrations, the sidechains of His residues from three or CC four repeats contribute to the binding of a single copper ion. CC Alternatively, a copper ion can be bound by interaction with the CC sidechain and backbone amide nitrogen of a single His residue. The CC observed copper binding stoichiometry suggests that two repeat regions CC cooperate to stabilize the binding of a single copper ion. At higher CC copper concentrations, each octamer can bind one copper ion by CC interactions with the His sidechain and Gly backbone atoms. A mixture CC of binding types may occur, especially in the case of octamer repeat CC expansion. Copper binding may stabilize the conformation of this region CC and may promote oligomerization. {ECO:0000269|PubMed:11524679, CC ECO:0000269|PubMed:11900542, ECO:0000269|PubMed:20375014}. CC -!- PTM: The glycosylation pattern (the amount of mono-, di- and non- CC glycosylated forms or glycoforms) seems to differ in normal and CJD CC prion. {ECO:0000269|PubMed:12214108}. CC -!- POLYMORPHISM: The five tandem octapeptide repeats region is highly CC unstable. Insertions or deletions of octapeptide repeat units are CC associated to prion disease. {ECO:0000269|PubMed:1683708}. CC -!- POLYMORPHISM: A number of polymorphisms confer resistance to prion CC diseases (PubMed:1439789, PubMed:19923577, PubMed:26061765, CC PubMed:9482303). Val-127 has been selected for in response to the Kuru CC epidemic and confers resistance to prion disease by acting as a CC 'dominant negative' inhibitor of prion conversion (PubMed:26061765). CC Val-127 is not only itself resistant to conformational conversion, but CC also inhibits conversion of wild-type proteins. Confers protection CC against classical Creutzfeldt-Jakob disease (CJD) and Kuru in the CC heterozygous state, but can be infected with variant CJD prions, CC resulting from exposure to bovine spongiform encephalopathy prions. CC Confers complete resistance to all prion strains when homozygous CC (PubMed:26061765). Always associated with M-129 variant CC (PubMed:26061765). Val-129 confers relative protection against CC acquired, sporadic and some inherited prion diseases in the CC heterozygous state, possibly by preventing homodimerization CC (PubMed:1439789). Lys-219 confers relative protection against sporadic CC Creutzfeldt-Jakob disease (CJD) in the heterozygous state CC (PubMed:9482303). {ECO:0000269|PubMed:1439789, CC ECO:0000269|PubMed:26061765, ECO:0000269|PubMed:9482303}. CC -!- DISEASE: Note=PrP is found in high quantity in the brain of humans and CC animals infected with neurodegenerative diseases known as transmissible CC spongiform encephalopathies or prion diseases, like: Creutzfeldt-Jakob CC disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler CC disease (GSD), Huntington disease-like type 1 (HDL1) and kuru in CC humans; scrapie in sheep and goat; bovine spongiform encephalopathy CC (BSE) in cattle; transmissible mink encephalopathy (TME); chronic CC wasting disease (CWD) of mule deer and elk; feline spongiform CC encephalopathy (FSE) in cats and exotic ungulate encephalopathy (EUE) CC in nyala and greater kudu. The prion diseases illustrate three CC manifestations of CNS degeneration: (1) infectious (2) sporadic and (3) CC dominantly inherited forms. TME, CWD, BSE, FSE, EUE are all thought to CC occur after consumption of prion-infected foodstuffs. CC {ECO:0000269|PubMed:8105771}. CC -!- DISEASE: Creutzfeldt-Jakob disease (CJD) [MIM:123400]: Occurs primarily CC as a sporadic disorder (1 per million), while 10-15% are familial. CC Accidental transmission of CJD to humans appears to be iatrogenic CC (contaminated human growth hormone (HGH), corneal transplantation, CC electroencephalographic electrode implantation, etc.). Epidemiologic CC studies have failed to implicate the ingestion of infected animal meat CC in the pathogenesis of CJD in human. The triad of microscopic features CC that characterize the prion diseases consists of (1) spongiform CC degeneration of neurons, (2) severe astrocytic gliosis that often CC appears to be out of proportion to the degree of nerve cell loss, and CC (3) amyloid plaque formation. CJD is characterized by progressive CC dementia and myoclonic seizures, affecting adults in mid-life. Some CC patients present sleep disorders, abnormalities of high cortical CC function, cerebellar and corticospinal disturbances. The disease ends CC in death after a 3-12 months illness. {ECO:0000269|PubMed:10790216, CC ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:1671440, CC ECO:0000269|PubMed:1975028, ECO:0000269|PubMed:19927125, CC ECO:0000269|PubMed:7902693, ECO:0000269|PubMed:7906019, CC ECO:0000269|PubMed:7913755, ECO:0000269|PubMed:8461023, CC ECO:0000269|PubMed:8909447}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Fatal familial insomnia (FFI) [MIM:600072]: Autosomal dominant CC disorder and is characterized by neuronal degeneration limited to CC selected thalamic nuclei and progressive insomnia. CC {ECO:0000269|PubMed:1347910, ECO:0000269|PubMed:1439789, CC ECO:0000269|PubMed:19927125}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Gerstmann-Straussler disease (GSD) [MIM:137440]: A rare CC inherited prion disease characterized by adult onset of memory loss, CC dementia, ataxia, and pathologic deposition of amyloid-like plaques in CC the brain. GSD presents with progressive limb and truncal ataxia, CC dysarthria, and cognitive decline in the thirties and forties, and the CC average disease duration is 7 years. {ECO:0000269|PubMed:10581485, CC ECO:0000269|PubMed:11709001, ECO:0000269|PubMed:1363810, CC ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:19927125, CC ECO:0000269|PubMed:2564168, ECO:0000269|PubMed:7699395, CC ECO:0000269|PubMed:7783876, ECO:0000269|PubMed:7902972, CC ECO:0000269|PubMed:8797472, ECO:0000269|PubMed:9786248}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Huntington disease-like 1 (HDL1) [MIM:603218]: Autosomal CC dominant, early-onset neurodegenerative disorder with prominent CC psychiatric features. {ECO:0000269|PubMed:9792871}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Kuru (KURU) [MIM:245300]: Kuru is transmitted during CC ritualistic cannibalism, among natives of the New Guinea highlands. CC Patients exhibit various movement disorders like cerebellar CC abnormalities, rigidity of the limbs, and clonus. Emotional lability is CC present, and dementia is conspicuously absent. Death usually occurs CC from 3 to 12 month after onset. {ECO:0000269|PubMed:19923577, CC ECO:0000269|PubMed:26061765}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spongiform encephalopathy with neuropsychiatric features CC (SENF) [MIM:606688]: Autosomal dominant presenile dementia with a CC rapidly progressive and protracted clinical course. The dementia was CC characterized clinically by frontotemporal features, including early CC personality changes. Some patients had memory loss, several showed CC aggressiveness, hyperorality and verbal stereotypy, others had CC parkinsonian symptoms. {ECO:0000269|PubMed:12214108, CC ECO:0000269|PubMed:9266722}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: This protein is produced by a bicistronic gene which CC also produces the alternative prion protein/AltPrP (AC F7VJQ1) from an CC overlapping reading frame. {ECO:0000305|PubMed:21478263}. CC -!- MISCELLANEOUS: The alternative prion protein/AltPrP (AC F7VJQ1) and CC PRNP have no apparent direct functional relation since a mutation that CC removes the start codon of the AltPrP has no apparent effect on the CC biology of PRNP. In mouse and hamster, the alternative initiation AUG CC codon is absent and is replaced by a GUG codon. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the prion family. {ECO:0000305}. CC -!- CAUTION: An isoform was shown to be localized to both the cytoplasm and CC the nucleus and to be sumoylated with SUMO1 (PubMed:19059915). The CC article has later been withdrawn by the authors. CC {ECO:0000269|PubMed:19059915, ECO:0000305|PubMed:29222195}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=PRNP entry; CC URL="https://en.wikipedia.org/wiki/PRNP"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The shape of harm - Issue CC 179 of May 2016; CC URL="https://www.proteinspotlight.org/back_issues/179/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M13899; AAA60182.1; -; mRNA. DR EMBL; X83416; CAA58442.1; -; Genomic_DNA. DR EMBL; U29185; AAC78725.1; -; Genomic_DNA. DR EMBL; AF076976; AAD46098.1; -; Genomic_DNA. DR EMBL; AY008282; AAG21693.1; -; mRNA. DR EMBL; DQ408531; ABD63004.1; -; Genomic_DNA. DR EMBL; AL133396; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC012844; AAH12844.1; -; mRNA. DR EMBL; BC022532; AAH22532.1; -; mRNA. DR EMBL; D00015; BAA00011.1; -; mRNA. DR EMBL; M13667; AAA19664.1; -; mRNA. DR EMBL; M81929; AAB59442.1; -; Genomic_DNA. DR EMBL; M81930; AAB59443.1; -; Genomic_DNA. DR EMBL; AF030575; AAC05365.1; -; Genomic_DNA. DR EMBL; S80732; AAB50648.2; -; Genomic_DNA. DR EMBL; S80743; AAB50649.2; -; Genomic_DNA. DR EMBL; S71208; AAB20521.1; -; Genomic_DNA. DR EMBL; S71210; AAB20522.1; -; Genomic_DNA. DR EMBL; S71212; AAB20523.1; -; Genomic_DNA. DR CCDS; CCDS13080.1; -. [P04156-1] DR PIR; A24173; UJHU. DR RefSeq; NP_000302.1; NM_000311.5. [P04156-1] DR RefSeq; NP_001073590.1; NM_001080121.3. [P04156-1] DR RefSeq; NP_001073591.1; NM_001080122.3. [P04156-1] DR RefSeq; NP_001073592.1; NM_001080123.3. [P04156-1] DR RefSeq; NP_001258490.1; NM_001271561.2. DR RefSeq; NP_898902.1; NM_183079.4. [P04156-1] DR PDB; 1E1G; NMR; -; A=125-228. DR PDB; 1E1J; NMR; -; A=125-228. DR PDB; 1E1P; NMR; -; A=125-228. DR PDB; 1E1S; NMR; -; A=125-228. DR PDB; 1E1U; NMR; -; A=125-228. DR PDB; 1E1W; NMR; -; A=125-228. DR PDB; 1FKC; NMR; -; A=90-231. DR PDB; 1FO7; NMR; -; A=90-231. DR PDB; 1H0L; NMR; -; A=121-230. DR PDB; 1HJM; NMR; -; A=125-228. DR PDB; 1HJN; NMR; -; A=125-228. DR PDB; 1I4M; X-ray; 2.00 A; A=119-226. DR PDB; 1OEH; NMR; -; A=77-84. DR PDB; 1OEI; NMR; -; A=61-84. DR PDB; 1QLX; NMR; -; A=23-230. DR PDB; 1QLZ; NMR; -; A=23-230. DR PDB; 1QM0; NMR; -; A=90-230. DR PDB; 1QM1; NMR; -; A=90-230. DR PDB; 1QM2; NMR; -; A=121-230. DR PDB; 1QM3; NMR; -; A=121-230. DR PDB; 2IV4; NMR; -; A=180-195. DR PDB; 2IV5; NMR; -; A=173-195. DR PDB; 2IV6; NMR; -; A=173-195. DR PDB; 2K1D; NMR; -; A=90-231. DR PDB; 2KUN; NMR; -; A=90-231. DR PDB; 2LBG; NMR; -; A=110-136. DR PDB; 2LEJ; NMR; -; A=90-231. DR PDB; 2LFT; NMR; -; A=90-231. DR PDB; 2LSB; NMR; -; A=90-231. DR PDB; 2LV1; NMR; -; A=90-231. DR PDB; 2M8T; NMR; -; A=90-231. DR PDB; 2OL9; X-ray; 0.85 A; A=170-175. DR PDB; 2W9E; X-ray; 2.90 A; A=119-231. DR PDB; 3HAF; X-ray; 2.26 A; A=90-231. DR PDB; 3HAK; X-ray; 1.80 A; A=125-227. DR PDB; 3HEQ; X-ray; 1.80 A; A/B=90-231. DR PDB; 3HER; X-ray; 1.85 A; A/B=90-231. DR PDB; 3HES; X-ray; 2.00 A; A/B=90-231. DR PDB; 3HJ5; X-ray; 3.10 A; A/B=90-231. DR PDB; 3HJX; X-ray; 2.00 A; A=126-231. DR PDB; 3MD4; X-ray; 1.15 A; A/B=127-132. DR PDB; 3MD5; X-ray; 1.40 A; A/B=127-132. DR PDB; 3NHC; X-ray; 1.57 A; A/B=127-132. DR PDB; 3NHD; X-ray; 1.92 A; A/B=127-132. DR PDB; 3NVF; X-ray; 1.80 A; A=138-143. DR PDB; 4DGI; X-ray; 2.40 A; A=120-230. DR PDB; 4E1H; X-ray; 1.40 A; A/C/E/G/I/K=177-182, B/D/F/H/J/L=211-216. DR PDB; 4E1I; X-ray; 2.03 A; A/C/E/G/I/K=177-182, B/D/F/H/J/L=211-216. DR PDB; 4KML; X-ray; 1.50 A; A=24-231. DR PDB; 4N9O; X-ray; 1.50 A; A=90-231. DR PDB; 5L6R; NMR; -; A=90-226. DR PDB; 5YJ4; NMR; -; A=91-231. DR PDB; 5YJ5; NMR; -; A=91-231. DR PDB; 6DU9; X-ray; 2.33 A; A=90-230. DR PDB; 6LNI; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=23-231. DR PDB; 6PQ5; X-ray; 1.50 A; A/B=113-118. DR PDB; 6PQA; X-ray; 1.46 A; A=119-124. DR PDB; 6SUZ; X-ray; 2.50 A; A=125-223. DR PDB; 6SV2; X-ray; 2.30 A; A=119-231. DR PDB; 6UUR; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=94-178. DR PDB; 7DWV; EM; 3.07 A; A/B/C/D/E/F=23-231. DR PDB; 7FHQ; NMR; -; A=91-231. DR PDB; 7RL4; EM; 2.86 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T=23-144. DR PDB; 7RVC; EM; 1.00 A; A=168-176. DR PDB; 7RVE; EM; 0.85 A; A=168-176. DR PDB; 7RVJ; EM; 1.00 A; A/B=169-175. DR PDB; 7RVK; EM; 1.00 A; A=169-175. DR PDB; 7RVL; EM; 1.00 A; A=168-176. DR PDB; 7UMQ; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J=80-141. DR PDB; 7UN5; EM; 3.13 A; A/B/C/D/E/F/G/H/I/J=80-141. DR PDBsum; 1E1G; -. DR PDBsum; 1E1J; -. DR PDBsum; 1E1P; -. DR PDBsum; 1E1S; -. DR PDBsum; 1E1U; -. DR PDBsum; 1E1W; -. DR PDBsum; 1FKC; -. DR PDBsum; 1FO7; -. DR PDBsum; 1H0L; -. DR PDBsum; 1HJM; -. DR PDBsum; 1HJN; -. DR PDBsum; 1I4M; -. DR PDBsum; 1OEH; -. DR PDBsum; 1OEI; -. DR PDBsum; 1QLX; -. DR PDBsum; 1QLZ; -. DR PDBsum; 1QM0; -. DR PDBsum; 1QM1; -. DR PDBsum; 1QM2; -. DR PDBsum; 1QM3; -. DR PDBsum; 2IV4; -. DR PDBsum; 2IV5; -. DR PDBsum; 2IV6; -. DR PDBsum; 2K1D; -. DR PDBsum; 2KUN; -. DR PDBsum; 2LBG; -. DR PDBsum; 2LEJ; -. DR PDBsum; 2LFT; -. DR PDBsum; 2LSB; -. DR PDBsum; 2LV1; -. DR PDBsum; 2M8T; -. DR PDBsum; 2OL9; -. DR PDBsum; 2W9E; -. DR PDBsum; 3HAF; -. DR PDBsum; 3HAK; -. DR PDBsum; 3HEQ; -. DR PDBsum; 3HER; -. DR PDBsum; 3HES; -. DR PDBsum; 3HJ5; -. DR PDBsum; 3HJX; -. DR PDBsum; 3MD4; -. DR PDBsum; 3MD5; -. DR PDBsum; 3NHC; -. DR PDBsum; 3NHD; -. DR PDBsum; 3NVF; -. DR PDBsum; 4DGI; -. DR PDBsum; 4E1H; -. DR PDBsum; 4E1I; -. DR PDBsum; 4KML; -. DR PDBsum; 4N9O; -. DR PDBsum; 5L6R; -. DR PDBsum; 5YJ4; -. DR PDBsum; 5YJ5; -. DR PDBsum; 6DU9; -. DR PDBsum; 6LNI; -. DR PDBsum; 6PQ5; -. DR PDBsum; 6PQA; -. DR PDBsum; 6SUZ; -. DR PDBsum; 6SV2; -. DR PDBsum; 6UUR; -. DR PDBsum; 7DWV; -. DR PDBsum; 7FHQ; -. DR PDBsum; 7RL4; -. DR PDBsum; 7RVC; -. DR PDBsum; 7RVE; -. DR PDBsum; 7RVJ; -. DR PDBsum; 7RVK; -. DR PDBsum; 7RVL; -. DR PDBsum; 7UMQ; -. DR PDBsum; 7UN5; -. DR AlphaFoldDB; P04156; -. DR BMRB; P04156; -. DR EMDB; EMD-0931; -. DR EMDB; EMD-20900; -. DR EMDB; EMD-24514; -. DR EMDB; EMD-26607; -. DR EMDB; EMD-26613; -. DR EMDB; EMD-30887; -. DR SASBDB; P04156; -. DR SMR; P04156; -. DR BioGRID; 111606; 2255. DR CORUM; P04156; -. DR DIP; DIP-29933N; -. DR ELM; P04156; -. DR FunCoup; P04156; 501. DR IntAct; P04156; 454. DR MINT; P04156; -. DR STRING; 9606.ENSP00000399376; -. DR BindingDB; P04156; -. DR ChEMBL; CHEMBL4869; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB00759; Tetracycline. DR DrugCentral; P04156; -. DR MoonDB; P04156; Predicted. DR TCDB; 1.C.48.1.2; the prion peptide (prp) family. DR GlyConnect; 2056; 3 N-Linked glycans (1 site). DR GlyCosmos; P04156; 2 sites, 6 glycans. DR GlyGen; P04156; 4 sites, 12 N-linked glycans (2 sites), 2 O-linked glycans (2 sites). DR iPTMnet; P04156; -. DR MetOSite; P04156; -. DR PhosphoSitePlus; P04156; -. DR SwissPalm; P04156; -. DR BioMuta; PRNP; -. DR DMDM; 130912; -. DR jPOST; P04156; -. DR MassIVE; P04156; -. DR PaxDb; 9606-ENSP00000368752; -. DR PeptideAtlas; P04156; -. DR ProteomicsDB; 51667; -. [P04156-1] DR Pumba; P04156; -. DR ABCD; P04156; 3 sequenced antibodies. DR Antibodypedia; 3351; 881 antibodies from 47 providers. DR DNASU; 5621; -. DR Ensembl; ENST00000379440.9; ENSP00000368752.4; ENSG00000171867.19. DR Ensembl; ENST00000424424.2; ENSP00000411599.2; ENSG00000171867.19. DR Ensembl; ENST00000430350.2; ENSP00000399376.2; ENSG00000171867.19. DR Ensembl; ENST00000457586.2; ENSP00000415284.2; ENSG00000171867.19. DR GeneID; 5621; -. DR KEGG; hsa:5621; -. DR MANE-Select; ENST00000379440.9; ENSP00000368752.4; NM_000311.5; NP_000302.1. DR AGR; HGNC:9449; -. DR ClinPGx; PA33796; -. DR CTD; 5621; -. DR DisGeNET; 5621; -. DR GeneCards; PRNP; -. DR GeneReviews; PRNP; -. DR HGNC; HGNC:9449; PRNP. DR HPA; ENSG00000171867; Tissue enhanced (choroid). DR MalaCards; PRNP; -. DR MIM; 123400; phenotype. DR MIM; 137440; phenotype. DR MIM; 176640; gene. DR MIM; 245300; phenotype. DR MIM; 600072; phenotype. DR MIM; 603218; phenotype. DR MIM; 606688; phenotype. DR OpenTargets; ENSG00000171867; -. DR Orphanet; 280397; Familial Alzheimer-like prion disease. DR Orphanet; 466; Fatal familial insomnia. DR Orphanet; 356; Gerstmann-Straussler-Scheinker syndrome. DR Orphanet; 157941; Huntington disease-like 1. DR Orphanet; 282166; Inherited Creutzfeldt-Jakob disease. DR Orphanet; 454745; Kuru. DR Orphanet; 397606; PrP systemic amyloidosis. DR VEuPathDB; HostDB:ENSG00000171867; -. DR eggNOG; ENOG502S2A8; Eukaryota. DR GeneTree; ENSGT00510000049083; -. DR InParanoid; P04156; -. DR OMA; QMCTTQY; -. DR OrthoDB; 9048788at2759; -. DR PAN-GO; P04156; 3 GO annotations based on evolutionary models. DR PhylomeDB; P04156; -. DR PathwayCommons; P04156; -. DR Reactome; R-HSA-419037; NCAM1 interactions. DR Reactome; R-HSA-9609523; Insertion of tail-anchored proteins into the endoplasmic reticulum membrane. DR SignaLink; P04156; -. DR Agora; ENSG00000171867; -. DR BioGRID-ORCS; 5621; 10 hits in 1169 CRISPR screens. DR CD-CODE; 7A2E2A6F; Synthetic Condensate 000125. DR CD-CODE; 8188F968; Tau-Prion Multiphasic condensate. DR CD-CODE; 9F779CC8; Nuclear body. DR ChiTaRS; PRNP; human. DR EvolutionaryTrace; P04156; -. DR GenomeRNAi; 5621; -. DR Pharos; P04156; Tchem. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; P04156; protein. DR Bgee; ENSG00000171867; Expressed in Brodmann (1909) area 23 and 209 other cell types or tissues. DR ExpressionAtlas; P04156; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; TAS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0009897; C:external side of plasma membrane; NAS:ARUK-UCL. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0019898; C:extrinsic component of membrane; TAS:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0016234; C:inclusion body; IMP:CAFA. DR GO; GO:0045121; C:membrane raft; IDA:MGI. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; TAS:ARUK-UCL. DR GO; GO:0014069; C:postsynaptic density; ISS:ARUK-UCL. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0001540; F:amyloid-beta binding; IDA:ARUK-UCL. DR GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; ISS:ARUK-UCL. DR GO; GO:0043008; F:ATP-dependent protein binding; IEA:Ensembl. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903135; F:cupric ion binding; IEA:Ensembl. DR GO; GO:1903136; F:cuprous ion binding; IMP:CAFA. DR GO; GO:0005539; F:glycosaminoglycan binding; ISS:ARUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0005521; F:lamin binding; IEA:Ensembl. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0060090; F:molecular adaptor activity; IDA:DisProt. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:DisProt. DR GO; GO:0140677; F:molecular function activator activity; IEA:Ensembl. DR GO; GO:0002020; F:protease binding; ISS:ARUK-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IEA:Ensembl. DR GO; GO:0038023; F:signaling receptor activity; ISS:ARUK-UCL. DR GO; GO:0044325; F:transmembrane transporter binding; IEA:Ensembl. DR GO; GO:0015631; F:tubulin binding; IDA:UniProtKB. DR GO; GO:0031802; F:type 5 metabotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0071280; P:cellular response to copper ion; IDA:MGI. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0097062; P:dendritic spine maintenance; TAS:ARUK-UCL. DR GO; GO:0006878; P:intracellular copper ion homeostasis; NAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ARUK-UCL. DR GO; GO:0007611; P:learning or memory; ISS:ARUK-UCL. DR GO; GO:0007616; P:long-term memory; TAS:ARUK-UCL. DR GO; GO:0046007; P:negative regulation of activated T cell proliferation; ISS:BHF-UCL. DR GO; GO:1902992; P:negative regulation of amyloid precursor protein catabolic process; ISS:ARUK-UCL. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; ISS:ARUK-UCL. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; ISS:BHF-UCL. DR GO; GO:1902951; P:negative regulation of dendritic spine maintenance; ISS:ARUK-UCL. DR GO; GO:0032700; P:negative regulation of interleukin-17 production; ISS:BHF-UCL. DR GO; GO:0032703; P:negative regulation of interleukin-2 production; ISS:BHF-UCL. DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0010955; P:negative regulation of protein processing; TAS:ARUK-UCL. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0032689; P:negative regulation of type II interferon production; ISS:BHF-UCL. DR GO; GO:1990535; P:neuron projection maintenance; ISS:ARUK-UCL. DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IGI:ARUK-UCL. DR GO; GO:1900451; P:positive regulation of glutamate receptor signaling pathway; IGI:ARUK-UCL. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:CAFA. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IEA:Ensembl. DR GO; GO:0090314; P:positive regulation of protein targeting to membrane; ISS:ARUK-UCL. DR GO; GO:0031648; P:protein destabilization; IMP:CAFA. DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro. DR GO; GO:1905664; P:regulation of calcium ion import across plasma membrane; ISS:ARUK-UCL. DR GO; GO:0051726; P:regulation of cell cycle; IEA:UniProtKB-KW. DR GO; GO:1900449; P:regulation of glutamate receptor signaling pathway; ISS:ARUK-UCL. DR GO; GO:1901379; P:regulation of potassium ion transmembrane transport; IEA:Ensembl. DR GO; GO:1904645; P:response to amyloid-beta; ISS:ARUK-UCL. DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; ISS:UniProtKB. DR DisProt; DP00466; -. DR FunFam; 1.10.790.10:FF:000001; Major prion protein; 1. DR Gene3D; 1.10.790.10; Prion/Doppel protein, beta-ribbon domain; 1. DR InterPro; IPR000817; Prion. DR InterPro; IPR036924; Prion/Doppel_b-ribbon_dom_sf. DR InterPro; IPR022416; Prion/Doppel_prot_b-ribbon_dom. DR InterPro; IPR020949; Prion_copper_b_octapeptide. DR InterPro; IPR025860; Prion_N. DR PANTHER; PTHR15506; DOPPEL PRION; 1. DR PANTHER; PTHR15506:SF2; MAJOR PRION PROTEIN; 1. DR Pfam; PF00377; Prion; 1. DR Pfam; PF11587; Prion_bPrPp; 1. DR Pfam; PF03991; Prion_octapep; 1. DR PRINTS; PR00341; PRION. DR SMART; SM00157; PRP; 1. DR SUPFAM; SSF54098; Prion-like; 1. DR PROSITE; PS00291; PRION_1; 1. DR PROSITE; PS00706; PRION_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Amyloid; Amyloidosis; Cell cycle; KW Cell membrane; Copper; Direct protein sequencing; Disease variant; KW Disulfide bond; Glycoprotein; Golgi apparatus; GPI-anchor; Growth arrest; KW Lipoprotein; Membrane; Metal-binding; Prion; Proteomics identification; KW Reference proteome; Repeat; Signal; Zinc. FT SIGNAL 1..22 FT /evidence="ECO:0000250|UniProtKB:P04925" FT CHAIN 23..230 FT /note="Major prion protein" FT /id="PRO_0000025675" FT PROPEP 231..253 FT /note="Removed in mature form" FT /evidence="ECO:0000250|UniProtKB:P04273" FT /id="PRO_0000025676" FT REPEAT 51..59 FT /note="1" FT REPEAT 60..67 FT /note="2" FT REPEAT 68..75 FT /note="3" FT REPEAT 76..83 FT /note="4" FT REPEAT 84..91 FT /note="5" FT REGION 23..230 FT /note="Interaction with GRB2, ERI3 and SYN1" FT /evidence="ECO:0000250|UniProtKB:P04925" FT REGION 23..38 FT /note="Interaction with ADGRG6" FT /evidence="ECO:0000250|UniProtKB:P04925" FT REGION 26..108 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 51..91 FT /note="5 X 8 AA tandem repeats of P-H-G-G-G-W-G-Q" FT COMPBIAS 52..95 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 61 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 62 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 63 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:11900542" FT BINDING 69 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 70 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 71 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 77 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 78 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 79 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="3" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 85 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 86 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT BINDING 87 FT /ligand="Cu(2+)" FT /ligand_id="ChEBI:CHEBI:29036" FT /ligand_label="4" FT /evidence="ECO:0000305|PubMed:11900542" FT LIPID 230 FT /note="GPI-anchor amidated serine" FT /evidence="ECO:0000250|UniProtKB:P04273" FT CARBOHYD 181 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12214108" FT CARBOHYD 197 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT DISULFID 179..214 FT /evidence="ECO:0000269|PubMed:14623188" FT VARIANT 56..63 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:1363802, FT ECO:0000269|PubMed:1678248, ECO:0000269|PubMed:7485229" FT /id="VAR_013763" FT VARIANT 102 FT /note="P -> L (in GSD and early-onset dementia; FT dbSNP:rs74315401)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:2564168, ECO:0000269|PubMed:2783132, FT ECO:0000269|PubMed:7783876, ECO:0000269|PubMed:8797472" FT /id="VAR_006464" FT VARIANT 105 FT /note="P -> L (in GSD; dbSNP:rs11538758)" FT /evidence="ECO:0000269|PubMed:7699395, FT ECO:0000269|PubMed:7902972" FT /id="VAR_006465" FT VARIANT 117 FT /note="A -> V (linked to development of dementing FT Gerstmann-Straussler disease; dbSNP:rs74315402)" FT /evidence="ECO:0000269|PubMed:2783132" FT /id="VAR_006466" FT VARIANT 127 FT /note="G -> V (protective factor against Kuru; protective FT factor against prion disease; confers protection against FT classical Creutzfeldt-Jakob disease (CJD) and Kuru in the FT heterozygous state but can be infected with variant CJD FT prions resulting from exposure to bovine spongiform FT encephalopathy prions; confers complete resistance to all FT prion strains when homozygous; acts as a 'dominant FT negative' inhibitor of prion conversion; is not only itself FT resistant to conformational conversion, but also inhibits FT conversion of wild-type proteins; dbSNP:rs267606980)" FT /evidence="ECO:0000269|PubMed:19923577, FT ECO:0000269|PubMed:26061765" FT /id="VAR_073722" FT VARIANT 129 FT /note="M -> V (protective factor against acquired, sporadic FT and some inherited prion diseases in the heterozygous FT state, possibly by preventing homodimerization; determines FT the disease phenotype in patients who have a PrP mutation FT at position 178; patients with M-129 develop FFI, those FT with V-129 develop CJD; dbSNP:rs1799990)" FT /evidence="ECO:0000269|PubMed:12690204, FT ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:19927125, FT ECO:0000269|PubMed:2783132" FT /id="VAR_006467" FT VARIANT 131 FT /note="G -> V (in GSD; dbSNP:rs74315410)" FT /evidence="ECO:0000269|PubMed:11709001" FT /id="VAR_014264" FT VARIANT 171 FT /note="N -> S (in schizoaffective disorder; FT dbSNP:rs16990018)" FT /evidence="ECO:0000269|PubMed:9384372" FT /id="VAR_006468" FT VARIANT 178 FT /note="D -> N (in FFI and CJD; dbSNP:rs74315403)" FT /evidence="ECO:0000269|PubMed:1347910, FT ECO:0000269|PubMed:1439789, ECO:0000269|PubMed:1671440, FT ECO:0000269|PubMed:19927125" FT /id="VAR_006469" FT VARIANT 180 FT /note="V -> I (in CJD; dbSNP:rs74315408)" FT /evidence="ECO:0000269|PubMed:1439789, FT ECO:0000269|PubMed:19927125, ECO:0000269|PubMed:8461023" FT /id="VAR_006470" FT VARIANT 183 FT /note="T -> A (in SENF and early-onset dementia; induces FT loss of glycosylation at N-181; dbSNP:rs74315411)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:12214108, ECO:0000269|PubMed:9266722" FT /id="VAR_006471" FT VARIANT 187 FT /note="H -> R (in GSD; dbSNP:rs74315413)" FT /evidence="ECO:0000269|PubMed:10581485" FT /id="VAR_008746" FT VARIANT 188 FT /note="T -> K (in early-onset dementia and dementia due to FT prion diseases)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_008748" FT VARIANT 188 FT /note="T -> R (in dbSNP:rs372878791)" FT /evidence="ECO:0000269|PubMed:10987652" FT /id="VAR_008747" FT VARIANT 196 FT /note="E -> K (in CJD)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008749" FT VARIANT 198 FT /note="F -> S (in GSD; atypical form with neurofibrillary FT tangles; dbSNP:rs74315405)" FT /evidence="ECO:0000269|PubMed:19927125" FT /id="VAR_006472" FT VARIANT 200 FT /note="E -> K (in CJD; dbSNP:rs28933385)" FT /evidence="ECO:0000269|PubMed:1975028, FT ECO:0000269|PubMed:7906019, ECO:0000269|PubMed:7913755" FT /id="VAR_006473" FT VARIANT 202 FT /note="D -> N (in GSD; dbSNP:rs761807915)" FT /evidence="ECO:0000269|PubMed:9786248" FT /id="VAR_008750" FT VARIANT 203 FT /note="V -> I (in CJD; uncertain significance; FT dbSNP:rs776593792)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008751" FT VARIANT 208 FT /note="R -> H (in CJD; dbSNP:rs74315412)" FT /evidence="ECO:0000269|PubMed:8909447" FT /id="VAR_006474" FT VARIANT 210 FT /note="V -> I (in CJD; dbSNP:rs74315407)" FT /evidence="ECO:0000269|PubMed:7902693" FT /id="VAR_006475" FT VARIANT 211 FT /note="E -> Q (in CJD; dbSNP:rs398122370)" FT /evidence="ECO:0000269|PubMed:10790216" FT /id="VAR_008752" FT VARIANT 212 FT /note="Q -> P (in GSD; dbSNP:rs751882709)" FT /evidence="ECO:0000269|PubMed:9786248" FT /id="VAR_008753" FT VARIANT 217 FT /note="Q -> R (in GSD; with neurofibrillary tangles; FT dbSNP:rs74315406)" FT /evidence="ECO:0000269|PubMed:1363810" FT /id="VAR_006476" FT VARIANT 219 FT /note="E -> K (confers relative protection against sporadic FT Creutzfeldt-Jakob disease (CJD) in the heterozygous state; FT dbSNP:rs1800014)" FT /evidence="ECO:0000269|PubMed:8797472, FT ECO:0000269|PubMed:9482303" FT /id="VAR_006477" FT VARIANT 232 FT /note="M -> R (in CJD; dbSNP:rs74315409)" FT /evidence="ECO:0000269|PubMed:8461023" FT /id="VAR_006478" FT VARIANT 238 FT /note="P -> S" FT /evidence="ECO:0000269|PubMed:10987652" FT /id="VAR_008754" FT CONFLICT 118 FT /note="Missing (in Ref. 9; AAA19664/BAA00011)" FT /evidence="ECO:0000305" FT CONFLICT 169 FT /note="Y -> H (in Ref. 6; ABD63004)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="Q -> K (in Ref. 8; AAH22532)" FT /evidence="ECO:0000305" FT STRAND 63..67 FT /evidence="ECO:0007829|PDB:1OEI" FT STRAND 70..73 FT /evidence="ECO:0007829|PDB:1OEI" FT TURN 74..76 FT /evidence="ECO:0007829|PDB:1OEI" FT STRAND 79..82 FT /evidence="ECO:0007829|PDB:1OEH" FT STRAND 92..95 FT /evidence="ECO:0007829|PDB:5YJ4" FT STRAND 99..101 FT /evidence="ECO:0007829|PDB:5L6R" FT STRAND 109..112 FT /evidence="ECO:0007829|PDB:7RL4" FT TURN 114..117 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 118..122 FT /evidence="ECO:0007829|PDB:4KML" FT STRAND 125..127 FT /evidence="ECO:0007829|PDB:1H0L" FT STRAND 128..131 FT /evidence="ECO:0007829|PDB:3MD4" FT STRAND 133..135 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 138..140 FT /evidence="ECO:0007829|PDB:7RL4" FT STRAND 141..143 FT /evidence="ECO:0007829|PDB:1E1S" FT HELIX 144..153 FT /evidence="ECO:0007829|PDB:4KML" FT HELIX 154..156 FT /evidence="ECO:0007829|PDB:4KML" FT STRAND 159..163 FT /evidence="ECO:0007829|PDB:1E1U" FT HELIX 166..168 FT /evidence="ECO:0007829|PDB:4KML" FT TURN 171..173 FT /evidence="ECO:0007829|PDB:1QM0" FT STRAND 178..181 FT /evidence="ECO:0007829|PDB:4E1H" FT STRAND 182..185 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 189..192 FT /evidence="ECO:0007829|PDB:6LNI" FT TURN 193..195 FT /evidence="ECO:0007829|PDB:3HAK" FT STRAND 196..202 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 205..210 FT /evidence="ECO:0007829|PDB:6LNI" FT STRAND 212..215 FT /evidence="ECO:0007829|PDB:4E1H" FT TURN 223..225 FT /evidence="ECO:0007829|PDB:3HER" FT TURN 228..230 FT /evidence="ECO:0007829|PDB:2LFT" SQ SEQUENCE 253 AA; 27661 MW; 43DB596BAAA66484 CRC64; MANLGCWMLV LFVATWSDLG LCKKRPKPGG WNTGGSRYPG QGSPGGNRYP PQGGGGWGQP HGGGWGQPHG GGWGQPHGGG WGQPHGGGWG QGGGTHSQWN KPSKPKTNMK HMAGAAAAGA VVGGLGGYML GSAMSRPIIH FGSDYEDRYY RENMHRYPNQ VYYRPMDEYS NQNNFVHDCV NITIKQHTVT TTTKGENFTE TDVKMMERVV EQMCITQYER ESQAYYQRGS SMVLFSSPPV ILLISFLIFL IVG // ID PSN1_HUMAN Reviewed; 467 AA. AC P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 263. DE RecName: Full=Presenilin-1 {ECO:0000303|PubMed:9144240}; DE Short=PS-1 {ECO:0000303|PubMed:9298817}; DE EC=3.4.23.- {ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:26280335}; DE AltName: Full=Protein S182 {ECO:0000303|PubMed:7550356}; DE Contains: DE RecName: Full=Presenilin-1 NTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF12 {ECO:0000305|PubMed:9485372}; DE Short=PS1-CTF12; GN Name=PSEN1 {ECO:0000312|HGNC:HGNC:9508}; Synonyms=AD3, PS1, PSNL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANTS AD3 RP LEU-146; ARG-163; GLU-246 AND VAL-286, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=7596406; DOI=10.1038/375754a0; RA Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M., RA Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.-F., RA Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L., RA Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W., RA da Silva H.A.R., Haines J.L., Pericak-Vance M.A., Tanzi R.E., Roses A.D., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Cloning of a gene bearing missense mutations in early-onset familial RT Alzheimer's disease."; RL Nature 375:754-760(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND TISSUE SPECIFICITY. RC TISSUE=Blood, and Brain; RX PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3; RA Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M., RA Shirasawa T., Mori H.; RT "Identification and characterization of presenilin I-467, I-463 and I- RT 374."; RL FEBS Lett. 381:7-11(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RA Powell C.S., Gegg M.E., Palmer M.S.; RT "Human presenilin 1 gene encodes an alternative protein-minilin."; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A., Madan A., RA Dickhoff R., Shaffer T., James R., Lasky S., Hood L.; RT "Complete sequence of the gene for presenilin 1."; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RA Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.; RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Tongue; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113. RX PubMed=9070286; DOI=10.1006/bbrc.1996.6043; RA Tsujimura A., Yasojima K., Hashimoto-Gotoh T.; RT "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential RT expression in oogenesis and embryogenesis."; RL Biochem. Biophys. Res. Commun. 231:392-396(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING (ISOFORMS 6 RP AND 7). RC TISSUE=Megakaryocyte, and Platelet; RX PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9; RA Vidal R., Ghiso J., Wisniewski T., Frangione B.; RT "Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. RT Identification of a novel splice variant."; RL FEBS Lett. 393:19-23(1996). RN [12] RP PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; RP 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, RP IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, RP AND SUBCELLULAR LOCATION. RX PubMed=15274632; DOI=10.1021/bi0494976; RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J., RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.; RT "Purification and characterization of the human gamma-secretase complex."; RL Biochemistry 43:9774-9789(2004). RN [13] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=8574969; DOI=10.1038/nm0296-224; RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E., RA Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., RA Tanzi R.E., Wasco W.; RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and RT localization to intracellular membranes in mammalian cells."; RL Nat. Med. 2:224-229(1996). RN [14] RP PROTEOLYTIC PROCESSING. RX PubMed=9173929; DOI=10.1006/nbdi.1997.0129; RA Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., RA Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P., RA St George-Hyslop P.H., Teplow D.B., Selkoe D.J.; RT "Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 RT and Ala299 and occur as stable N- and C-terminal fragments in normal and RT Alzheimer brain tissue."; RL Neurobiol. Dis. 3:325-337(1997). RN [15] RP PHOSPHORYLATION. RX PubMed=9144240; DOI=10.1073/pnas.94.10.5349; RA Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M., RA Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C.; RT "Proteolytic processing of the Alzheimer disease-associated presenilin-1 RT generates an in vivo substrate for protein kinase C."; RL Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997). RN [16] RP CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385. RX PubMed=9485372; DOI=10.1021/bi972106l; RA Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C.; RT "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa RT C-terminal fragment are death substrates for proteases of the caspase RT family."; RL Biochemistry 37:2263-2270(1998). RN [17] RP FUNCTION, INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=9738936; DOI=10.1016/s0014-5793(98)00886-2; RA Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X., RA Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.; RT "Direct association of presenilin-1 with beta-catenin."; RL FEBS Lett. 433:73-77(1998). RN [18] RP INTERACTION WITH FLNA AND FLNB. RX PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998; RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.; RT "Interaction of presenilins with the filamin family of actin-binding RT proteins."; RL J. Neurosci. 18:914-922(1998). RN [19] RP FUNCTION, MUTAGENESIS OF MET-292, AND PROTEOLYTIC PROCESSING. RX PubMed=10545183; DOI=10.1021/bi9914210; RA Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., RA Loetscher H., Jacobsen H., Haass C.; RT "Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 RT in the absence of endoproteolysis."; RL Biochemistry 38:14600-14605(1999). RN [20] RP INTERACTION WITH MTCH1. RX PubMed=10551805; DOI=10.1074/jbc.274.46.32543; RA Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.; RT "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting RT with the C terminus of presenilin-1."; RL J. Biol. Chem. 274:32543-32546(1999). RN [21] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NOTCH. RX PubMed=10593990; DOI=10.1074/jbc.274.51.36801; RA Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M., RA Selkoe D.J., Kopan R., Goate A.M.; RT "Cell surface presenilin-1 participates in the gamma-secretase-like RT proteolysis of Notch."; RL J. Biol. Chem. 274:36801-36807(1999). RN [22] RP INTERACTION WITH CTNND2 AND CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x; RA Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D., RA Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L., RA VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E., RA St George-Hyslop P.H.; RT "Presenilins interact with armadillo proteins including neural-specific RT plakophilin-related protein and beta-catenin."; RL J. Neurochem. 72:999-1008(1999). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10206644; DOI=10.1038/19077; RA Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T., RA Selkoe D.J.; RT "Two transmembrane aspartates in presenilin-1 required for presenilin RT endoproteolysis and gamma-secretase activity."; RL Nature 398:513-517(1999). RN [24] RP INTERACTION WITH DOCK3. RX PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x; RA Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R., RA Schubert D., Kimura H.; RT "Isolation and characterization of novel presenilin binding protein."; RL J. Neurochem. 75:109-116(2000). RN [25] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x; RA Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W., RA Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.; RT "Aspartate mutations in presenilin and gamma-secretase inhibitors both RT impair notch1 proteolysis and nuclear translocation with relative RT preservation of notch1 signaling."; RL J. Neurochem. 75:583-593(2000). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LEU-286. RX PubMed=10811883; DOI=10.1073/pnas.100049897; RA Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H., RA Capell A., Steiner H., Haass C.; RT "Separation of presenilin function in amyloid beta-peptide generation and RT endoproteolysis of Notch."; RL Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000). RN [27] RP INTERACTION WITH PARL. RX PubMed=12214059; DOI=10.3233/jad-2001-3203; RA Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K., RA Fowlkes B.J., Koonin E.V., D'Adamio L.; RT "PAMP and PARL, two novel putative metalloproteases interacting with the RT COOH-terminus of presenilin-1 and -2."; RL J. Alzheimers Dis. 3:181-190(2001). RN [28] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=11987239; DOI=10.1006/bcmd.2002.0486; RA Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L., RA Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.; RT "Identification of the presenilins in hematopoietic cells with localization RT of presenilin 1 to neutrophil and platelet granules."; RL Blood Cells Mol. Dis. 28:28-38(2002). RN [29] RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH CDH1 RP AND CTNNB1. RX PubMed=11953314; DOI=10.1093/emboj/21.8.1948; RA Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V., RA Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K.; RT "A presenilin-1/gamma-secretase cleavage releases the E-cadherin RT intracellular domain and regulates disassembly of adherens junctions."; RL EMBO J. 21:1948-1956(2002). RN [30] RP INTERACTION WITH HERPUD1. RX PubMed=11799129; DOI=10.1074/jbc.m112372200; RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., RA Yanagisawa K., Komano H.; RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin- RT mediated generation of amyloid beta-protein."; RL J. Biol. Chem. 277:12915-12920(2002). RN [31] RP INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; RP 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF VARIANTS RP AD3 VAL-79 AND LEU-82. RX PubMed=12058025; DOI=10.1074/jbc.m112121200; RA Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P., RA Jorgensen A.L.; RT "A new splice variant of glial fibrillary acidic protein GFAPepsilon, RT interacts with the presenilin proteins."; RL J. Biol. Chem. 277:29983-29991(2002). RN [32] RP INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-385. RX PubMed=14515347; DOI=10.1002/jnr.10753; RA Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K., RA Shibasaki H., Shimohama S.; RT "Presenilin 1 is involved in maturation and trafficking of N-cadherin to RT the plasma membrane."; RL J. Neurosci. Res. 74:184-191(2003). RN [33] RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, CATALYTIC ACTIVITY, FUNCTION, RP AND SUBUNIT. RX PubMed=12679784; DOI=10.1038/ncb960; RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.; RT "Reconstitution of gamma-secretase activity."; RL Nat. Cell Biol. 5:486-488(2003). RN [34] RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN. RX PubMed=12740439; DOI=10.1073/pnas.1037392100; RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., RA Selkoe D.J.; RT "Gamma-secretase is a membrane protein complex comprised of presenilin, RT nicastrin, Aph-1, and Pen-2."; RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003). RN [35] RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S). RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8; RA Hillman R.T., Green R.E., Brenner S.E.; RT "An unappreciated role for RNA surveillance."; RL Genome Biol. 5:R8.1-R8.16(2004). RN [36] RP FUNCTION, SUBCELLULAR LOCATION, VARIANT AD3 SER-117, AND CHARACTERIZATION RP OF VARIANTS AD3 LEU-117 AND SER-117. RX PubMed=15004326; DOI=10.3233/jad-2004-6105; RA Dowjat W.K., Kuchna I., Wisniewski T., Wegiel J.; RT "A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 RT (Pro117Ser): Comparison of clinical, neuropathological and cell culture RT phenotypes of Pro117Leu and Pro117Ser mutations."; RL J. Alzheimers Dis. 6:31-43(2004). RN [37] RP PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND RP SER-346. RX PubMed=14576165; DOI=10.1074/jbc.m306653200; RA Fluhrer R., Friedlein A., Haass C., Walter J.; RT "Phosphorylation of presenilin 1 at the caspase recognition site regulates RT its proteolytic processing and the progression of apoptosis."; RL J. Biol. Chem. 279:1585-1593(2004). RN [38] RP TOPOLOGY. RX PubMed=15385547; DOI=10.1074/jbc.m407898200; RA Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G., RA Martoglio B.; RT "Consensus analysis of signal peptide peptidase and homologous human RT aspartic proteases reveals opposite topology of catalytic domains compared RT with presenilins."; RL J. Biol. Chem. 279:50790-50798(2004). RN [39] RP FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF TYR-256; RP ASP-257; ASP-385 AND TYR-389. RX PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x; RA Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A., RA De Strooper B., Shearman M.S., Beher D.; RT "Conserved residues within the putative active site of gamma-secretase RT differentially influence enzyme activity and inhibitor binding."; RL J. Neurochem. 90:1312-1320(2004). RN [40] RP INTERACTION WITH CDH1 AND CTNNB1. RX PubMed=16126725; DOI=10.1074/jbc.m507503200; RA Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J., RA Robakis N.K.; RT "Cadherins mediate both the association between PS1 and beta-catenin and RT the effects of PS1 on beta-catenin stability."; RL J. Biol. Chem. 280:36007-36012(2005). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [42] RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD3 VAL-146. RX PubMed=16959576; DOI=10.1016/j.cell.2006.06.059; RA Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H., RA Serneels L., De Strooper B., Yu G., Bezprozvanny I.; RT "Presenilins form ER Ca2+ leak channels, a function disrupted by familial RT Alzheimer's disease-linked mutations."; RL Cell 126:981-993(2006). RN [43] RP FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435, AND RP CHARACTERIZATION OF VARIANT AD3 PHE-435. RX PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x; RA Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.; RT "C-terminal PAL motif of presenilin and presenilin homologues required for RT normal active site conformation."; RL J. Neurochem. 96:218-227(2006). RN [44] RP VARIANTS AD3 ILE-139 AND CYS-289. RX PubMed=8875251; DOI=10.1093/hmg/5.supplement_1.1449; RA Cruts M., Hendriks L., Van Broeckhoven C.; RT "The presenilin genes: a new gene family involved in Alzheimer disease RT pathology."; RL Hum. Mol. Genet. 5:1449-1455(1996). RN [45] RP REVIEW ON VARIANTS. RX PubMed=9521418; RX DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j; RA Cruts M., van Broeckhoven C.; RT "Presenilin mutations in Alzheimer's disease."; RL Hum. Mutat. 11:183-190(1998). RN [46] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [47] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [49] RP IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, AND INTERACTION WITH CRB2. RX PubMed=20299451; DOI=10.1074/jbc.m109.038760; RA Mitsuishi Y., Hasegawa H., Matsuo A., Araki W., Suzuki T., Tagami S., RA Okochi M., Takeda M., Roepman R., Nishimura M.; RT "Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein RT by binding to the presenilin complex."; RL J. Biol. Chem. 285:14920-14931(2010). RN [50] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [51] RP INVOLVEMENT IN ACNINV3. RX PubMed=20929727; DOI=10.1126/science.1196284; RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y., RA Qu T., Chen M., Sun M., Shen Y., Zhang X.; RT "Gamma-secretase gene mutations in familial acne inversa."; RL Science 330:1065-1065(2010). RN [52] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [53] RP SUBCELLULAR LOCATION, AND INTERACTION WITH UBQLN1. RX PubMed=21143716; DOI=10.1111/j.1600-0854.2010.01149.x; RA Viswanathan J., Haapasalo A., Bottcher C., Miettinen R., Kurkinen K.M., RA Lu A., Thomas A., Maynard C.J., Romano D., Hyman B.T., Berezovska O., RA Bertram L., Soininen H., Dantuma N.P., Tanzi R.E., Hiltunen M.; RT "Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 RT accumulation and aggresome formation."; RL Traffic 12:330-348(2011). RN [54] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [55] RP FUNCTION, INTERACTION WITH APH1A/APH1B AND PEN2, SUBCELLULAR LOCATION, AND RP CHARACTERIZATION OF VARIANT AD3 ASP-206. RX PubMed=25394380; DOI=10.1007/s12035-014-8969-1; RA Chen W.T., Hsieh Y.F., Huang Y.J., Lin C.C., Lin Y.T., Liu Y.C., Lien C.C., RA Cheng I.H.; RT "G206D mutation of presenilin-1 reduces Pen2 interaction, increases RT Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation."; RL Mol. Neurobiol. 52:1835-1849(2015). RN [56] {ECO:0007744|PDB:2KR6} RP STRUCTURE BY NMR OF 292-467. RA Doetsch V.; RT "Solution structure of presenilin-1 CTF subunit."; RL Submitted (DEC-2009) to the PDB data bank. RN [57] RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, SUBUNIT, AND TOPOLOGY. RX PubMed=25043039; DOI=10.1038/nature13567; RA Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R., RA Scheres S.H., Shi Y.; RT "Three-dimensional structure of human gamma-secretase."; RL Nature 512:166-170(2014). RN [58] {ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5} RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, AND TOPOLOGY. RX PubMed=26623517; DOI=10.7554/elife.11182; RA Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.; RT "Sampling the conformational space of the catalytic subunit of human gamma- RT secretase."; RL Elife 4:0-0(2015). RN [59] {ECO:0007744|PDB:5A63} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, RP TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF RP VARIANTS AD3 LEU-213; ILE-237 AND PHE-261, AND MUTAGENESIS OF ILE-202; RP LEU-226; LEU-248 AND LEU-424. RX PubMed=26280335; DOI=10.1038/nature14892; RA Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H., RA Shi Y.; RT "An atomic structure of human gamma-secretase."; RL Nature 525:212-217(2015). RN [60] {ECO:0007744|PDB:4UIS} RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 81-463, SUBUNIT, AND RP TOPOLOGY. RX PubMed=25918421; DOI=10.1073/pnas.1506242112; RA Sun L., Zhao L., Yang G., Yan C., Zhou R., Zhou X., Xie T., Zhao Y., Wu S., RA Li X., Shi Y.; RT "Structural basis of human gamma-secretase assembly."; RL Proc. Natl. Acad. Sci. U.S.A. 112:6003-6008(2015). RN [61] RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH NOTCH1; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, CATALYTIC RP ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF GLN-112; 288-TYR--SER-290; RP 377-ARG--LEU-381; ASP-385; LEU-432 AND 432-LEU--ALA-434, AND DOMAIN. RX PubMed=30598546; DOI=10.1038/s41586-018-0813-8; RA Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.; RT "Structural basis of Notch recognition by human gamma-secretase."; RL Nature 565:192-197(2019). RN [62] RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH APP CHAIN C83; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, RP CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF RP GLN-112; 288-TYR--SER-290; 377-ARG--LEU-381; ASP-385; LEU-432 AND RP 432-LEU--ALA-434. RX PubMed=30630874; DOI=10.1126/science.aaw0930; RA Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.; RT "Recognition of the amyloid precursor protein by human gamma-secretase."; RL Science 0:0-0(2019). RN [63] RP VARIANTS AD3 THR-143 AND ALA-384. RX PubMed=8634711; DOI=10.1093/hmg/4.12.2363; RA Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J., RA de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M., RA Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L., RA Van Broeckhoven C.; RT "Molecular genetic analysis of familial early-onset Alzheimer's disease RT linked to chromosome 14q24.3."; RL Hum. Mol. Genet. 4:2363-2372(1995). RN [64] RP VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392 RP AND TYR-410. RX PubMed=8634712; DOI=10.1093/hmg/4.12.2373; RA Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C., RA Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M., RA Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M., RA Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T.; RT "Mutations of the presenilin I gene in families with early-onset RT Alzheimer's disease."; RL Hum. Mol. Genet. 4:2373-2377(1995). RN [65] RP VARIANTS AD3 VAL-260; VAL-285 AND VAL-392. RX PubMed=7651536; DOI=10.1038/376775a0; RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., RA Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., RA Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Familial Alzheimer's disease in kindreds with missense mutations in a gene RT on chromosome 1 related to the Alzheimer's disease type 3 gene."; RL Nature 376:775-778(1995). RN [66] RP VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280. RX PubMed=7550356; DOI=10.1038/ng1095-219; RA Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C., RA Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A., RA Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J., RA Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J., RA Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L., RA Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R., RA Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L., RA Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B., RA Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D., RA Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D., RA Hardy J., Goate A.M.; RT "The structure of the presenilin 1 (S182) gene and identification of six RT novel mutations in early onset AD families."; RL Nat. Genet. 11:219-222(1995). RN [67] RP VARIANT AD3 ALA-280, AND INVOLVEMENT IN AD3. RX PubMed=8837617; DOI=10.1038/nm1096-1146; RA Lemere C.A., Lopera F., Kosik K.S., Lendon C.L., Ossa J., Saido T.C., RA Yamaguchi H., Ruiz A., Martinez A., Madrigal L., Hincapie L., Arango J.C., RA Anthony D.C., Koo E.H., Goate A.M., Selkoe D.J., Arango J.C.; RT "The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 RT deposition and severe cerebellar pathology."; RL Nat. Med. 2:1146-1150(1996). RN [68] RP VARIANTS AD3 PHE-96; ARG-163 AND THR-213. RX PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8; RA Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H., RA Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T.; RT "Three different mutations of presenilin 1 gene in early-onset Alzheimer's RT disease families."; RL Neurosci. Lett. 208:195-198(1996). RN [69] RP VARIANT AD3 ASP-135. RX PubMed=9225696; DOI=10.1002/ana.410420121; RA Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M., RA Hutton M., Haltia T., Hardy J., Galasko D.; RT "Early-onset Alzheimer's disease with a presenilin-1 mutation at the site RT corresponding to the Volga German presenilin-2 mutation."; RL Ann. Neurol. 42:124-128(1997). RN [70] RP VARIANT AD3 ALA-280. RX PubMed=9298817; RX DOI=10.1002/(sici)1098-1004(1997)10:3<186::aid-humu2>3.0.co;2-h; RA Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J., RA Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C., RA Ossa J., Ruiz A., Goate A.M., Lopera F.; RT "E280A PS-1 mutation causes Alzheimer's disease but age of onset is not RT modified by ApoE alleles."; RL Hum. Mutat. 10:186-195(1997). RN [71] RP VARIANTS AD3 THR-233 AND THR-278. RX PubMed=9172170; DOI=10.1097/00001756-199704140-00043; RA Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A., RA Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H., RA Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E., RA Schofield P.R., Martins R.N.; RT "Two novel (M233T and R278T) presenilin-1 mutations in early-onset RT Alzheimer's disease pedigrees and preliminary evidence for association of RT presenilin-1 mutations with a novel phenotype."; RL NeuroReport 8:1537-1542(1997). RN [72] RP VARIANT AD3 PRO-171. RX PubMed=9833068; RA Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C., RA Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H., RA Cantu J.M.; RT "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with RT early onset Alzheimer disease."; RL Ann. Genet. 41:149-153(1998). RN [73] RP VARIANT GLY-318. RX PubMed=9851443; DOI=10.1002/ana.410440617; RA Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M., RA Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L.; RT "The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause RT Alzheimer's disease."; RL Ann. Neurol. 44:965-967(1998). RN [74] RP VARIANT GLY-318. RX PubMed=9851450; DOI=10.1002/ana.410440624; RA Aldudo J., Bullido M.J., Frank A., Valdivieso F.; RT "Missense mutation E318G of the presenilin-1 gene appears to be a RT nonpathogenic polymorphism."; RL Ann. Neurol. 44:985-986(1998). RN [75] RP VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318. RX PubMed=9384602; DOI=10.1093/hmg/7.1.43; RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A., RA Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H., RA Hofman A., van Broeckhoven C.; RT "Estimation of the genetic contribution of presenilin-1 and -2 mutations in RT a population-based study of presenile Alzheimer disease."; RL Hum. Mol. Genet. 7:43-51(1998). RN [76] RP VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND RP PRO-426. RX PubMed=9521423; RX DOI=10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f; RA Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H., RA White J., Heston L., Bird T.D., Schellenberg G.D.; RT "Missense mutations in the chromosome 14 familial Alzheimer's disease RT presenilin 1 gene."; RL Hum. Mutat. 11:216-221(1998). RN [77] RP VARIANT AD3 GLU-378. RX PubMed=10200054; RX DOI=10.1002/(sici)1098-1004(1998)11:6<481::aid-humu12>3.0.co;2-q; RA Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E., RA Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A.; RT "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a RT French family with early-onset Alzheimer's disease and transmission study RT by mismatch enhanced allele specific amplification."; RL Hum. Mutat. 11:481-481(1998). RN [78] RP VARIANT AD3 LYS-139. RX PubMed=9719376; DOI=10.1136/jmg.35.8.672; RA Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V., RA Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.; RT "De novo presenilin 1 mutations are rare in clinically sporadic, early RT onset Alzheimer's disease cases."; RL J. Med. Genet. 35:672-673(1998). RN [79] RP VARIANT AD3 LEU-117. RX PubMed=9507958; DOI=10.1097/00001756-199801260-00008; RA Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S., RA Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B.; RT "A novel Polish presenilin-1 mutation (P117L) is associated with familial RT Alzheimer's disease and leads to death as early as the age of 28 years."; RL NeuroReport 9:217-221(1998). RN [80] RP VARIANTS AD3 LEU-169 AND GLN-436. RX PubMed=9831473; DOI=10.1097/00001756-199810050-00034; RA Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M., RA Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R., RA Martins R.N.; RT "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with RT very early onset Alzheimer's disease."; RL NeuroReport 9:3335-3339(1998). RN [81] RP VARIANT GLY-318. RX PubMed=9915968; DOI=10.1086/302200; RA Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C., RA Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A., RA van Duijn C.M., van Broeckhoven C.; RT "The Glu318Gly substitution in presenilin 1 is not causally related to RT Alzheimer disease."; RL Am. J. Hum. Genet. 64:290-292(1999). RN [82] RP VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163; RP CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND RP TYR-410, AND VARIANT GLY-318. RX PubMed=10441572; DOI=10.1086/302553; RA Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., RA Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G., RA Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F., RA Brice A., Frebourg T.; RT "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic RT heterogeneity, and mutation spectrum."; RL Am. J. Hum. Genet. 65:664-670(1999). RN [83] RP VARIANTS AD3 PHE-143 AND SER-436. RX PubMed=10090481; RX DOI=10.1002/(sici)1098-1004(1999)13:3<256::aid-humu11>3.0.co;2-p; RA Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K., RA Fox N.C., Harvey R., Rossor M.N., Collinge J.; RT "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset RT Alzheimer's disease in the UK."; RL Hum. Mutat. 13:256-256(1999). RN [84] RP VARIANT AD3 ARG-209. RX PubMed=10447269; RX DOI=10.1002/(sici)1098-1004(1999)14:1<90::aid-humu19>3.0.co;2-s; RA Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y., RA Iseki E., Kosaka K.; RT "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a RT Japanese family with presenile familial Alzheimer's disease."; RL Hum. Mutat. 14:90-90(1999). RN [85] RP VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318. RX PubMed=10533070; RX DOI=10.1002/(sici)1098-1004(199911)14:5<433::aid-humu10>3.0.co;2-k; RA Aldudo J., Bullido M.J., Valdivieso F.; RT "DGGE method for the mutational analysis of the coding and proximal RT promoter regions of the Alzheimer's disease presenilin-1 gene: two novel RT mutations."; RL Hum. Mutat. 14:433-439(1999). RN [86] RP VARIANT AD3 PRO-169. RX PubMed=10025789; DOI=10.1212/wnl.52.3.566; RA Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.; RT "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and RT myoclonic seizures."; RL Neurology 52:566-570(1999). RN [87] RP VARIANT AD3 PRO-219. RX PubMed=10208579; DOI=10.1097/00001756-199902250-00011; RA Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K., RA Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.; RT "Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of RT the presenilin-1 gene."; RL NeuroReport 10:503-507(1999). RN [88] RP VARIANT AD3 ASN-116. RX PubMed=10439444; DOI=10.1097/00001756-199908020-00006; RA Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D., RA Havsager A.-M., Joergensen A.L.; RT "A presenilin-1 Thr116Asn substitution in a family with early-onset RT Alzheimer's disease."; RL NeuroReport 10:2255-2260(1999). RN [89] RP VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [90] RP VARIANT AD3 SER-405. RX PubMed=10644793; DOI=10.1136/jnnp.68.2.220; RA Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S., RA Maeda K., Tanaka C.; RT "Novel presenilin-1 mutation with widespread cortical amyloid deposition RT but limited cerebral amyloid angiopathy."; RL J. Neurol. Neurosurg. Psych. 68:220-223(2000). RN [91] RP VARIANT AD3 SER-92. RX PubMed=11027672; DOI=10.1006/bbrc.2000.3646; RA Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.; RT "The presenilin 1 C92S mutation increases abeta 42 production."; RL Biochem. Biophys. Res. Commun. 277:261-263(2000). RN [92] RP VARIANT FTD1 PRO-113. RX PubMed=11094121; DOI=10.1212/wnl.55.10.1577; RA Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P., RA Hannequin D., Brice A., Frebourg T., Campion D.; RT "Dementia with prominent frontotemporal features associated with L113P RT presenilin 1 mutation."; RL Neurology 55:1577-1578(2000). RN [93] RP VARIANTS AD3 MET-94; THR-143 AND ALA-280, AND VARIANT GLY-318. RX PubMed=11568920; RX DOI=10.1002/1096-8628(20011001)103:2<138::aid-ajmg1529>3.0.co;2-8; RA Arango D., Cruts M., Torres O., Backhovens H., Serrano M.L., Villareal E., RA Montanes P., Matallana D., Cano C., Van Broeckhoven C., Jacquier M.; RT "Systematic genetic study of Alzheimer disease in Latin America: mutation RT frequencies of the amyloid beta precursor protein and presenilin genes in RT Colombia."; RL Am. J. Med. Genet. 103:138-143(2001). RN [94] RP VARIANT AD3 VAL-282, AND CHARACTERIZATION OF VARIANT AD3 VAL-282. RX PubMed=11701593; DOI=10.1093/brain/124.12.2383; RA Dermaut B., Kumar-Singh S., De Jonghe C., Cruts M., Loefgren A., Luebke U., RA Cras P., Dom R., De Deyn P.P., Martin J.J., Van Broeckhoven C.; RT "Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease RT due to a novel presenilin 1 mutation."; RL Brain 124:2383-2392(2001). RN [95] RP ERRATUM OF PUBMED:11701593, AND VARIANT AD3 GLU-431. RA Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.; RL Hum. Genet. 109:242-242(2001). RN [96] RP VARIANT AD3 ALA-206. RX PubMed=11710891; DOI=10.1001/jama.286.18.2257; RA Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H., RA Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E., RA Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K., RA Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.; RT "A founder mutation in presenilin 1 causing early-onset Alzheimer disease RT in unrelated Caribbean Hispanic families."; RL JAMA 286:2257-2263(2001). RN [97] RP VARIANT AD3 ILE-237. RX PubMed=11561050; DOI=10.1136/jnnp.71.4.556; RA Sodeyama N., Iwata T., Ishikawa K., Mizusawa H., Yamada M., Itoh Y., RA Otomo E., Matsushita M., Komatsuzaki Y.; RT "Very early onset Alzheimer's disease with spastic paraparesis associated RT with a novel presenilin 1 mutation (Phe237Ile)."; RL J. Neurol. Neurosurg. Psych. 71:556-557(2001). RN [98] RP VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; RP VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; RP ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; RP PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; RP GLU-431; PHE-435 AND VAL-439, AND VARIANT GLY-318. RX PubMed=11524469; DOI=10.1212/wnl.57.4.621; RA Rogaeva E.A., Fafel K.C., Song Y.Q., Medeiros H., Sato C., Liang Y., RA Richard E., Rogaev E.I., Frommelt P., Sadovnick A.D., Meschino W., RA Rockwood K., Boss M.A., Mayeux R., St George-Hyslop P.; RT "Screening for PS1 mutations in a referral-based series of AD cases: 21 RT novel mutations."; RL Neurology 57:621-625(2001). RN [99] RP VARIANT AD3 SER-266. RX PubMed=11920851; DOI=10.1002/ajmg.10250; RA Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K., RA Kohara K., Miyoshi K., Miki T.; RT "Molecular evidence of presenilin 1 mutation in familial early onset RT dementia."; RL Am. J. Med. Genet. 114:292-298(2002). RN [100] RP VARIANT AD3 LEU-89. RX PubMed=11796781; DOI=10.1136/jnnp.72.2.266; RA Queralt R., Ezquerra M., Lleo A., Castellvi M., Gelpi J., Ferrer I., RA Acarin N., Pasarin L., Blesa R., Oliva R.; RT "A novel mutation (V89L) in the presenilin 1 gene in a family with early RT onset Alzheimer's disease and marked behavioural disturbances."; RL J. Neurol. Neurosurg. Psych. 72:266-269(2002). RN [101] RP VARIANT AD3 GLY-280. RX PubMed=12370477; DOI=10.1212/wnl.59.7.1108; RA O'Riordan S., McMonagle P., Janssen J.C., Fox N.C., Farrell M., RA Collinge J., Rossor M.N., Hutchinson M.; RT "Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white- RT matter abnormalities."; RL Neurology 59:1108-1110(2002). RN [102] RP VARIANT AD3 PRO-166. RX PubMed=12048239; DOI=10.1073/pnas.112686799; RA Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A., RA Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.; RT "Presenilin-1 mutations of leucine 166 equally affect the generation of the RT Notch and APP intracellular domains independent of their effect on Abeta 42 RT production."; RL Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002). RN [103] RP VARIANT AD3 MET-174. RX PubMed=12484344; DOI=10.1007/s10048-002-0136-6; RA Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J., RA Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M., RA van Duijn C.M., Heredero Baute L., Heutink P.; RT "A novel presenilin 1 mutation (L174 M) in a large Cuban family with early RT onset Alzheimer disease."; RL Neurogenetics 4:97-104(2002). RN [104] RP VARIANT AD3 VAL-271. RX PubMed=12493737; DOI=10.1074/jbc.m211827200; RA Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O., RA Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A., RA Gandy S.E., Schofield P.R.; RT "Presenilin-1 mutation L271V results in altered exon 8 splicing and RT Alzheimer's disease with non-cored plaques and no neuritic dystrophy."; RL J. Biol. Chem. 278:6748-6754(2003). RN [105] RP VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171; RP ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND RP VAL-378, AND VARIANT GLY-318. RX PubMed=12552037; DOI=10.1212/01.wnl.0000042088.22694.e3; RA Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C., RA Harvey R.J., Houlden H., Rossor M.N., Collinge J.; RT "Early onset familial Alzheimer's disease: Mutation frequency in 31 RT families."; RL Neurology 60:235-239(2003). RN [106] RP VARIANT PIDB VAL-183, CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282, RP AND CHARACTERIZATION OF VARIANT PIDB VAL-183. RX PubMed=15122701; DOI=10.1002/ana.20083; RA Dermaut B., Kumar-Singh S., Engelborghs S., Theuns J., Rademakers R., RA Saerens J., Pickut B.A., Peeters K., van den Broeck M., Vennekens K., RA Claes S., Cruts M., Cras P., Martin J.J., Van Broeckhoven C., De Deyn P.P.; RT "A novel presenilin 1 mutation associated with Pick's disease but not beta- RT amyloid plaques."; RL Ann. Neurol. 55:617-626(2004). RN [107] RP VARIANT AD3 PRO-85, AND CHARACTERIZATION OF VARIANT AD3 PRO-85. RX PubMed=15534188; DOI=10.1001/archneur.61.11.1773; RA Ataka S., Tomiyama T., Takuma H., Yamashita T., Shimada H., Tsutada T., RA Kawabata K., Mori H., Miki T.; RT "A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease RT with spastic paraparesis."; RL Arch. Neurol. 61:1773-1776(2004). RN [108] RP VARIANT AD3 ILE-278. RX PubMed=15534260; DOI=10.1212/01.wnl.0000143060.98164.1a; RA Godbolt A.K., Beck J.A., Collinge J., Garrard P., Warren J.D., Fox N.C., RA Rossor M.N.; RT "A presenilin 1 R278I mutation presenting with language impairment."; RL Neurology 63:1702-1704(2004). RN [109] RP VARIANT AD3 ASN-154. RX PubMed=15364419; DOI=10.1016/j.neulet.2004.07.057; RA Hattori S., Sakuma K., Wakutani Y., Wada K., Shimoda M., Urakami K., RA Kowa H., Nakashima K.; RT "A novel presenilin 1 mutation (Y154N) in a patient with early onset RT Alzheimer's disease with spastic paraparesis."; RL Neurosci. Lett. 368:319-322(2004). RN [110] RP VARIANT AD3 PHE-170. RX PubMed=16344340; DOI=10.1001/archneur.62.12.1821; RA Snider B.J., Norton J., Coats M.A., Chakraverty S., Hou C.E., Jervis R., RA Lendon C.L., Goate A.M., McKeel D.W. Jr., Morris J.C.; RT "Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy RT bodies in the third decade of life."; RL Arch. Neurol. 62:1821-1830(2005). RN [111] RP VARIANT AD3 LEU-97. RX PubMed=15851849; DOI=10.3233/jad-2005-7204; RA Jia J., Xu E., Shao Y., Jia J., Sun Y., Li D.; RT "One novel presenilin-1 gene mutation in a Chinese pedigree of familial RT Alzheimer's disease."; RL J. Alzheimers Dis. 7:119-124(2005). RN [112] RP VARIANT CMD1U GLY-333. RX PubMed=17186461; DOI=10.1086/509900; RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S., RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M., RA Hershberger R.E.; RT "Mutations of presenilin genes in dilated cardiomyopathy and heart RT failure."; RL Am. J. Hum. Genet. 79:1030-1039(2006). RN [113] RP CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262; RP PHE-263; VAL-282 AND ALA-384. RX PubMed=16752394; DOI=10.1002/humu.20336; RA Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K., RA Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.; RT "Mean age-of-onset of familial alzheimer disease caused by presenilin RT mutations correlates with both increased Abeta42 and decreased Abeta40."; RL Hum. Mutat. 27:686-695(2006). RN [114] RP VARIANT AD3 GLU-431. RX PubMed=16628450; DOI=10.1007/s10048-006-0043-3; RA Yescas P., Huertas-Vazquez A., Villarreal-Molina M.T., Rasmussen A., RA Tusie-Luna M.T., Lopez M., Canizales-Quinteros S., Alonso M.E.; RT "Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing RT early-onset Alzheimer's disease in Mexican families."; RL Neurogenetics 7:195-200(2006). RN [115] RP VARIANT AD3 GLU-431. RX PubMed=16897084; DOI=10.1007/s10048-006-0053-1; RA Murrell J., Ghetti B., Cochran E., Macias-Islas M.A., Medina L., RA Varpetian A., Cummings J.L., Mendez M.F., Kawas C., Chui H., Ringman J.M.; RT "The A431E mutation in PSEN1 causing familial Alzheimer's disease RT originating in Jalisco State, Mexico: an additional fifteen families."; RL Neurogenetics 7:277-279(2006). RN [116] RP VARIANT AD3 VAL-79, AND CHARACTERIZATION OF VARIANT AD3 VAL-79. RX PubMed=17366635; DOI=10.1002/ana.21099; RA Kauwe J.S., Jacquart S., Chakraverty S., Wang J., Mayo K., Fagan A.M., RA Holtzman D.M., Morris J.C., Goate A.M.; RT "Extreme cerebrospinal fluid amyloid beta levels identify family with late- RT onset Alzheimer's disease presenilin 1 mutation."; RL Ann. Neurol. 61:446-453(2007). RN [117] RP VARIANT AD3 PHE-170. RX PubMed=17502474; DOI=10.1001/archneur.64.5.738; RA Piccini A., Zanusso G., Borghi R., Noviello C., Monaco S., Russo R., RA Damonte G., Armirotti A., Gelati M., Giordano R., Zambenedetti P., RA Russo C., Ghetti B., Tabaton M.; RT "Association of a presenilin 1 S170F mutation with a novel Alzheimer RT disease molecular phenotype."; RL Arch. Neurol. 64:738-745(2007). RN [118] RP CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260; RP LEU-264 AND GLY-280, FUNCTION, AND MUTAGENESIS OF ASP-257. RX PubMed=17428795; DOI=10.1074/jbc.m611449200; RA Litterst C., Georgakopoulos A., Shioi J., Ghersi E., Wisniewski T., RA Wang R., Ludwig A., Robakis N.K.; RT "Ligand binding and calcium influx induce distinct ectodomain/gamma- RT secretase-processing pathways of EphB2 receptor."; RL J. Biol. Chem. 282:16155-16163(2007). RN [119] RP VARIANT GLY-318. RX PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014; RA Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F., RA Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J., RA Emans J.B., Turnpenny P.D., Pourquie O.; RT "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin RT syndrome."; RL Am. J. Hum. Genet. 82:1334-1341(2008). RN [120] RP CHARACTERIZATION OF VARIANT AD3 THR-213. RX PubMed=18430735; DOI=10.1074/jbc.m801279200; RA Shimojo M., Sahara N., Mizoroki T., Funamoto S., Morishima-Kawashima M., RA Kudo T., Takeda M., Ihara Y., Ichinose H., Takashima A.; RT "Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in RT cell models and knock-in mouse brains: familial Alzheimer disease-linked RT mutation impairs gamma-site cleavage of amyloid precursor protein C- RT terminal fragment beta."; RL J. Biol. Chem. 283:16488-16496(2008). RN [121] RP VARIANT AD3 VAL-381. RX PubMed=19797784; DOI=10.1177/1533317509341464; RA Dintchov Traykov L., Mehrabian S., Van den Broeck M., RA Radoslavova Raycheva M., Cruts M., Kirilova Jordanova A., RA Van Broeckhoven C.; RT "Novel PSEN1 mutation in a Bulgarian patient with very early-onset RT Alzheimer's disease, spastic paraparesis, and extrapyramidal signs."; RL Am. J. Alzheimers Dis. Other Demen. 24:404-407(2009). RN [122] RP VARIANT AD3 ARG-217, AND CHARACTERIZATION OF VARIANT AD3 ARG-217. RX PubMed=19667325; DOI=10.1212/wnl.0b013e3181b163ba; RA Norton J.B., Cairns N.J., Chakraverty S., Wang J., Levitch D., Galvin J.E., RA Goate A.; RT "Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool RT plaques."; RL Neurology 73:480-482(2009). RN [123] RP VARIANT AD3 LEU-146. RX PubMed=20164095; DOI=10.1212/wnl.0b013e3181d52785; RA Bruni A.C., Bernardi L., Colao R., Rubino E., Smirne N., Frangipane F., RA Terni B., Curcio S.A., Mirabelli M., Clodomiro A., Di Lorenzo R., RA Maletta R., Anfossi M., Gallo M., Geracitano S., Tomaino C., Muraca M.G., RA Leotta A., Lio S.G., Pinessi L., Rainero I., Sorbi S., Nee L., Milan G., RA Pappata S., Postiglione A., Abbamondi N., Forloni G., St George Hyslop P., RA Rogaeva E., Bugiani O., Giaccone G., Foncin J.F., Spillantini M.G., RA Puccio G.; RT "Worldwide distribution of PSEN1 Met146Leu mutation: a large variability RT for a founder mutation."; RL Neurology 74:798-806(2010). RN [124] RP VARIANT AD3 PHE-435, CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND RP SER-436, MUTAGENESIS OF PRO-433 AND LEU-435, AND FUNCTION. RX PubMed=20460383; DOI=10.1074/jbc.m110.116962; RA Heilig E.A., Xia W., Shen J., Kelleher R.J. III; RT "A presenilin-1 mutation identified in familial Alzheimer disease with RT cotton wool plaques causes a nearly complete loss of gamma-secretase RT activity."; RL J. Biol. Chem. 285:22350-22359(2010). RN [125] RP VARIANT AD3 ASP-206. RX PubMed=21335660; DOI=10.3233/jad-2011-102031; RA Wu Y.Y., Cheng I.H., Lee C.C., Chiu M.J., Lee M.J., Chen T.F., Hsu J.L.; RT "Clinical phenotype of G206D mutation in the presenilin 1 gene in RT pathologically confirmed familial Alzheimer's disease."; RL J. Alzheimers Dis. 25:145-150(2011). RN [126] RP VARIANT CYS-315. RX PubMed=21248752; DOI=10.1038/nature09639; RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H., RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J., RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M., RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L., RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J., RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A., RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K., RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.; RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene RT PBRM1 in renal carcinoma."; RL Nature 469:539-542(2011). RN [127] RP VARIANT AD3 ARG-235. RX PubMed=21501661; DOI=10.1016/j.neulet.2011.03.084; RA Antonell A., Balasa M., Oliva R., Llado A., Bosch B., Fabregat N., RA Fortea J., Molinuevo J.L., Sanchez-Valle R.; RT "A novel PSEN1 gene mutation (L235R) associated with familial early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 496:40-42(2011). RN [128] RP CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280. RX PubMed=22461631; DOI=10.1074/jbc.m111.300483; RA Chau D.M., Crump C.J., Villa J.C., Scheinberg D.A., Li Y.M.; RT "Familial Alzheimer disease presenilin-1 mutations alter the active site RT conformation of gamma-secretase."; RL J. Biol. Chem. 287:17288-17296(2012). RN [129] RP VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214. RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020; RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B., RA Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.; RT "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish RT dementia patients."; RL Neurobiol. Aging 33:1850.E17-1850.E27(2012). RN [130] RP VARIANT AD3 PHE-159. RX PubMed=23123781; DOI=10.1016/j.neulet.2012.10.037; RA Kerchner G.A., Holbrook K.; RT "Novel presenilin-1 Y159F sequence variant associated with early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 531:142-144(2012). RN [131] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166 AND GLN-436, AND MUTAGENESIS OF RP ASP-257 AND ASP-385. RX PubMed=22529981; DOI=10.1371/journal.pone.0035133; RA Cacquevel M., Aeschbach L., Houacine J., Fraering P.C.; RT "Alzheimer's disease-linked mutations in presenilin-1 result in a drastic RT loss of activity in purified gamma-secretase complexes."; RL PLoS ONE 7:E35133-E35133(2012). RN [132] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392; RP TYR-410 AND PHE-435. RX PubMed=23843529; DOI=10.1523/jneurosci.0954-13.2013; RA Heilig E.A., Gutti U., Tai T., Shen J., Kelleher R.J. III; RT "Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma- RT secretase activity and Abeta production."; RL J. Neurosci. 33:11606-11617(2013). RN [133] RP VARIANT AD3 PHE-381. RX PubMed=24121961; DOI=10.3233/jad-131340; RA Dolzhanskaya N., Gonzalez M.A., Sperziani F., Stefl S., Messing J., RA Wen G.Y., Alexov E., Zuchner S., Velinov M.; RT "A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very RT early onset and unusually fast progressing dementia as well as lysosomal RT inclusions typically seen in Kufs disease."; RL J. Alzheimers Dis. 39:23-27(2014). RN [134] RP VARIANT AD3 VAL-153. RX PubMed=24495933; DOI=10.1016/j.neulet.2014.01.016; RA Cornejo-Olivas M.R., Yu C.E., Mazzetti P., Mata I.F., Meza M., RA Lindo-Samanamud S., Leverenz J.B., Bird T.D.; RT "Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a RT Peruvian family with early-onset Alzheimer's disease."; RL Neurosci. Lett. 563:140-143(2014). RN [135] RP VARIANT AD3 VAL-275. RX PubMed=24582897; DOI=10.1016/j.neulet.2014.02.034; RA Luedecke D., Becktepe J.S., Lehmbeck J.T., Finckh U., Yamamoto R., Jahn H., RA Boelmans K.; RT "A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial RT Alzheimer disease."; RL Neurosci. Lett. 566:115-119(2014). RN [136] RP VARIANT AD3 THR-83. RX PubMed=26145164; DOI=10.1016/j.neurobiolaging.2015.06.007; RA Achouri-Rassas A., Ben Ali N., Fray S., Hadj Fredj S., Kechaou M., RA Zakraoui N.O., Cherif A., Chabbi S., Anane N., Messaoud T., Gouider R., RA Belal S.; RT "Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset RT Alzheimer's disease."; RL Neurobiol. Aging 36:2904.E09-2904.E11(2015). RN [137] RP VARIANTS AD3 ALA-206 AND VAL-378. RX PubMed=27073747; RA Ravenscroft T.A., Pottier C., Murray M.E., Baker M., Christopher E., RA Levitch D., Brown P.H., Barker W., Duara R., Greig-Custo M., Betancourt A., RA English M., Sun X., Ertekin-Taner N., Graff-Radford N.R., Dickson D.W., RA Rademakers R.; RT "The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset RT Alzheimer's disease in Hispanics in Florida."; RL Am. J. Neurodegener. Dis. 5:94-101(2016). RN [138] RP VARIANT AD3 THR-408. RX PubMed=26549787; DOI=10.1016/j.neulet.2015.11.004; RA Tedde A., Bartoli A., Piaceri I., Ferrara S., Bagnoli S., Serio A., RA Sorbi S., Nacmias B.; RT "Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late- RT onset Alzheimer's disease."; RL Neurosci. Lett. 610:150-153(2016). RN [139] RP VARIANT ARG-311, CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311, AND RP FUNCTION. RX PubMed=28269784; DOI=10.3233/jad-161188; RA Dong J., Qin W., Wei C., Tang Y., Wang Q., Jia J.; RT "A novel PSEN1 K311R mutation discovered in Chinese families with late- RT onset Alzheimer's disease affects amyloid-beta production and tau RT phosphorylation."; RL J. Alzheimers Dis. 57:613-623(2017). RN [140] RP CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; RP SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; RP ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; RP ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; RP LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; RP LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; RP PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; RP ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; RP ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; RP VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; RP THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439, RP CHARACTERIZATION OF VARIANT CMD1U GLY-333, AND MUTAGENESIS OF THR-99; RP PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; RP LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; RP LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; RP TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; RP ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437. RX PubMed=27930341; DOI=10.1073/pnas.1618657114; RA Sun L., Zhou R., Yang G., Shi Y.; RT "Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro RT production of Abeta42 and Abeta40 peptides by gamma-secretase."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017). RN [141] RP VARIANT AD3 ILE-116. RX PubMed=30200536; DOI=10.3390/ijms19092604; RA Bagyinszky E., Lee H.M., Van Giau V., Koh S.B., Jeong J.H., An S.S.A., RA Kim S.; RT "PSEN1 p.Thr116Ile variant in two Korean families with young onset RT Alzheimer's disease."; RL Int. J. Mol. Sci. 19:0-0(2018). RN [142] RP VARIANT AD3 ASN-116. RX PubMed=29404783; DOI=10.1007/s00702-018-1850-z; RA Sutovsky S., Smolek T., Turcani P., Petrovic R., Brandoburova P., RA Jadhav S., Novak P., Attems J., Zilka N.; RT "Neuropathology and biochemistry of early onset familial Alzheimer's RT disease caused by presenilin-1 missense mutation Thr116Asn."; RL J. Neural Transm. 125:965-976(2018). RN [143] RP VARIANTS AD3 PHE-142 AND ASP-206. RX PubMed=29175279; DOI=10.1016/j.neurobiolaging.2017.10.011; RA Wang J.C., Alinaghi S., Tafakhori A., Sikora E., Azcona L.J., RA Karkheiran S., Goate A., Paisan-Ruiz C., Darvish H.; RT "Genetic screening in two Iranian families with early-onset Alzheimer's RT disease identified a novel PSEN1 mutation."; RL Neurobiol. Aging 62:E15-E17(2018). RN [144] RP VARIANT AD3 ALA-417. RX PubMed=30180983; DOI=10.1016/j.neurobiolaging.2018.08.003; RA Giau V.V., Wang M.J., Bagyinszky E., Youn Y.C., An S.S.A., Kim S.; RT "Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset RT Alzheimer's disease with parkinsonism."; RL Neurobiol. Aging 72:E13-E17(2018). RN [145] RP VARIANT AD3 PHE-170. RX PubMed=29466804; DOI=10.1159/000485899; RA Tiedt H.O., Benjamin B., Niedeggen M., Lueschow A.; RT "Phenotypic variability in autosomal dominant familial Alzheimer disease RT due to the S170F mutation of presenilin-1."; RL Neurodegener. Dis. 18:57-68(2018). CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an CC endoprotease complex that catalyzes the intramembrane cleavage of CC integral membrane proteins such as Notch receptors and APP (amyloid- CC beta precursor protein) (PubMed:10206644, PubMed:10545183, CC PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039, CC PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). CC Requires the presence of the other members of the gamma-secretase CC complex for protease activity (PubMed:15274632, PubMed:25043039, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in CC Notch and Wnt signaling cascades and regulation of downstream processes CC via its role in processing key regulatory proteins, and by regulating CC cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883, CC PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its CC interaction with CDH1; this stabilizes the complexes between CDH1 (E- CC cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 CC and JUP (gamma-catenin) (PubMed:11953314). Under conditions of CC apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This CC promotes the disassembly of the complexes between CDH1 and CTNND1, JUP CC and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby CC negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936). CC Required for normal embryonic brain and skeleton development, and for CC normal angiogenesis (By similarity). Mediates the proteolytic cleavage CC of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The CC holoprotein functions as a calcium-leak channel that allows the passive CC movement of calcium from endoplasmic reticulum to cytosol and is CC therefore involved in calcium homeostasis (PubMed:16959576, CC PubMed:25394380). Involved in the regulation of neurite outgrowth CC (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic CC facilitation, spike transmission and synaptic vesicles replenishment in CC a process that depends on gamma-secretase activity. It acts through the CC control of SYT7 presynaptic expression (By similarity). CC {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644, CC ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15004326, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:28269784, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, CC ECO:0000269|PubMed:9738936}. CC -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed CC of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), CC nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:25394380, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Such minimal CC complex is sufficient for secretase activity (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:26280335, CC PubMed:30598546, PubMed:30630874). Other components which are CC associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 CC isoform 3. As part of the gamma-secretase complex, interacts with CRB2 CC (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer CC of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment CC (PubMed:15274632). Associates with proteolytic processed C-terminal CC fragments C83 and C99 of the amyloid precursor protein (APP) (via CC transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via CC transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates CC with cadherin/catenin adhesion complexes through direct binding to CDH1 CC or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). CC Interaction with CDH1 stabilizes the complex and stimulates cell-cell CC aggregation (PubMed:11953314). Interaction with CDH2 is essential for CC trafficking of CDH2 from the endoplasmic reticulum to the plasma CC membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, CC HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:10037471, CC PubMed:10551805, PubMed:11799129, PubMed:11953314, PubMed:12214059, CC PubMed:16126725, PubMed:9437013, PubMed:9738936). Interacts through its CC N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with CC DOCK3; this interaction mediates the membrane association of DOCK3 CC (PubMed:10854253). Interacts with isoform 1 and isoform 3 of UBQLN1 CC (PubMed:21143716). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10037471, ECO:0000269|PubMed:10551805, CC ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:14515347, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:16126725, CC ECO:0000269|PubMed:20299451, ECO:0000269|PubMed:21143716, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:9437013, CC ECO:0000269|PubMed:9738936}. CC -!- INTERACTION: CC P49768; Q02410: APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690; CC P49768; Q96BI3: APH1A; NbExp=3; IntAct=EBI-297277, EBI-2606935; CC P49768; P05067: APP; NbExp=6; IntAct=EBI-297277, EBI-77613; CC P49768; P05067-4: APP; NbExp=4; IntAct=EBI-297277, EBI-302641; CC P49768; P56817: BACE1; NbExp=6; IntAct=EBI-297277, EBI-2433139; CC P49768; Q16543: CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634; CC P49768; P12830: CDH1; NbExp=2; IntAct=EBI-297277, EBI-727477; CC P49768; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452; CC P49768; P21333: FLNA; NbExp=2; IntAct=EBI-297277, EBI-350432; CC P49768; O75369: FLNB; NbExp=2; IntAct=EBI-297277, EBI-352089; CC P49768; Q92542: NCSTN; NbExp=6; IntAct=EBI-297277, EBI-998440; CC P49768; Q99569: PKP4; NbExp=3; IntAct=EBI-297277, EBI-726447; CC P49768; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-297277, EBI-998468; CC P49768; P50502: ST13; NbExp=3; IntAct=EBI-297277, EBI-357285; CC P49768; P55061: TMBIM6; NbExp=12; IntAct=EBI-297277, EBI-1045825; CC P49768; P49755: TMED10; NbExp=4; IntAct=EBI-297277, EBI-998422; CC P49768; Q9NZC2: TREM2; NbExp=5; IntAct=EBI-297277, EBI-14036387; CC P49768; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-297277, EBI-741480; CC P49768; O35430: Apba1; Xeno; NbExp=2; IntAct=EBI-297277, EBI-704760; CC P49768; P98084: Apba2; Xeno; NbExp=2; IntAct=EBI-297277, EBI-81669; CC P49768; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-297277, EBI-7030357; CC P49768-2; P63010-2: AP2B1; NbExp=6; IntAct=EBI-11047108, EBI-11529439; CC P49768-2; P05067: APP; NbExp=6; IntAct=EBI-11047108, EBI-77613; CC P49768-2; P16870: CPE; NbExp=3; IntAct=EBI-11047108, EBI-711320; CC P49768-2; Q5D0E6-2: DALRD3; NbExp=3; IntAct=EBI-11047108, EBI-9090939; CC P49768-2; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-11047108, EBI-3508943; CC P49768-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-11047108, EBI-396453; CC P49768-2; Q06787-7: FMR1; NbExp=3; IntAct=EBI-11047108, EBI-25856644; CC P49768-2; P02792: FTL; NbExp=3; IntAct=EBI-11047108, EBI-713279; CC P49768-2; P68431: H3C12; NbExp=6; IntAct=EBI-11047108, EBI-79722; CC P49768-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-11047108, EBI-2806068; CC P49768-2; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-11047108, EBI-21911304; CC P49768-2; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-11047108, EBI-25871195; CC P49768-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-11047108, EBI-1044640; CC P49768-2; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-11047108, EBI-1108377; CC P49768-2; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-11047108, EBI-4397720; CC P49768-2; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-11047108, EBI-21250407; CC P49768-2; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-11047108, EBI-995714; CC P49768-2; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-11047108, EBI-25888682; CC P49768-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-11047108, EBI-1058491; CC P49768-2; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-11047108, EBI-716063; CC P49768-2; P53350: PLK1; NbExp=3; IntAct=EBI-11047108, EBI-476768; CC P49768-2; O14494: PLPP1; NbExp=3; IntAct=EBI-11047108, EBI-2865290; CC P49768-2; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-11047108, EBI-998468; CC P49768-2; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-11047108, EBI-21535400; CC P49768-2; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-11047108, EBI-25829984; CC P49768-2; Q8N488: RYBP; NbExp=6; IntAct=EBI-11047108, EBI-752324; CC P49768-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-11047108, EBI-10182463; CC P49768-2; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-11047108, EBI-358545; CC P49768-2; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11047108, EBI-18159983; CC P49768-2; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-11047108, EBI-11959123; CC P49768-2; O00300: TNFRSF11B; NbExp=3; IntAct=EBI-11047108, EBI-15481185; CC P49768-2; Q96NC0: ZMAT2; NbExp=6; IntAct=EBI-11047108, EBI-2682299; CC PRO_0000025591; Q63053: Arc; Xeno; NbExp=3; IntAct=EBI-2606326, EBI-5275794; CC PRO_0000025592; P35613: BSG; NbExp=6; IntAct=EBI-2606356, EBI-750709; CC PRO_0000025592; Q92542: NCSTN; NbExp=2; IntAct=EBI-2606356, EBI-998440; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum CC {ECO:0000269|PubMed:25394380}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:9738936, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Golgi CC apparatus membrane {ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:8574969, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cytoplasmic CC granule {ECO:0000269|PubMed:11987239}. Cell membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11953314, CC ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716}; Multi-pass CC membrane protein {ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Cell projection, growth cone CC {ECO:0000269|PubMed:15004326}. Early endosome CC {ECO:0000269|PubMed:25394380}. Early endosome membrane CC {ECO:0000305|PubMed:25394380}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cell CC projection, neuron projection {ECO:0000269|PubMed:15004326}. Cell CC projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Synapse CC {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1 CC from the endoplasmic reticulum and/or Golgi to the cell surface CC (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell CC contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the CC proximity of the plasma membrane (PubMed:9738936). Also present in CC azurophil granules of neutrophils (PubMed:11987239). Colocalizes with CC UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures CC called aggresomes (PubMed:21143716). Also highly enriched in CC mitochondria-associated endoplasmic reticulum membrane contact site (By CC similarity). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:9738936}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; Synonyms=I-467; CC IsoId=P49768-1; Sequence=Displayed; CC Name=2; Synonyms=I-463; CC IsoId=P49768-2; Sequence=VSP_005191; CC Name=3; Synonyms=I-374; CC IsoId=P49768-3; Sequence=VSP_005191, VSP_005192; CC Name=4; Synonyms=Minilin; CC IsoId=P49768-4; Sequence=VSP_007986, VSP_007987; CC Name=5; CC IsoId=P49768-5; Sequence=VSP_005192; CC Name=6; CC IsoId=P49768-6; Sequence=VSP_012288; CC Name=7; CC IsoId=P49768-7; Sequence=VSP_041440; CC -!- TISSUE SPECIFICITY: Detected in azurophile granules in neutrophils and CC in platelet cytoplasmic granules (at protein level) (PubMed:11987239). CC Expressed in a wide range of tissues including various regions of the CC brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8574969, CC PubMed:8641442). {ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:8641442}. CC -!- DOMAIN: The PAL motif is required for normal active site conformation. CC {ECO:0000269|PubMed:16305624}. CC -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between CC PSEN1 transmembrane domains and via the first lumenal loop and the CC cytoplasmic loop between the sixth and seventh transmembrane domains. CC Substrate binding causes a conformation change and formation of an CC intermolecular antiparallel beta-sheet between PSEN1 and its CC substrates. {ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF) CC and C-terminal (CTF) fragments of approximately 35 and 20 kDa, CC respectively. During apoptosis, the C-terminal fragment (CTF) is CC further cleaved by caspase-3 to produce the fragment, PS1-CTF12. CC {ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:15274632, CC ECO:0000269|PubMed:9173929, ECO:0000269|PubMed:9485372}. CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is CC phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on CC Ser-346 inhibits endoproteolysis. {ECO:0000269|PubMed:14576165, CC ECO:0000269|PubMed:9144240}. CC -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative CC disorder characterized by progressive dementia, loss of cognitive CC abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481, CC ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, CC ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, CC ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, CC ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, CC ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, CC ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920, CC ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891, CC ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851, CC ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344, CC ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037, CC ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701, CC ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188, CC ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340, CC ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394, CC ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795, CC ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735, CC ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784, CC ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661, CC ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161, CC ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781, CC ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961, CC ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897, CC ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, CC ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341, CC ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783, CC ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983, CC ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, CC ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, CC ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617, CC ECO:0000269|PubMed:8875251, ECO:0000269|PubMed:9172170, CC ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, CC ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, CC ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, CC ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, CC ECO:0000269|Ref.95}. Note=The disease is caused by variants affecting CC the gene represented in this entry. CC -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. In some cases, parkinsonian CC symptoms are prominent. Neuropathological changes include CC frontotemporal atrophy often associated with atrophy of the basal CC ganglia, substantia nigra, amygdala. In most cases, protein tau CC deposits are found in glial cells and/or neurons. CC {ECO:0000269|PubMed:11094121}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Cardiomyopathy, dilated, 1U (CMD1U) [MIM:613694]: A disorder CC characterized by ventricular dilation and impaired systolic function, CC resulting in congestive heart failure and arrhythmia. Patients are at CC risk of premature death. {ECO:0000269|PubMed:17186461, CC ECO:0000269|PubMed:27930341}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic CC relapsing inflammatory disease of the hair follicles characterized by CC recurrent draining sinuses, painful skin abscesses, and disfiguring CC scars. Manifestations typically appear after puberty. CC {ECO:0000269|PubMed:20929727}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of CC dementia pathologically defined by severe atrophy, neuronal loss and CC gliosis. It is characterized by the occurrence of tau-positive CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal CC inclusions known as Pick bodies that disproportionally affect the CC frontal and temporal cortical regions. Clinical features include CC aphasia, apraxia, confusion, anomia, memory loss and personality CC deterioration. {ECO:0000269|PubMed:15122701}. Note=The gene represented CC in this entry may be involved in disease pathogenesis. CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins CC mutations; CC URL="https://www.alzforum.org/mutations/psen-1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L42110; AAB46416.1; -; mRNA. DR EMBL; L76517; AAB46370.1; -; mRNA. DR EMBL; L76528; AAB46371.1; -; Genomic_DNA. DR EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; U40379; AAB05894.1; -; mRNA. DR EMBL; U40380; AAB05895.1; -; mRNA. DR EMBL; AJ008005; CAA07825.1; -; mRNA. DR EMBL; AF109907; AAC97960.1; -; Genomic_DNA. DR EMBL; AF416717; AAL16811.1; -; mRNA. DR EMBL; AK312531; BAG35430.1; -; mRNA. DR EMBL; AC004858; AAF19253.1; -; Genomic_DNA. DR EMBL; AC004858; AAF19254.1; -; Genomic_DNA. DR EMBL; CH471061; EAW81092.1; -; Genomic_DNA. DR EMBL; BC011729; AAH11729.1; -; mRNA. DR EMBL; D84149; BAA20883.1; -; Genomic_DNA. DR CCDS; CCDS9812.1; -. [P49768-1] DR CCDS; CCDS9813.1; -. [P49768-2] DR PIR; S58396; S58396. DR PIR; S63683; S63683. DR PIR; S63684; S63684. DR RefSeq; NP_000012.1; NM_000021.4. [P49768-1] DR RefSeq; NP_015557.2; NM_007318.3. [P49768-2] DR RefSeq; XP_005267921.1; XM_005267864.4. [P49768-1] DR RefSeq; XP_005267923.1; XM_005267866.3. [P49768-2] DR RefSeq; XP_011535274.1; XM_011536972.3. [P49768-1] DR RefSeq; XP_011535275.1; XM_011536973.3. [P49768-2] DR RefSeq; XP_011535276.1; XM_011536974.3. [P49768-2] DR RefSeq; XP_047287556.1; XM_047431600.1. [P49768-1] DR RefSeq; XP_047287557.1; XM_047431601.1. [P49768-1] DR RefSeq; XP_047287558.1; XM_047431602.1. [P49768-2] DR RefSeq; XP_054232388.1; XM_054376413.1. [P49768-1] DR RefSeq; XP_054232389.1; XM_054376414.1. [P49768-1] DR RefSeq; XP_054232390.1; XM_054376415.1. [P49768-1] DR RefSeq; XP_054232391.1; XM_054376416.1. [P49768-1] DR RefSeq; XP_054232392.1; XM_054376417.1. [P49768-2] DR RefSeq; XP_054232393.1; XM_054376418.1. [P49768-2] DR RefSeq; XP_054232394.1; XM_054376419.1. [P49768-2] DR RefSeq; XP_054232395.1; XM_054376420.1. [P49768-2] DR PDB; 2KR6; NMR; -; A=292-467. DR PDB; 4UIS; EM; 4.40 A; B=81-463. DR PDB; 5A63; EM; 3.40 A; B=1-467. DR PDB; 5FN2; EM; 4.20 A; B=1-467. DR PDB; 5FN3; EM; 4.10 A; B=1-467. DR PDB; 5FN4; EM; 4.00 A; B=1-467. DR PDB; 5FN5; EM; 4.30 A; B=1-467. DR PDB; 6IDF; EM; 2.70 A; B=1-467. DR PDB; 6IYC; EM; 2.60 A; B=1-467. DR PDB; 6LQG; EM; 3.10 A; B=1-467. DR PDB; 6LR4; EM; 3.00 A; B=1-467. DR PDB; 7C9I; EM; 3.10 A; B=1-467. DR PDB; 7D8X; EM; 2.60 A; B=1-467. DR PDB; 7Y5T; EM; 2.90 A; B=1-467. DR PDB; 8IM7; EM; 3.40 A; B=1-467. DR PDB; 8K8E; EM; 2.60 A; B=1-467. DR PDB; 8KCO; EM; 2.80 A; B=1-467. DR PDB; 8KCP; EM; 3.00 A; B=1-467. DR PDB; 8KCS; EM; 2.40 A; B=1-467. DR PDB; 8KCT; EM; 2.60 A; B=1-467. DR PDB; 8KCU; EM; 2.70 A; B=1-467. DR PDB; 8OQY; EM; 3.30 A; B=1-467. DR PDB; 8OQZ; EM; 3.40 A; B=1-467. DR PDB; 8X52; EM; 2.90 A; B=1-467. DR PDB; 8X53; EM; 3.00 A; B=1-467. DR PDB; 8X54; EM; 2.90 A; B=1-467. DR PDBsum; 2KR6; -. DR PDBsum; 4UIS; -. DR PDBsum; 5A63; -. DR PDBsum; 5FN2; -. DR PDBsum; 5FN3; -. DR PDBsum; 5FN4; -. DR PDBsum; 5FN5; -. DR PDBsum; 6IDF; -. DR PDBsum; 6IYC; -. DR PDBsum; 6LQG; -. DR PDBsum; 6LR4; -. DR PDBsum; 7C9I; -. DR PDBsum; 7D8X; -. DR PDBsum; 7Y5T; -. DR PDBsum; 8IM7; -. DR PDBsum; 8K8E; -. DR PDBsum; 8KCO; -. DR PDBsum; 8KCP; -. DR PDBsum; 8KCS; -. DR PDBsum; 8KCT; -. DR PDBsum; 8KCU; -. DR PDBsum; 8OQY; -. DR PDBsum; 8OQZ; -. DR PDBsum; 8X52; -. DR PDBsum; 8X53; -. DR PDBsum; 8X54; -. DR AlphaFoldDB; P49768; -. DR EMDB; EMD-0944; -. DR EMDB; EMD-0957; -. DR EMDB; EMD-17112; -. DR EMDB; EMD-17113; -. DR EMDB; EMD-2477; -. DR EMDB; EMD-2478; -. DR EMDB; EMD-30312; -. DR EMDB; EMD-30614; -. DR EMDB; EMD-33624; -. DR EMDB; EMD-35572; -. DR EMDB; EMD-36948; -. DR EMDB; EMD-37106; -. DR EMDB; EMD-37107; -. DR EMDB; EMD-37108; -. DR EMDB; EMD-37109; -. DR EMDB; EMD-37110; -. DR EMDB; EMD-38059; -. DR EMDB; EMD-38060; -. DR EMDB; EMD-38061; -. DR EMDB; EMD-9648; -. DR EMDB; EMD-9751; -. DR SMR; P49768; -. DR BioGRID; 111642; 203. DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant. DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant. DR CORUM; P49768; -. DR DIP; DIP-1134N; -. DR ELM; P49768; -. DR FunCoup; P49768; 2287. DR IntAct; P49768; 299. DR MINT; P49768; -. DR STRING; 9606.ENSP00000326366; -. DR BindingDB; P49768; -. DR ChEMBL; CHEMBL2473; -. DR DrugBank; DB11893; Avagacestat. DR DrugBank; DB12263; Begacestat. DR DrugBank; DB05171; E-2012. DR DrugBank; DB16159; Esflurbiprofen. DR DrugBank; DB12819; GSI-136. DR DrugBank; DB16825; Itanapraced. DR DrugBank; DB12852; MK-0752. DR DrugBank; DB12005; Nirogacestat. DR DrugBank; DB11870; RG-4733. DR DrugBank; DB12463; Semagacestat. DR DrugBank; DB05289; Tarenflurbil. DR GuidetoPHARMACOLOGY; 2402; -. DR MEROPS; A22.001; -. DR TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family. DR iPTMnet; P49768; -. DR PhosphoSitePlus; P49768; -. DR SwissPalm; P49768; -. DR BioMuta; PSEN1; -. DR DMDM; 1709856; -. DR jPOST; P49768; -. DR MassIVE; P49768; -. DR PaxDb; 9606-ENSP00000326366; -. DR PeptideAtlas; P49768; -. DR ProteomicsDB; 56106; -. [P49768-1] DR ProteomicsDB; 56107; -. [P49768-2] DR ProteomicsDB; 56108; -. [P49768-3] DR ProteomicsDB; 56109; -. [P49768-4] DR ProteomicsDB; 56110; -. [P49768-5] DR ProteomicsDB; 56111; -. [P49768-6] DR ProteomicsDB; 56112; -. [P49768-7] DR Pumba; P49768; -. DR Antibodypedia; 3480; 972 antibodies from 47 providers. DR DNASU; 5663; -. DR Ensembl; ENST00000324501.10; ENSP00000326366.5; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000357710.8; ENSP00000350342.4; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000394157.7; ENSP00000377712.3; ENSG00000080815.21. [P49768-4] DR Ensembl; ENST00000394164.5; ENSP00000377719.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553599.6; ENSP00000452477.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553855.5; ENSP00000452242.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000554131.6; ENSP00000451915.2; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000555386.6; ENSP00000450845.1; ENSG00000080815.21. [P49768-3] DR Ensembl; ENST00000556951.6; ENSP00000450551.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000557511.5; ENSP00000451429.1; ENSG00000080815.21. [P49768-6] DR Ensembl; ENST00000700265.1; ENSP00000514901.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700267.1; ENSP00000514903.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700268.1; ENSP00000514904.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700269.1; ENSP00000514905.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700273.1; ENSP00000514908.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700306.1; ENSP00000514933.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700313.1; ENSP00000514940.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700317.1; ENSP00000514944.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700321.1; ENSP00000514948.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700322.1; ENSP00000514949.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700323.1; ENSP00000514950.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700324.1; ENSP00000514951.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700375.1; ENSP00000514966.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700378.1; ENSP00000514968.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700389.1; ENSP00000514970.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700436.1; ENSP00000514987.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000700469.1; ENSP00000515002.1; ENSG00000080815.21. [P49768-2] DR GeneID; 5663; -. DR KEGG; hsa:5663; -. DR MANE-Select; ENST00000324501.10; ENSP00000326366.5; NM_000021.4; NP_000012.1. DR UCSC; uc001xnq.5; human. [P49768-1] DR AGR; HGNC:9508; -. DR ClinPGx; PA33855; -. DR CTD; 5663; -. DR DisGeNET; 5663; -. DR GeneCards; PSEN1; -. DR GeneReviews; PSEN1; -. DR HGNC; HGNC:9508; PSEN1. DR HPA; ENSG00000080815; Low tissue specificity. DR MalaCards; PSEN1; -. DR MIM; 104311; gene. DR MIM; 172700; phenotype. DR MIM; 600274; phenotype. DR MIM; 607822; phenotype. DR MIM; 613694; phenotype. DR MIM; 613737; phenotype. DR OpenTargets; ENSG00000080815; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000080815; -. DR eggNOG; KOG2736; Eukaryota. DR GeneTree; ENSGT00940000158751; -. DR HOGENOM; CLU_022975_3_0_1; -. DR InParanoid; P49768; -. DR OMA; NATCNQQ; -. DR OrthoDB; 20287at2759; -. DR PAN-GO; P49768; 26 GO annotations based on evolutionary models. DR PhylomeDB; P49768; -. DR PathwayCommons; P49768; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3. DR Reactome; R-HSA-9839383; TGFBR3 PTM regulation. DR SignaLink; P49768; -. DR SIGNOR; P49768; -. DR Agora; ENSG00000080815; -. DR BioGRID-ORCS; 5663; 16 hits in 1162 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PSEN1; human. DR EvolutionaryTrace; P49768; -. DR GeneWiki; PSEN1; -. DR GenomeRNAi; 5663; -. DR Pharos; P49768; Tchem. DR PRO; PR:P49768; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P49768; protein. DR Bgee; ENSG00000080815; Expressed in middle frontal gyrus and 202 other cell types or tissues. DR ExpressionAtlas; P49768; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:UniProtKB. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0005938; C:cell cortex; IEA:Ensembl. DR GO; GO:0030054; C:cell junction; IDA:HPA. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0035253; C:ciliary rootlet; IEA:Ensembl. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0043198; C:dendritic shaft; IEA:Ensembl. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl. DR GO; GO:0043005; C:neuron projection; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB. DR GO; GO:0005640; C:nuclear outer membrane; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IMP:CAFA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA. DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; NAS:ARUK-UCL. DR GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IPI:UniProtKB. DR GO; GO:0045296; F:cadherin binding; IEA:Ensembl. DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB. DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI. DR GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL. DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL. DR GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL. DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl. DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl. DR GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl. DR GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central. DR GO; GO:0001708; P:cell fate specification; IEA:Ensembl. DR GO; GO:0098609; P:cell-cell adhesion; IMP:MGI. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl. DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl. DR GO; GO:0015871; P:choline transport; IEA:Ensembl. DR GO; GO:0006974; P:DNA damage response; IDA:ARUK-UCL. DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl. DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl. DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IDA:MGI. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0098712; P:L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL. DR GO; GO:0040011; P:locomotion; IEA:Ensembl. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:0007613; P:memory; IGI:ARUK-UCL. DR GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl. DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0003407; P:neural retina development; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0001764; P:neuron migration; IEA:Ensembl. DR GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL. DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; IGI:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:CACAO. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:CACAO. DR GO; GO:0010628; P:positive regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL. DR GO; GO:0002038; P:positive regulation of L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL. DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl. DR GO; GO:0140249; P:protein catabolic process at postsynapse; IEA:Ensembl. DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL. DR GO; GO:0015031; P:protein transport; IEA:Ensembl. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0010975; P:regulation of neuron projection development; IMP:UniProtKB. DR GO; GO:0099175; P:regulation of postsynapse organization; IEA:Ensembl. DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl. DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0098693; P:regulation of synaptic vesicle cycle; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0051208; P:sequestering of calcium ion; IEA:Ensembl. DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl. DR GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl. DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl. DR GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL. DR GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl. DR GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl. DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR DisProt; DP01292; -. DR FunFam; 1.10.472.100:FF:000001; Presenilin; 1. DR Gene3D; 1.10.472.100; Presenilin; 1. DR InterPro; IPR002031; Pept_A22A_PS1. DR InterPro; IPR001108; Peptidase_A22A. DR InterPro; IPR006639; Preselin/SPP. DR InterPro; IPR042524; Presenilin_C. DR PANTHER; PTHR10202; PRESENILIN; 1. DR PANTHER; PTHR10202:SF18; PRESENILIN-1; 1. DR Pfam; PF01080; Presenilin; 1. DR PRINTS; PR01072; PRESENILIN. DR PRINTS; PR01073; PRESENILIN1. DR SMART; SM00730; PSN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Apoptosis; Cardiomyopathy; Cell adhesion; Cell membrane; Cell projection; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Endosome; Golgi apparatus; Hydrolase; Membrane; Neurodegeneration; KW Notch signaling pathway; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; Synapse; Transmembrane; KW Transmembrane helix. FT CHAIN 1..298 FT /note="Presenilin-1 NTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025591" FT CHAIN 299..467 FT /note="Presenilin-1 CTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025592" FT CHAIN 346..467 FT /note="Presenilin-1 CTF12" FT /evidence="ECO:0000269|PubMed:9485372" FT /id="PRO_0000236055" FT TOPO_DOM 1..82 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 83..103 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 104..132 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 133..153 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 154..166 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 167..189 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 190..194 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 195..216 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 217..220 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 221..241 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 242..248 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 249..272 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 273..380 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 381..401 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 402..407 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 408..428 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 429..432 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 433..453 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 454..467 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT REGION 13..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 288..290 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 305..333 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 322..450 FT /note="Required for interaction with CTNNB1" FT /evidence="ECO:0000269|PubMed:9738936" FT REGION 372..399 FT /note="Required for interaction with CTNND2" FT /evidence="ECO:0000269|PubMed:10037471" FT REGION 377..381 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 432..434 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 464..467 FT /note="Interaction with MTCH1" FT /evidence="ECO:0000269|PubMed:10551805" FT MOTIF 433..435 FT /note="PAL" FT /evidence="ECO:0000305|PubMed:16305624" FT COMPBIAS 13..29 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 30..45 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 257 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515" FT ACT_SITE 385 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515, FT ECO:0000305|PubMed:30598546, ECO:0000305|PubMed:30630874" FT SITE 291..292 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 292..293 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 298..299 FT /note="Cleavage" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 345..346 FT /note="Cleavage; by caspase" FT /evidence="ECO:0000269|PubMed:9485372" FT MOD_RES 43 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 51 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97887" FT MOD_RES 310 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 346 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 367 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 26..29 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:7596406, ECO:0000303|PubMed:8641442" FT /id="VSP_005191" FT VAR_SEQ 162..184 FT /note="IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFLWLGILVTVT FT (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007986" FT VAR_SEQ 185..467 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007987" FT VAR_SEQ 257..289 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000305" FT /id="VSP_041440" FT VAR_SEQ 319..467 FT /note="STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILA FT GEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFK FT KALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPM FT APRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI (in isoform 3 FT and isoform 5)" FT /evidence="ECO:0000303|PubMed:8641442, ECO:0000303|Ref.5" FT /id="VSP_005192" FT VAR_SEQ 319..376 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_012288" FT VARIANT 35 FT /note="R -> Q (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750592)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075260" FT VARIANT 79 FT /note="A -> V (in AD3; also found in late-onset Alzheimer FT disease; impaired protease activity with APP; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; no effect on interaction with FT GFAP; dbSNP:rs63749824)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:12058025, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:17366635, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9384602" FT /id="VAR_006413" FT VARIANT 82 FT /note="V -> L (in AD3; decreased protease activity with FT APP; no effect on interaction with GFAP; dbSNP:rs63749967)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006414" FT VARIANT 83 FT /note="I -> T (in AD3)" FT /evidence="ECO:0000269|PubMed:26145164" FT /id="VAR_075261" FT VARIANT 85 FT /note="L -> P (in AD3; the patient also manifest spastic FT paraparesis and apraxia; loss of protease activity with APP FT in vitro; altered amyloid-beta production in cells FT transfected with the mutant and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs63750599)" FT /evidence="ECO:0000269|PubMed:15534188, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081228" FT VARIANT 89 FT /note="V -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750815)" FT /evidence="ECO:0000269|PubMed:11796781" FT /id="VAR_081229" FT VARIANT 92 FT /note="C -> S (in AD3; loss of protease activity with APP; FT dbSNP:rs63751141)" FT /evidence="ECO:0000269|PubMed:11027672, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016214" FT VARIANT 94 FT /note="V -> M (in AD3; uncertain significance; reduced FT protease activity with APP; no relevant change in amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750831)" FT /evidence="ECO:0000269|PubMed:11568920" FT /id="VAR_081230" FT VARIANT 96 FT /note="V -> F (in AD3; loss of protease activity with APP; FT dbSNP:rs63750601)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006415" FT VARIANT 97 FT /note="V -> L (in AD3; uncertain significance; slightly FT reduced protease activity with APP; dbSNP:rs63750852)" FT /evidence="ECO:0000269|PubMed:15851849, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081231" FT VARIANT 105 FT /note="F -> L (in AD3; dbSNP:rs63750321)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_009208" FT VARIANT 113 FT /note="L -> P (in FTD1; dbSNP:rs63751399)" FT /evidence="ECO:0000269|PubMed:11094121" FT /id="VAR_016215" FT VARIANT 115 FT /note="Y -> C (in AD3; dbSNP:rs63750450)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:9384602" FT /id="VAR_006416" FT VARIANT 115 FT /note="Y -> H (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:8634712" FT /id="VAR_006417" FT VARIANT 116 FT /note="T -> I (in AD3; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:30200536" FT /id="VAR_081232" FT VARIANT 116 FT /note="T -> N (in AD3; unusual amyloid cotton wool plaques FT detected in one patient's brain; severe decrease of FT protease activity with APP; results in increased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:10439444, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29404783" FT /id="VAR_010120" FT VARIANT 117 FT /note="P -> L (in AD3; impaired ability to cleave Ephb2/ FT CTF1; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; impaired FT regulation of neurite outgrowth; dbSNP:rs63749805)" FT /evidence="ECO:0000269|PubMed:15004326, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:9507958" FT /id="VAR_009209" FT VARIANT 117 FT /note="P -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; impaired regulation of neurite outgrowth; FT dbSNP:rs63750550)" FT /evidence="ECO:0000269|PubMed:15004326" FT /id="VAR_081233" FT VARIANT 120 FT /note="E -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751272)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9521423" FT /id="VAR_006418" FT VARIANT 120 FT /note="E -> K (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750800)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006419" FT VARIANT 134 FT /note="L -> R (in AD3; uncertain significance; loss of FT protease activity with APP; dbSNP:rs1595002439)" FT /evidence="ECO:0000269|PubMed:22503161, FT ECO:0000269|PubMed:27930341" FT /id="VAR_070023" FT VARIANT 135 FT /note="N -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750353)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9225696" FT /id="VAR_010121" FT VARIANT 139 FT /note="M -> I (in AD3; dbSNP:rs63750522)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_006420" FT VARIANT 139 FT /note="M -> K (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:9719376" FT /id="VAR_010122" FT VARIANT 139 FT /note="M -> T (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006421" FT VARIANT 139 FT /note="M -> V (in AD3; increased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751037)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7550356" FT /id="VAR_006422" FT VARIANT 142 FT /note="V -> F (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:29175279" FT /id="VAR_081234" FT VARIANT 143 FT /note="I -> F (in AD3; dbSNP:rs63750322)" FT /evidence="ECO:0000269|PubMed:10090481" FT /id="VAR_006423" FT VARIANT 143 FT /note="I -> T (in AD3; impaired protease activity with APP; FT results in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750004)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006424" FT VARIANT 146 FT /note="M -> I (in AD3; dbSNP:rs63750391)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037" FT /id="VAR_006425" FT VARIANT 146 FT /note="M -> L (in AD3; disease phenotype shows high FT clinical variability; founder mutation originating from FT Southern Italy and distributed worldwide; alters the FT conformation of the active site; slightly increased FT protease activity with APP; decreased activity for Notch1 FT cleavage; no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006426" FT VARIANT 146 FT /note="M -> V (in AD3; loss of function as calcium-leak FT channel; results in calcium overload in the endoplasmic FT reticulum; dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:7550356" FT /id="VAR_006427" FT VARIANT 147 FT /note="T -> I (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750907)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010123" FT VARIANT 153 FT /note="L -> V (in AD3; abolishes protease activity with APP FT resulting in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63751441)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:27930341" FT /id="VAR_081235" FT VARIANT 154 FT /note="Y -> C (in AD3; uncertain significance; FT dbSNP:rs63751292)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081236" FT VARIANT 154 FT /note="Y -> N (in AD3; disease phenotype includes spastic FT paraparesis; abolishes protease activity with APP resulting FT in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63750588)" FT /evidence="ECO:0000269|PubMed:15364419, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081237" FT VARIANT 156 FT /note="Y -> FTY (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075262" FT VARIANT 159 FT /note="Y -> F (in AD3; uncertain significance; FT dbSNP:rs778630379)" FT /evidence="ECO:0000269|PubMed:23123781" FT /id="VAR_081238" FT VARIANT 163 FT /note="H -> R (in AD3; abolishes protease activity with FT APP; decreased activity for Notch cleavage; FT dbSNP:rs63750590)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8634712, FT ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9521423" FT /id="VAR_006428" FT VARIANT 163 FT /note="H -> Y (in AD3; slightly increased protease activity FT with APP and slightly increased amyloid-beta 42 production; FT dbSNP:rs63749885)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006429" FT VARIANT 165 FT /note="W -> C (in AD3; dbSNP:rs63751484)" FT /evidence="ECO:0000269|PubMed:10441572" FT /id="VAR_010124" FT VARIANT 166 FT /note="L -> P (in AD3; onset in adolescence; severe FT decrease of protease activity with APP; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; results in reduced Notch FT proteolysis; dbSNP:rs63750265)" FT /evidence="ECO:0000269|PubMed:12048239, FT ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23843529, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016216" FT VARIANT 168 FT /note="Missing (in AD3; uncertain significance; abolishes FT protease activity with APP resulting in decreased amyloid- FT beta 42 and amyloid-beta 40 production)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081239" FT VARIANT 169 FT /note="S -> L (in AD3; dbSNP:rs63751210)" FT /evidence="ECO:0000269|PubMed:9831473" FT /id="VAR_006430" FT VARIANT 169 FT /note="S -> P (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750418)" FT /evidence="ECO:0000269|PubMed:10025789, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006431" FT VARIANT 170 FT /note="S -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750577)" FT /evidence="ECO:0000269|PubMed:16344340, FT ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29466804" FT /id="VAR_081240" FT VARIANT 171 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750963)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9833068" FT /id="VAR_006432" FT VARIANT 173 FT /note="L -> W (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750299)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010125" FT VARIANT 174 FT /note="L -> M (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751144)" FT /evidence="ECO:0000269|PubMed:12484344, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016217" FT VARIANT 177 FT /note="F -> L (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749911)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075263" FT VARIANT 177 FT /note="F -> S (in AD3; uncertain significance; FT dbSNP:rs63749806)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075264" FT VARIANT 178 FT /note="S -> P (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750155)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075265" FT VARIANT 183 FT /note="G -> V (in PIDB and AD3; uncertain significance; FT neuropathologic examination of brain sections from a FT patient shows the presence of Pick bodies and absence of FT beta-amyloid plaques; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro; dbSNP:rs63751068)" FT /evidence="ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081241" FT VARIANT 184 FT /note="E -> D (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750311)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081242" FT VARIANT 205 FT /note="F -> L (in dbSNP:rs1042864)" FT /id="VAR_011876" FT VARIANT 206 FT /note="G -> A (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:27073747, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016218" FT VARIANT 206 FT /note="G -> D (in AD3; affects APP processing resulting in FT increased amyloid-beta 42/amyloid-beta 40 ratio; does not FT affect NOTCH processing; does not affect endoproteolysis; FT reduced interaction with PEN2; results in decreased protein FT levels in the endoplasmic reticulum but increased levels in FT early endosome; reduced ability to maintain ER calcium FT homeostasis; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:21335660, FT ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:29175279" FT /id="VAR_081243" FT VARIANT 206 FT /note="G -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750569)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075266" FT VARIANT 209 FT /note="G -> E (in AD3; uncertain significance; FT dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075267" FT VARIANT 209 FT /note="G -> R (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749880)" FT /evidence="ECO:0000269|PubMed:10447269, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009210" FT VARIANT 209 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006433" FT VARIANT 213 FT /note="I -> L (in AD3; increases protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750861)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075268" FT VARIANT 213 FT /note="I -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751309)" FT /evidence="ECO:0000269|PubMed:18430735, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006434" FT VARIANT 214 FT /note="H -> Y (found in a patient with dementia; uncertain FT significance; dbSNP:rs63751003)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070024" FT VARIANT 217 FT /note="G -> R (in AD3; with unusual amyloid cotton wool FT plaques; decreased protease activity with APP resulting in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs267606983)" FT /evidence="ECO:0000269|PubMed:19667325, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081244" FT VARIANT 219 FT /note="L -> P (in AD3; dbSNP:rs63750761)" FT /evidence="ECO:0000269|PubMed:10208579" FT /id="VAR_010126" FT VARIANT 222 FT /note="Q -> R (in AD3; uncertain significance; slightly FT increased protease activity with APP and slightly increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750009)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075269" FT VARIANT 229 FT /note="I -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749970)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081245" FT VARIANT 231 FT /note="A -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749836)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006435" FT VARIANT 231 FT /note="A -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750799)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:9384602" FT /id="VAR_006436" FT VARIANT 233 FT /note="M -> L (in AD3; slightly decreased protease activity FT with APP resulting in altered amyloid-beta production and FT mildly increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751287)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_009211" FT VARIANT 233 FT /note="M -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751024)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9172170" FT /id="VAR_006437" FT VARIANT 235 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63749835)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_006438" FT VARIANT 235 FT /note="L -> R (in AD3; abolishes protease activity with FT APP)" FT /evidence="ECO:0000269|PubMed:21501661, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081246" FT VARIANT 235 FT /note="L -> V (in AD3; reduced APP cleavage resulting in FT decreased amyloid-beta 42 and amyloid-beta 40 production; FT no relevant change in amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751130)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081247" FT VARIANT 237 FT /note="F -> I (in AD3; uncertain significance; disease FT phenotype includes spastic paraparesis; severe decrease of FT protease activity with APP; results in decreased amyloid- FT beta 42 and amyloid-beta 40 production; dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:11561050, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_081248" FT VARIANT 237 FT /note="F -> L (in AD3; uncertain significance; FT dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081249" FT VARIANT 246 FT /note="A -> E (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750526)" FT /evidence="ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006439" FT VARIANT 250 FT /note="L -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751163)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006440" FT VARIANT 260 FT /note="A -> V (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63751420)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9521423" FT /id="VAR_006441" FT VARIANT 261 FT /note="V -> F (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750964)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075270" FT VARIANT 262 FT /note="L -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750248)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006442" FT VARIANT 262 FT /note="L -> V (in AD3)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070025" FT VARIANT 263 FT /note="C -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751102)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:16752394" FT /id="VAR_081250" FT VARIANT 263 FT /note="C -> R (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750543)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006443" FT VARIANT 264 FT /note="P -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63750301)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006444" FT VARIANT 266 FT /note="G -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs121917807)" FT /evidence="ECO:0000269|PubMed:11920851, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016219" FT VARIANT 267 FT /note="P -> S (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751229)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006445" FT VARIANT 269 FT /note="R -> G (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751019)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006447" FT VARIANT 269 FT /note="R -> H (in AD3; dbSNP:rs63750900)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_006448" FT VARIANT 271 FT /note="L -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750886)" FT /evidence="ECO:0000269|PubMed:12493737, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016220" FT VARIANT 274 FT /note="T -> R (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750284)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075271" FT VARIANT 275 FT /note="A -> V (in AD3; uncertain significance; reduced FT protease activity with APP resulting in reduced amyloid- FT beta 40 levels but no relevant changes in amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs1555355869)" FT /evidence="ECO:0000269|PubMed:24582897, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081251" FT VARIANT 278 FT /note="R -> I (in AD3; atypical phenotype presenting as FT language impairment, impaired frontal executive function FT and relative preservation of memory; severe decrease of APP FT and Notch proteolysis; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:15534260, FT ECO:0000269|PubMed:23843529" FT /id="VAR_081252" FT VARIANT 278 FT /note="R -> T (in AD3; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:9172170" FT /id="VAR_006449" FT VARIANT 280 FT /note="E -> A (in AD3; strong deposition of amyloid-beta 42 FT is observed in brain regions of AD3 patients; decreased FT protease activity with APP resulting in altered amyloid- FT beta production and increased amyloid-beta 42/amyloid-beta FT 40 ratio; decreased activity for Notch1 cleavage; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:28269784, ECO:0000269|PubMed:7550356, FT ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9298817" FT /id="VAR_006450" FT VARIANT 280 FT /note="E -> G (in AD3; some AD3 patients manifest spastic FT paraparesis and unusual amyloid plaques with prominent FT amyloid angiopathy on brain biopsy; decreased protease FT activity with APP; increased amyloid-beta 42/amyloid-beta FT 40 ratio; impaired ability to cleave Ephb2/CTF1; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:12370477, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006451" FT VARIANT 282 FT /note="L -> R (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750050)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009212" FT VARIANT 282 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749937)" FT /evidence="ECO:0000269|PubMed:11701593, FT ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:16752394" FT /id="VAR_081253" FT VARIANT 285 FT /note="A -> V (in AD3; slightly decreased protease activity FT with APP and slightly decreased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751139)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536" FT /id="VAR_006452" FT VARIANT 286 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751235)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406" FT /id="VAR_006453" FT VARIANT 289 FT /note="S -> C (in AD3)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_010127" FT VARIANT 311 FT /note="K -> R (found in patients with late-onset Alzheimer FT disease; uncertain significance; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs115865530)" FT /evidence="ECO:0000269|PubMed:28269784" FT /id="VAR_081254" FT VARIANT 315 FT /note="Y -> C (found in a renal cell carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:21248752" FT /id="VAR_064747" FT VARIANT 318 FT /note="E -> G (in dbSNP:rs17125721)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:18485326, FT ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9851443, FT ECO:0000269|PubMed:9851450, ECO:0000269|PubMed:9915968" FT /id="VAR_006454" FT VARIANT 333 FT /note="D -> G (in CMD1U; results in slightly decreased FT protease activity with APP and slightly decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs121917809)" FT /evidence="ECO:0000269|PubMed:17186461, FT ECO:0000269|PubMed:27930341" FT /id="VAR_064902" FT VARIANT 352 FT /note="R -> RR (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075272" FT VARIANT 354 FT /note="T -> I (in AD3; uncertain significance; results in FT decreased protease activity with APP and decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63751164)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075273" FT VARIANT 358 FT /note="R -> Q (in AD3; uncertain significance; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs63751174)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075274" FT VARIANT 365 FT /note="S -> Y (in AD3; uncertain significance; FT dbSNP:rs63750941)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075275" FT VARIANT 377 FT /note="R -> M (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081255" FT VARIANT 378 FT /note="G -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10200054, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006455" FT VARIANT 378 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750323)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341" FT /id="VAR_081256" FT VARIANT 381 FT /note="L -> F (in AD3; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:24121961" FT /id="VAR_081257" FT VARIANT 381 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:19797784, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081258" FT VARIANT 384 FT /note="G -> A (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750646)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006456" FT VARIANT 390 FT /note="S -> I (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750883)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010128" FT VARIANT 392 FT /note="L -> V (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751416)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634712" FT /id="VAR_006457" FT VARIANT 394 FT /note="G -> V (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750929)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075276" FT VARIANT 396 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_070026" FT VARIANT 405 FT /note="N -> S (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63751254)" FT /evidence="ECO:0000269|PubMed:10644793, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010129" FT VARIANT 408 FT /note="I -> T (in AD3; dbSNP:rs906454643)" FT /evidence="ECO:0000269|PubMed:26549787" FT /id="VAR_075277" FT VARIANT 409 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750227)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009213" FT VARIANT 410 FT /note="C -> Y (in AD3; results in reduced APP and Notch FT proteolysis; dbSNP:rs661)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006458" FT VARIANT 417 FT /note="G -> A (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:30180983" FT /id="VAR_081259" FT VARIANT 418 FT /note="L -> F (in AD3; uncertain significance; nearly FT abolishes protease activity with APP; dbSNP:rs63751316)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075278" FT VARIANT 426 FT /note="A -> P (in AD3; uncertain significance; slightly FT decreased protease activity with APP; dbSNP:rs63751223)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006459" FT VARIANT 431 FT /note="A -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750083)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16897084, FT ECO:0000269|PubMed:27930341, ECO:0000269|Ref.95" FT /id="VAR_025605" FT VARIANT 435 FT /note="L -> F (in AD3; with unusual amyloid cotton wool FT plaques; almost abolishes gamma-secretase activity; no FT endoproteolytic cleavage; no APP nor NOTCH1 processing; no FT detectable amyloid-beta; dbSNP:rs63750001)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341" FT /id="VAR_075280" FT VARIANT 436 FT /note="P -> Q (in AD3; severe decrease of protease activity FT with APP; dbSNP:rs121917808)" FT /evidence="ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:9831473" FT /id="VAR_006460" FT VARIANT 436 FT /note="P -> S (in AD3; partially abolishes gamma-secretase FT activity; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63749925)" FT /evidence="ECO:0000269|PubMed:10090481, FT ECO:0000269|PubMed:21248752, ECO:0000269|PubMed:27930341" FT /id="VAR_008141" FT VARIANT 439 FT /note="I -> V (in AD3; uncertain significance; no FT significant change of protease activity with APP; FT dbSNP:rs63750249)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075282" FT MUTAGEN 66..72 FT /note="Missing: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 76..77 FT /note="KY->AA: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82..83 FT /note="VI->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82 FT /note="V->K,E: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 84..85 FT /note="ML->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 99 FT /note="T->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 105 FT /note="F->I: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 108 FT /note="R->Q: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 112 FT /note="Q->C: Formation of an artifactual disulfide bond FT with a substrate protein." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 113 FT /note="L->Q: Severe decrease of protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 117 FT /note="P->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 123 FT /note="E->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 131 FT /note="H->R: Severe decrease of protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 136 FT /note="A->G: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 143 FT /note="I->V: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 150 FT /note="L->P: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 165 FT /note="W->G: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 168 FT /note="I->T: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 176 FT /note="F->L: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 184 FT /note="E->G: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 202 FT /note="I->F: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 212 FT /note="S->Y: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 214 FT /note="H->D: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 219 FT /note="L->F: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 223 FT /note="Q->R: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 226 FT /note="L->F: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 230 FT /note="S->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 238 FT /note="I->M: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 239 FT /note="K->N: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 245 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 248 FT /note="L->R: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 256 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 256 FT /note="Y->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 257 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Reduces production of NICD in NOTCH1 FT processing. Impaired ability to cleave Ephb2/CTF1." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:22529981" FT MUTAGEN 257 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515" FT MUTAGEN 272 FT /note="V->A: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 273 FT /note="E->A: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 278 FT /note="R->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 284 FT /note="P->S: No significant change of protease activity FT with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 286 FT /note="L->A,E,P,Q,R,W: Increases production of amyloid-beta FT in APP processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 286 FT /note="L->E,R: Reduces production of NICD in NOTCH1 FT processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 288..290 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 291 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 292 FT /note="M->D: Loss of endoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10545183" FT MUTAGEN 310 FT /note="S->A: Abolishes PKA-mediated phosphorylation; no FT effect on caspase-mediated cleavage." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 345 FT /note="D->N: Abolishes caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 346 FT /note="S->A: Abolishes PKC-mediated phosphorylation; no FT effect on PKA-mediated phosphorylation." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 346 FT /note="S->E: Inhibits caspase-mediated cleavage. Modulates FT progression of apoptosis." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 352 FT /note="R->C: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 365 FT /note="S->A: Slightly increased protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 373 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 377..381 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 377 FT /note="R->W: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 385 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of FT the N-cadherin/PS1 complex at the cell surface. Impairs FT CDH2 processing." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 386 FT /note="F->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 389 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 391 FT /note="V->F: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 412 FT /note="V->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 420 FT /note="L->R: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 424 FT /note="L->V: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 432..434 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 432 FT /note="L->P: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 433 FT /note="P->A: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Slightly increased FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 433 FT /note="P->D,F,L,N,V: No endoproteolytic cleavage; no APP, FT nor NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:20460383" FT MUTAGEN 433 FT /note="P->G: Very little endoproteolysis. Little APP FT processing. No NOTCH1 processing. Very low levels amyloid- FT beta protein 40 and no detectable amyloid-beta protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->C: Some loss of endoproteolytic cleavage. Some FT loss of APP and NOTCH1 processing. 6 to 13-fold increase in FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 434 FT /note="A->D,I,L,V: No endoproteolytic cleavage. No APP nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->G: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Reduced amyloid-beta FT protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->A: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. FT Greatly reduced amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->G: Greatly reduced endoproteolytic cleavage. Very FT little APP and NOTCH1 processing. Very low levels of FT amyloid-beta protein 40 and no detectable amyloid-beta FT protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->I: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->R: No endoproteolytic cleavage; no APP, nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:20460383" FT MUTAGEN 435 FT /note="L->V: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. Some FT increase in amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 437 FT /note="I->V: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT CONFLICT 128 FT /note="R -> G (in Ref. 7; AAL16811)" FT /evidence="ECO:0000305" FT STRAND 77..80 FT /evidence="ECO:0007829|PDB:6LR4" FT HELIX 83..102 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:8X52" FT STRAND 120..123 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 125..155 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 159..175 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 177..188 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 195..214 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 219..240 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 243..262 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 263..266 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 267..277 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:6IDF" FT TURN 284..286 FT /evidence="ECO:0007829|PDB:8KCU" FT STRAND 287..289 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 293..299 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 341..345 FT /evidence="ECO:0007829|PDB:2KR6" FT HELIX 356..368 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 380..382 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 383..398 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 400..402 FT /evidence="ECO:0007829|PDB:8OQY" FT HELIX 403..428 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 435..451 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 454..463 FT /evidence="ECO:0007829|PDB:8KCS" SQ SEQUENCE 467 AA; 52668 MW; 5E0F451EF82BCF20 CRC64; MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI // ID REST_HUMAN Reviewed; 1097 AA. AC Q13127; A2RUE0; B9EGJ0; Q12956; Q12957; Q13134; Q59ER1; Q8IWI3; DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 28-JAN-2026, entry version 209. DE RecName: Full=RE1-silencing transcription factor; DE AltName: Full=Neural-restrictive silencer factor; DE AltName: Full=X2 box repressor; GN Name=REST; Synonyms=NRSF, XBR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=7697725; DOI=10.1016/0092-8674(95)90298-8; RA Chong J.A., Tapia-Ramirez J., Kim S., Toledo-Aral J.J., Zheng Y., RA Boutros M.C., Altshuller Y.M., Frohman M.A., Kraner S.D., Mandel G.; RT "REST: a mammalian silencer protein that restricts sodium channel gene RT expression to neurons."; RL Cell 80:949-957(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF 1-599 RP (ISOFORM 1), AND FUNCTION. RX PubMed=7871435; DOI=10.1126/science.7871435; RA Schoenherr C.J., Anderson D.J.; RT "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of RT multiple neuron-specific genes."; RL Science 267:1360-1363(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND RP VARIANT LEU-797. RX PubMed=8568247; RA Scholl T., Stevens M.B., Mahanta S., Strominger J.L.; RT "A zinc finger protein that represses transcription of the human MHC class RT II gene, DPA."; RL J. Immunol. 156:1448-1457(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ILE-626. RC TISSUE=Testis, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 3 AND 4). RX PubMed=10521596; DOI=10.1016/s0169-328x(99)00196-5; RA Palm K., Metsis M., Timmusk T.; RT "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR RT is frequent in neuroblastomas and conserved in human, mouse and rat."; RL Brain Res. Mol. Brain Res. 72:30-39(1999). RN [9] RP FUNCTION, AND INTERACTION WITH RCOR1. RX PubMed=10449787; DOI=10.1073/pnas.96.17.9873; RA Andres M.E., Burger C., Peral-Rubio M.J., Battaglioli E., Anderson M.E., RA Grimes J., Dallman J., Ballas N., Mandel G.; RT "CoREST: a functional corepressor required for regulation of neural- RT specific gene expression."; RL Proc. Natl. Acad. Sci. U.S.A. 96:9873-9878(1999). RN [10] RP FUNCTION, AND INTERACTION WITH RCOR1 AND SIN3A. RX PubMed=10734093; DOI=10.1074/jbc.275.13.9461; RA Grimes J.A., Nielsen S.J., Battaglioli E., Miska E.A., Speh J.C., RA Berry D.L., Atouf F., Holdener B.C., Mandel G., Kouzarides T.; RT "The co-repressor mSin3A is a functional component of the REST-CoREST RT repressor complex."; RL J. Biol. Chem. 275:9461-9467(2000). RN [11] RP FUNCTION. RX PubMed=11779185; DOI=10.1006/bbrc.2001.6194; RA Tabuchi A., Yamada T., Sasagawa S., Naruse Y., Mori N., Tsuda M.; RT "REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene RT promoter activation."; RL Biochem. Biophys. Res. Commun. 290:415-420(2002). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION (ISOFORM 3). RX PubMed=11741002; DOI=10.1016/s0197-0186(01)00091-2; RA Magin A., Lietz M., Cibelli G., Thiel G.; RT "RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional RT repressor nor a de-repressor."; RL Neurochem. Int. 40:195-202(2002). RN [13] RP FUNCTION. RX PubMed=12399542; DOI=10.1126/science.1076469; RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RT "Corepressor-dependent silencing of chromosomal regions encoding neuronal RT genes."; RL Science 298:1747-1752(2002). RN [14] RP ERRATUM OF PUBMED:12399542. RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RL Science 299:1663-1663(2003). RN [15] RP INTERACTION WITH PRICKLE1. RC TISSUE=Brain; RX PubMed=14645515; DOI=10.1128/mcb.23.24.9025-9031.2003; RA Shimojo M., Hersh L.B.; RT "REST/NRSF-interacting LIM domain protein, a putative nuclear translocation RT receptor."; RL Mol. Cell. Biol. 23:9025-9031(2003). RN [16] RP INTERACTION WITH PRICKLE1, SUBCELLULAR LOCATION (ISOFORMS 1; 2; 3 AND 4), RP AND MUTAGENESIS OF 512-LYS--LYS-522. RX PubMed=16442230; DOI=10.1016/j.neulet.2005.12.080; RA Shimojo M.; RT "Characterization of the nuclear targeting signal of REST/NRSF."; RL Neurosci. Lett. 398:161-166(2006). RN [17] RP FUNCTION, INTERACTION WITH CDYL; EHMT1 AND EHMT2, AND IDENTIFICATION IN A RP COMPLEX WITH CDYL; SETB1; EHMT1; EHMT2 AND WIZ. RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025; RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B., Macia E., RA Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J., Shi Y.; RT "CDYL bridges REST and histone methyltransferases for gene repression and RT suppression of cellular transformation."; RL Mol. Cell 32:718-726(2008). RN [18] RP INTERACTION WITH FBXW11 AND BTRC, DEVELOPMENTAL STAGE, PHOSPHORYLATION, RP UBIQUITINATION BY BTRC, AND MUTAGENESIS OF 1009-GLU--SER-1013. RX PubMed=18354482; DOI=10.1038/nature06641; RA Guardavaccaro D., Frescas D., Dorrello N.V., Peschiaroli A., Multani A.S., RA Cardozo T., Lasorella A., Iavarone A., Chang S., Hernando E., Pagano M.; RT "Control of chromosome stability by the beta-TrCP-REST-Mad2 axis."; RL Nature 452:365-369(2008). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP INTERACTION WITH ZFP90. RX PubMed=21284946; DOI=10.1016/j.yjmcc.2011.01.017; RA Hata L., Murakami M., Kuwahara K., Nakagawa Y., Kinoshita H., Usami S., RA Yasuno S., Fujiwara M., Kuwabara Y., Minami T., Yamada Y., Yamada C., RA Nakao K., Ueshima K., Nishikimi T., Nakao K.; RT "Zinc-finger protein 90 negatively regulates neuron-restrictive silencer RT factor-mediated transcriptional repression of fetal cardiac genes."; RL J. Mol. Cell. Cardiol. 50:972-981(2011). RN [22] RP FUNCTION, INTERACTION WITH USP7, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP INDUCTION, UBIQUITINATION BY BTRC, DEUBIQUITINATION BY USP7, AND RP MUTAGENESIS OF SER-313 AND SER-1042. RX PubMed=21258371; DOI=10.1038/ncb2153; RA Huang Z., Wu Q., Guryanova O.A., Cheng L., Shou W., Rich J.N., Bao S.; RT "Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural RT progenitor cells."; RL Nat. Cell Biol. 13:142-152(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, RP AND INDUCTION BY WNT SIGNALING; AGING AND OXIDATIVE STRESS. RX PubMed=24670762; DOI=10.1038/nature13163; RA Lu T., Aron L., Zullo J., Pan Y., Kim H., Chen Y., Yang T.H., Kim H.M., RA Drake D., Liu X.S., Bennett D.A., Colaiacovo M.P., Yankner B.A.; RT "REST and stress resistance in ageing and Alzheimer's disease."; RL Nature 507:448-454(2014). RN [25] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=26053433; DOI=10.1038/srep11207; RA Lee N.S., Evgrafov O.V., Souaiaia T., Bonyad A., Herstein J., Lee J.Y., RA Kim J., Ning Y., Sixto M., Weitz A.C., Lenz H.J., Wang K., Knowles J.A., RA Press M.F., Salvaterra P.M., Shung K.K., Chow R.H.; RT "Non-coding RNAs derived from an alternatively spliced REST transcript RT (REST-003) regulate breast cancer invasiveness."; RL Sci. Rep. 5:11207-11207(2015). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27531581; DOI=10.1038/srep31355; RA Cavadas M.A., Mesnieres M., Crifo B., Manresa M.C., Selfridge A.C., RA Keogh C.E., Fabian Z., Scholz C.C., Nolan K.A., Rocha L.M., Tambuwala M.M., RA Brown S., Wdowicz A., Corbett D., Murphy K.J., Godson C., Cummins E.P., RA Taylor C.T., Cheong A.; RT "REST is a hypoxia-responsive transcriptional repressor."; RL Sci. Rep. 6:31355-31355(2016). RN [27] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30684677; DOI=10.1016/j.neulet.2019.01.042; RA Kawamura M., Sato S., Matsumoto G., Fukuda T., Shiba-Fukushima K., Noda S., RA Takanashi M., Mori N., Hattori N.; RT "Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's RT disease patients."; RL Neurosci. Lett. 699:59-63(2019). RN [28] RP STRUCTURE BY NMR OF 43-57 IN COMPLEX WITH SIN3B, AND INTERACTION WITH RP SIN3B. RX PubMed=16288918; DOI=10.1016/j.jmb.2005.10.008; RA Nomura M., Uda-Tochio H., Murai K., Mori N., Nishimura Y.; RT "The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 RT corepressor by using its distinct short hydrophobic helix."; RL J. Mol. Biol. 354:903-915(2005). RN [29] RP INVOLVEMENT IN WT6, VARIANTS WT6 PRO-160; TYR-290; ARG-322 AND GLN-412, RP CHARACTERIZATION OF VARIANT PRO-160; TYR-290 AND ARG-322, FUNCTION, AND RP MUTAGENESIS OF GLU-91; MET-420; SER-593; ALA-642 AND HIS-918. RX PubMed=26551668; DOI=10.1038/ng.3440; RA Mahamdallie S.S., Hanks S., Karlin K.L., Zachariou A., Perdeaux E.R., RA Ruark E., Shaw C.A., Renwick A., Ramsay E., Yost S., Elliott A., Birch J., RA Capra M., Gray J., Hale J., Kingston J., Levitt G., McLean T., Sheridan E., RA Renwick A., Seal S., Stiller C., Sebire N., Westbrook T.F., Rahman N.; RT "Mutations in the transcriptional repressor REST predispose to Wilms RT tumor."; RL Nat. Genet. 47:1471-1474(2015). RN [30] RP INVOLVEMENT IN GINGF5, AND VARIANT GINGF5 437-LEU--GLU-1097 DEL. RX PubMed=28686854; DOI=10.1016/j.ajhg.2017.06.006; RG Baylor-Hopkins Center for Mendelian Genomics; RA Bayram Y., White J.J., Elcioglu N., Cho M.T., Zadeh N., Gedikbasi A., RA Palanduz S., Ozturk S., Cefle K., Kasapcopur O., Coban Akdemir Z., RA Pehlivan D., Begtrup A., Carvalho C.M.B., Paine I.S., Mentes A., RA Bektas-Kayhan K., Karaca E., Jhangiani S.N., Muzny D.M., Gibbs R.A., RA Lupski J.R.; RT "REST final-exon-truncating mutations cause hereditary gingival RT fibromatosis."; RL Am. J. Hum. Genet. 101:149-156(2017). RN [31] RP INVOLVEMENT IN DFNA27, AND ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=29961578; DOI=10.1016/j.cell.2018.06.004; RA Nakano Y., Kelly M.C., Rehman A.U., Boger E.T., Morell R.J., Kelley M.W., RA Friedman T.B., Banfi B.; RT "Defects in the Alternative Splicing-Dependent Regulation of REST Cause RT Deafness."; RL Cell 174:536-548.E21(2018). CC -!- FUNCTION: Transcriptional repressor which binds neuron-restrictive CC silencer element (NRSE) and represses neuronal gene transcription in CC non-neuronal cells (PubMed:11741002, PubMed:11779185, PubMed:12399542, CC PubMed:26551668, PubMed:7697725, PubMed:7871435, PubMed:8568247). CC Restricts the expression of neuronal genes by associating with two CC distinct corepressors, SIN3A and RCOR1, which in turn recruit histone CC deacetylase to the promoters of REST-regulated genes (PubMed:10449787, CC PubMed:10734093). Mediates repression by recruiting the BHC complex at CC RE1/NRSE sites which acts by deacetylating and demethylating specific CC sites on histones, thereby acting as a chromatin modifier (By CC similarity). Transcriptional repression by REST-CDYL via the CC recruitment of histone methyltransferase EHMT2 may be important in CC transformation suppression (PubMed:19061646). Represses the expression CC of SRRM4 in non-neural cells to prevent the activation of neural- CC specific splicing events and to prevent production of REST isoform 3 CC (By similarity). Repressor activity may be inhibited by forming CC heterodimers with isoform 3, thereby preventing binding to NRSE or CC binding to corepressors and leading to derepression of target genes CC (PubMed:11779185). Also maintains repression of neuronal genes in CC neural stem cells, and allows transcription and differentiation into CC neurons by dissociation from RE1/NRSE sites of target genes (By CC similarity). Thereby is involved in maintaining the quiescent state of CC adult neural stem cells and preventing premature differentiation into CC mature neurons (PubMed:21258371). Plays a role in the developmental CC switch in synaptic NMDA receptor composition during postnatal CC development, by repressing GRIN2B expression and thereby altering NMDA CC receptor properties from containing primarily GRIN2B to primarily CC GRIN2A subunits (By similarity). Acts as a regulator of osteoblast CC differentiation (By similarity). Key repressor of gene expression in CC hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE CC site on their promoter regions (PubMed:27531581). May also function in CC stress resistance in the brain during aging; possibly by regulating CC expression of genes involved in cell death and in the stress response CC (PubMed:24670762). Repressor of gene expression in the hippocampus CC after ischemia by directly binding to RE1/NRSE sites and recruiting CC SIN3A and RCOR1 to promoters of target genes, thereby promoting changes CC in chromatin modifications and ischemia-induced cell death (By CC similarity). After ischemia, might play a role in repression of miR-132 CC expression in hippocampal neurons, thereby leading to neuronal cell CC death (By similarity). Negatively regulates the expression of SRRM3 in CC breast cancer cell lines (PubMed:26053433). CC {ECO:0000250|UniProtKB:O54963, ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:11779185, CC ECO:0000269|PubMed:12399542, ECO:0000269|PubMed:19061646, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:26053433, ECO:0000269|PubMed:26551668, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:7697725, CC ECO:0000269|PubMed:7871435, ECO:0000269|PubMed:8568247}. CC -!- FUNCTION: [Isoform 3]: Binds to the 3' region of the neuron-restrictive CC silencer element (NRSE), with lower affinity than full-length REST CC isoform 1 (By similarity). Exhibits weaker repressor activity compared CC to isoform 1 (PubMed:11779185). May negatively regulate the repressor CC activity of isoform 1 by binding to isoform 1, thereby preventing its CC binding to NRSE and leading to derepression of target genes CC (PubMed:11779185). However, in another study, does not appear to be CC implicated in repressor activity of a NRSE motif-containing reporter CC construct nor in inhibitory activity on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). Post-transcriptional inactivation CC of REST by SRRM4-dependent alternative splicing into isoform 3 is CC required in mechanosensory hair cells in the inner ear for derepression CC of neuronal genes and hearing (By similarity). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SUBUNIT: Isoform 1 and isoform 3 form heterodimers (By similarity). CC Isoform 3: Forms homodimers and homooligomers; binds to the neuron- CC restrictive silencer element (NRSE) as monomer (By similarity). CC Interacts with SIN3A, SIN3B and RCOR1 (PubMed:10449787, CC PubMed:10734093, PubMed:16288918). Interacts with CDYL CC (PubMed:19061646). Interacts with EHMT1 and EHMT2 only in the presence CC of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, CC REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts (via CC zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the CC interaction inhibits REST repressor activity (PubMed:21284946). CC Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (PubMed:14645515, CC PubMed:16442230). Interacts with FBXW11 and BTRC (PubMed:18354482). CC Interacts with USP7 (PubMed:21258371). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:14645515, ECO:0000269|PubMed:16288918, CC ECO:0000269|PubMed:16442230, ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:19061646, ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:21284946}. CC -!- INTERACTION: CC Q13127; Q9Y297: BTRC; NbExp=10; IntAct=EBI-926706, EBI-307461; CC Q13127; Q9UKB1: FBXW11; NbExp=3; IntAct=EBI-926706, EBI-355189; CC Q13127; P07900: HSP90AA1; NbExp=4; IntAct=EBI-926706, EBI-296047; CC Q13127; P41229: KDM5C; NbExp=3; IntAct=EBI-926706, EBI-1246541; CC Q13127; P51532: SMARCA4; NbExp=2; IntAct=EBI-926706, EBI-302489; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16442230, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:30684677}. Cytoplasm CC {ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. Note=Colocalizes with ZFP90 in the CC nucleus (By similarity). In response to hypoxia, there is a more CC pronounced increase in levels in the nucleus as compared to the CC cytoplasm (PubMed:27531581). In aging neurons, increased levels in the CC nucleus as compared to the cytoplasm (PubMed:24670762, CC PubMed:30684677). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Nucleus CC {ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=REST1 {ECO:0000303|PubMed:16442230}; CC IsoId=Q13127-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13127-2; Sequence=VSP_022064, VSP_022065; CC Name=3; Synonyms=N4, REST4 {ECO:0000303|PubMed:11779185}; CC IsoId=Q13127-3; Sequence=VSP_022066, VSP_022068; CC Name=4; CC IsoId=Q13127-4; Sequence=VSP_022067; CC -!- TISSUE SPECIFICITY: Expressed in neurons of the prefrontal cortex, in CC hippocampal pyramidal neurons, dentate gyrus granule neurons and CC cerebellar Purkinje and granule neurons (at protein level) CC (PubMed:24670762). Expressed in dopaminergic neurons of the substantia CC nigra (at protein level) (PubMed:30684677). Expressed in neural CC progenitor cells (at protein level) (PubMed:21258371). In patients CC suffering from Alzheimer disease, frontotemporal dementia or dementia CC with Lewy bodies, decreased nuclear levels have been observed in CC neurons of the prefrontal cortex and the hippocampus, but not in CC neurons of the dentate gyrus and cerebellum (at protein level) CC (PubMed:24670762). In patients with Parkinson disease or dementia with CC Lewy bodies, decreased nuclear levels have been observed in CC dopaminergic neurons and in cortical neurons and localization to Lewy CC bodies and pale bodies was detected (at protein level) CC (PubMed:30684677). Expressed at higher levels in weakly invasive breast CC cancer cell lines and at lower levels in highly invasive breast cancer CC lines (at protein level) (PubMed:26053433). Ubiquitous CC (PubMed:8568247). Expressed at higher levels in the tissues of the CC lymphocytic compartment, including spleen, thymus, peripheral blood CC lymphocytes and ovary (PubMed:8568247). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:26053433, CC ECO:0000269|PubMed:30684677, ECO:0000269|PubMed:8568247}. CC -!- DEVELOPMENTAL STAGE: Expression is cell cycle-dependent with decreased CC levels in G2 phase; mediated by proteasomal degradation (at protein CC level) (PubMed:18354482). In aged individuals, increased expression in CC hippocampal CA1, CA3 and CA4 pyramidal neurons and in dentate granule CC cell neurons, but not in the cerebellum (PubMed:24670762). CC {ECO:0000269|PubMed:18354482, ECO:0000269|PubMed:24670762}. CC -!- INDUCTION: Up-regulated by Wnt signaling (PubMed:24670762). Up- CC regulated in the brain of aging individuals but not in Alzheimer CC disease patients (PubMed:24670762). Up-regulated by oxidative stress CC (PubMed:24670762). Down-regulated during neural progenitor cell CC differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762}. CC -!- DOMAIN: The C2H2-type zinc finger 5 is required for nuclear CC localization. {ECO:0000269|PubMed:16442230}. CC -!- PTM: O-glycosylated. {ECO:0000250|UniProtKB:Q8VIG1}. CC -!- PTM: Phosphorylated; phosphorylation is required for ubiquitination. CC {ECO:0000269|PubMed:18354482}. CC -!- PTM: Ubiquitinated; ubiquitination is mediated by BTRC and leads to CC proteasomal degradation in G2 phase (PubMed:18354482, PubMed:21258371). CC Ubiquitination increases during neuronal differentiation CC (PubMed:21258371). Deubiquitinated by USP7; leading to its CC stabilization and promoting the maintenance of neural progenitor cells CC (PubMed:21258371). {ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:21258371}. CC -!- DISEASE: Wilms tumor 6 (WT6) [MIM:616806]: A pediatric malignancy of CC kidney, and the most common childhood abdominal malignancy. It is CC caused by the uncontrolled multiplication of renal stem, stromal, and CC epithelial cells. {ECO:0000269|PubMed:26551668}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Fibromatosis, gingival, 5 (GINGF5) [MIM:617626]: An autosomal CC dominant form of hereditary gingival fibromatosis, a rare condition CC characterized by a slow, progressive overgrowth of the gingiva. The CC excess gingival tissue can cover part of or the entire crown, and can CC result in diastemas, teeth displacement, or retention of primary or CC impacted teeth. {ECO:0000269|PubMed:28686854}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=An intronic variant that affects alternative splicing of CC REST into isoform 3 and inactivation of REST repressor activity is CC associated with progressive hearing loss and deafness. CC {ECO:0000269|PubMed:29961578}. CC -!- DISEASE: Deafness, autosomal dominant, 27 (DFNA27) [MIM:612431]: A form CC of non-syndromic deafness characterized by postlingual, progressive, CC moderate to profound sensorineural hearing loss. CC {ECO:0000269|PubMed:29961578}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. An intronic CC variant that affects alternative splicing of REST and inactivation of CC REST repressor activity fully segregates with deafness in a 3- CC generation family. {ECO:0000269|PubMed:29961578}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by SRRM4-dependent alternative CC splicing in neurons and inner ear hair cells (By similarity). Lacks the CC four C-terminal zinc fingers and the RCOR1 corepressor interaction site CC found in full length REST isoform 1, which are required for full DNA- CC binding and repressive activity (PubMed:11741002). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002}. CC -!- CAUTION: [Isoform 3]: Controversial data exists concerning the CC repressor activity of isoform 3. A study showed that isoform 3 exhibits CC weak repressor activity of a NRSE motif-containing reporter construct CC (PubMed:11779185). Another report, however, does not observe any CC isoform 3 transcriptional repressor activity of a NRSE motif-containing CC reporter construct (PubMed:11741002). Controversial data also exists CC regarding the function of isoform 3 on the negative regulation of CC isoform 1. It was shown that isoform 3 negatively regulates the CC repressor activity of isoform 1 by binding to isoform 1, thereby CC preventing its binding to NRSE and leading to derepression of target CC genes (PubMed:11779185). Another study, however, did not observe any CC inhibitory activity of isoform 3 on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). {ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA98503.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAC50114.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC50115.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH38985.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=BAD92987.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44266/REST"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U22314; AAB17211.1; -; mRNA. DR EMBL; U13877; AAC50114.1; ALT_INIT; mRNA. DR EMBL; U13879; AAC50115.1; ALT_INIT; mRNA. DR EMBL; U22680; AAA98503.1; ALT_FRAME; mRNA. DR EMBL; AB209750; BAD92987.1; ALT_INIT; mRNA. DR EMBL; AC069307; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471057; EAX05517.1; -; Genomic_DNA. DR EMBL; BC038985; AAH38985.1; ALT_SEQ; mRNA. DR EMBL; BC132859; AAI32860.1; -; mRNA. DR EMBL; BC136491; AAI36492.1; -; mRNA. DR CCDS; CCDS3509.1; -. [Q13127-1] DR PIR; A56138; A56138. DR PIR; I38754; I38754. DR PIR; I38755; I38755. DR RefSeq; NP_001180437.1; NM_001193508.2. [Q13127-1] DR RefSeq; NP_001350382.1; NM_001363453.3. [Q13127-1] DR RefSeq; NP_005603.3; NM_005612.4. [Q13127-1] DR PDB; 2CZY; NMR; -; B=43-57. DR PDB; 6DU2; X-ray; 2.50 A; C/D=858-869. DR PDB; 6DU3; X-ray; 2.58 A; C/D=858-869. DR PDBsum; 2CZY; -. DR PDBsum; 6DU2; -. DR PDBsum; 6DU3; -. DR AlphaFoldDB; Q13127; -. DR BMRB; Q13127; -. DR SMR; Q13127; -. DR BioGRID; 111910; 267. DR CORUM; Q13127; -. DR DIP; DIP-35264N; -. DR FunCoup; Q13127; 4087. DR IntAct; Q13127; 20. DR MINT; Q13127; -. DR STRING; 9606.ENSP00000311816; -. DR GlyGen; Q13127; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13127; -. DR PhosphoSitePlus; Q13127; -. DR BioMuta; REST; -. DR DMDM; 296452989; -. DR jPOST; Q13127; -. DR MassIVE; Q13127; -. DR PaxDb; 9606-ENSP00000311816; -. DR PeptideAtlas; Q13127; -. DR ProteomicsDB; 59175; -. [Q13127-1] DR ProteomicsDB; 59176; -. [Q13127-2] DR ProteomicsDB; 59177; -. [Q13127-3] DR ProteomicsDB; 59178; -. [Q13127-4] DR Pumba; Q13127; -. DR Antibodypedia; 1755; 291 antibodies from 38 providers. DR DNASU; 5978; -. DR Ensembl; ENST00000309042.12; ENSP00000311816.7; ENSG00000084093.20. [Q13127-1] DR Ensembl; ENST00000675105.1; ENSP00000502313.1; ENSG00000084093.20. [Q13127-1] DR GeneID; 5978; -. DR KEGG; hsa:5978; -. DR MANE-Select; ENST00000309042.12; ENSP00000311816.7; NM_005612.5; NP_005603.3. DR UCSC; uc003hch.4; human. [Q13127-1] DR AGR; HGNC:9966; -. DR ClinPGx; PA34334; -. DR CTD; 5978; -. DR DisGeNET; 5978; -. DR GeneCards; REST; -. DR HGNC; HGNC:9966; REST. DR HPA; ENSG00000084093; Low tissue specificity. DR MalaCards; REST; -. DR MIM; 600571; gene. DR MIM; 612431; phenotype. DR MIM; 616806; phenotype. DR MIM; 617626; phenotype. DR OpenTargets; ENSG00000084093; -. DR Orphanet; 2024; Hereditary gingival fibromatosis. DR Orphanet; 654; Nephroblastoma. DR VEuPathDB; HostDB:ENSG00000084093; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000155341; -. DR HOGENOM; CLU_009801_2_0_1; -. DR InParanoid; Q13127; -. DR OrthoDB; 427030at2759; -. DR PAN-GO; Q13127; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13127; -. DR PathwayCommons; Q13127; -. DR Reactome; R-HSA-3214815; HDACs deacetylate histones. DR Reactome; R-HSA-8943724; Regulation of PTEN gene transcription. DR Reactome; R-HSA-9031628; NGF-stimulated transcription. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription. DR SignaLink; Q13127; -. DR SIGNOR; Q13127; -. DR Agora; ENSG00000084093; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5978; 49 hits in 1187 CRISPR screens. DR ChiTaRS; REST; human. DR GeneWiki; RE1-silencing_transcription_factor; -. DR GenomeRNAi; 5978; -. DR Pharos; Q13127; Tbio. DR PRO; PR:Q13127; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q13127; protein. DR Bgee; ENSG00000084093; Expressed in primordial germ cell in gonad and 209 other cell types or tissues. DR ExpressionAtlas; Q13127; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0060088; P:auditory receptor cell stereocilium organization; ISS:UniProtKB. DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; ISS:UniProtKB. DR GO; GO:0071257; P:cellular response to electrical stimulus; IMP:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IDA:UniProtKB. DR GO; GO:0033554; P:cellular response to stress; IEA:Ensembl. DR GO; GO:0006338; P:chromatin remodeling; ISS:UniProtKB. DR GO; GO:0050910; P:detection of mechanical stimulus involved in sensory perception of sound; ISS:UniProtKB. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0043922; P:host-mediated suppression of viral transcription; IDA:UniProtKB. DR GO; GO:0099563; P:modification of synaptic structure; ISS:UniProtKB. DR GO; GO:0032348; P:negative regulation of aldosterone biosynthetic process; IMP:UniProtKB. DR GO; GO:2000798; P:negative regulation of amniotic stem cell differentiation; IMP:UniProtKB. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; ISS:UniProtKB. DR GO; GO:2000065; P:negative regulation of cortisol biosynthetic process; IMP:UniProtKB. DR GO; GO:2000706; P:negative regulation of dense core granule biogenesis; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:UniProtKB. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0050877; P:nervous system process; IMP:UniProtKB. DR GO; GO:0050885; P:neuromuscular process controlling balance; ISS:UniProtKB. DR GO; GO:0097150; P:neuronal stem cell population maintenance; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISS:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; ISS:UniProtKB. DR GO; GO:1902459; P:positive regulation of stem cell population maintenance; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0002931; P:response to ischemia; ISS:UniProtKB. DR GO; GO:0035019; P:somatic stem cell population maintenance; ISS:UniProtKB. DR FunFam; 3.30.160.60:FF:002187; RE1-silencing transcription factor; 1. DR FunFam; 3.30.160.60:FF:000448; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000662; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000805; RE1-silencing transcription factor B; 1. DR FunFam; 3.30.160.60:FF:000952; RE1-silencing transcription factor B; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 5. DR IDEAL; IID00169; -. DR InterPro; IPR057281; Zfn-C2H2_REST. DR InterPro; IPR050688; Zinc_finger/UBP_domain. DR InterPro; IPR036236; Znf_C2H2_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR24403:SF102; RE1-SILENCING TRANSCRIPTION FACTOR; 1. DR PANTHER; PTHR24403; ZINC FINGER PROTEIN; 1. DR Pfam; PF00096; zf-C2H2; 1. DR Pfam; PF24540; zf-C2H2_REST; 1. DR SMART; SM00355; ZnF_C2H2; 9. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 6. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; Disease variant; KW Metal-binding; Non-syndromic deafness; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation; Ubl conjugation; Zinc; KW Zinc-finger. FT CHAIN 1..1097 FT /note="RE1-silencing transcription factor" FT /id="PRO_0000269547" FT ZN_FING 159..181 FT /note="C2H2-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 216..238 FT /note="C2H2-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 248..270 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 276..298 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 304..326 FT /note="C2H2-type 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 332..355 FT /note="C2H2-type 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 361..383 FT /note="C2H2-type 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 389..412 FT /note="C2H2-type 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 1060..1082 FT /note="C2H2-type 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 32..122 FT /note="Interaction with SIN3A" FT /evidence="ECO:0000269|PubMed:10734093" FT REGION 43..57 FT /note="Interaction with SIN3B" FT /evidence="ECO:0000269|PubMed:16288918" FT REGION 83..103 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 127..159 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..418 FT /note="Interaction with ZFP90" FT /evidence="ECO:0000269|PubMed:21284946" FT REGION 201..212 FT /note="Required for binding to the neuron-restrictive FT silencer element" FT /evidence="ECO:0000250|UniProtKB:Q8VIG1" FT REGION 452..642 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 774..837 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 853..938 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 961..1049 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1009..1087 FT /note="Interaction with RCOR1" FT /evidence="ECO:0000269|PubMed:10449787" FT COMPBIAS 86..96 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 452..479 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 480..490 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 495..504 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 559..570 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 577..593 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 803..836 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 913..930 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 864 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 971 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O54963" FT VAR_SEQ 301..313 FT /note="ERPYKCELCPYSS -> KRSFLVHKFSSLF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022064" FT VAR_SEQ 304..326 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_022067" FT VAR_SEQ 314..1097 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022065" FT VAR_SEQ 329 FT /note="E -> W (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022066" FT VAR_SEQ 330..1097 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022068" FT VARIANT 160 FT /note="R -> P (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076333" FT VARIANT 290 FT /note="N -> Y (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076334" FT VARIANT 322 FT /note="H -> R (in WT6; inhibits transcriptional repression FT activity; dbSNP:rs869025312)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076335" FT VARIANT 412 FT /note="H -> Q (in WT6)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076336" FT VARIANT 437..1097 FT /note="Missing (in GINGF5)" FT /evidence="ECO:0000269|PubMed:28686854" FT /id="VAR_079529" FT VARIANT 626 FT /note="V -> I (in dbSNP:rs2228991)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_029795" FT VARIANT 692 FT /note="E -> D (in dbSNP:rs2227902)" FT /id="VAR_029796" FT VARIANT 762 FT /note="K -> Q (in dbSNP:rs2227903)" FT /id="VAR_029797" FT VARIANT 797 FT /note="P -> L (in dbSNP:rs3796529)" FT /evidence="ECO:0000269|PubMed:8568247" FT /id="VAR_029798" FT MUTAGEN 91 FT /note="E->G: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 313 FT /note="S->A: Lack of deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT MUTAGEN 420 FT /note="M->T: Inhibits transcriptional repression activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->AFSKTADSMDA: No effect on nuclear FT localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->GS: Reduced nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="Missing: No effect on nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 593 FT /note="S->N: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 642 FT /note="A->T: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 918 FT /note="H->Y: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 1009..1013 FT /note="EGIHS->AGIHA: Loss of interaction with BTRC. Reduced FT ubiquitination. Decreased proteasomal degradation in G2. FT Decreased average time from nuclear envelope breakdown to FT anaphase onset. Increased number of lagging chromosomes and FT chromosome bridges in anaphase and prematurely separated FT sister chromatids. Reduced MAD2 levels." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1009 FT /note="E->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1013 FT /note="S->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1042 FT /note="S->A: No impact on deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT CONFLICT 295 FT /note="V -> L (in Ref. 2; AAC50114)" FT /evidence="ECO:0000305" FT CONFLICT 596..599 FT /note="PQKE -> SRNS (in Ref. 2; AAC50115)" FT /evidence="ECO:0000305" FT CONFLICT 630 FT /note="P -> L (in Ref. 1; AAB17211)" FT /evidence="ECO:0000305" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:2CZY" SQ SEQUENCE 1097 AA; 121872 MW; EBC652EED19CA161 CRC64; MATQVMGQSS GGGGLFTSSG NIGMALPNDM YDLHDLSKAE LAAPQLIMLA NVALTGEVNG SCCDYLVGEE RQMAELMPVG DNNFSDSEEG EGLEESADIK GEPHGLENME LRSLELSVVE PQPVFEASGA PDIYSSNKDL PPETPGAEDK GKSSKTKPFR CKPCQYEAES EEQFVHHIRV HSAKKFFVEE SAEKQAKARE SGSSTAEEGD FSKGPIRCDR CGYNTNRYDH YTAHLKHHTR AGDNERVYKC IICTYTTVSE YHWRKHLRNH FPRKVYTCGK CNYFSDRKNN YVQHVRTHTG ERPYKCELCP YSSSQKTHLT RHMRTHSGEK PFKCDQCSYV ASNQHEVTRH ARQVHNGPKP LNCPHCDYKT ADRSNFKKHV ELHVNPRQFN CPVCDYAASK KCNLQYHFKS KHPTCPNKTM DVSKVKLKKT KKREADLPDN ITNEKTEIEQ TKIKGDVAGK KNEKSVKAEK RDVSKEKKPS NNVSVIQVTT RTRKSVTEVK EMDVHTGSNS EKFSKTKKSK RKLEVDSHSL HGPVNDEESS TKKKKKVESK SKNNSQEVPK GDSKVEENKK QNTCMKKSTK KKTLKNKSSK KSSKPPQKEP VEKGSAQMDP PQMGPAPTEA VQKGPVQVEP PPPMEHAQME GAQIRPAPDE PVQMEVVQEG PAQKELLPPV EPAQMVGAQI VLAHMELPPP METAQTEVAQ MGPAPMEPAQ MEVAQVESAP MQVVQKEPVQ MELSPPMEVV QKEPVQIELS PPMEVVQKEP VKIELSPPIE VVQKEPVQME LSPPMGVVQK EPAQREPPPP REPPLHMEPI SKKPPLRKDK KEKSNMQSER ARKEQVLIEV GLVPVKDSWL LKESVSTEDL SPPSPPLPKE NLREEASGDQ KLLNTGEGNK EAPLQKVGAE EADESLPGLA ANINESTHIS SSGQNLNTPE GETLNGKHQT DSIVCEMKMD TDQNTRENLT GINSTVEEPV SPMLPPSAVE EREAVSKTAL ASPPATMAAN ESQEIDEDEG IHSHEGSDLS DNMSEGSDDS GLHGARPVPQ ESSRKNAKEA LAVKAAKGDF VCIFCDRSFR KGKDYSKHLN RHLVNVYYLE EAAQGQE // ID SQSTM_HUMAN Reviewed; 440 AA. AC Q13501; A6NFN7; B2R661; B3KUW5; Q13446; Q9BUV7; Q9BVS6; Q9UEU1; DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 28-JAN-2026, entry version 237. DE RecName: Full=Sequestosome-1 {ECO:0000305}; DE AltName: Full=EBI3-associated protein of 60 kDa {ECO:0000303|PubMed:8551575}; DE Short=EBIAP; DE Short=p60 {ECO:0000303|PubMed:8551575}; DE AltName: Full=Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa {ECO:0000303|PubMed:8650207}; DE AltName: Full=Ubiquitin-binding protein p62 {ECO:0000303|PubMed:8650207}; DE Short=p62 {ECO:0000303|PubMed:30266909}; GN Name=SQSTM1 {ECO:0000303|PubMed:16286508, ECO:0000312|HGNC:HGNC:11280}; GN Synonyms=ORCA, OSIL; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|Proteomes:UP000005640}; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 345-361 AND RP 394-411, AND INTERACTION WITH EBI3. RC TISSUE=B-cell; RX PubMed=8551575; DOI=10.1128/jvi.70.2.1143-1153.1996; RA Devergne O., Hummel M., Koeppen H., Le Beau M.M., Nathanson E.C., Kieff E., RA Birkenbach M.; RT "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr RT virus infection in B lymphocytes."; RL J. Virol. 70:1143-1153(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 51-96; 184-187; RP 213-217; 239-264 AND 268-281, TISSUE SPECIFICITY, INTERACTION WITH LCK, AND RP MUTAGENESIS OF TYR-9. RC TISSUE=Cervix carcinoma; RX PubMed=8650207; DOI=10.1073/pnas.93.12.5991; RA Joung I., Strominger J.L., Shin J.; RT "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck RT SH2 domain."; RL Proc. Natl. Acad. Sci. U.S.A. 93:5991-5995(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Caudate nucleus, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Pancreas, Placenta, Skin, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, AND INDUCTION. RX PubMed=9762895; DOI=10.1016/s0014-5793(98)01021-7; RA Vadlamudi R.K., Shin J.; RT "Genomic structure and promoter analysis of the p62 gene encoding a non- RT proteasomal multiubiquitin chain binding protein."; RL FEBS Lett. 435:138-142(1998). RN [7] RP PROTEIN SEQUENCE OF 51-60; 166-174 AND 379-388. RX PubMed=10362795; DOI=10.1016/s0002-9440(10)65426-0; RA Stumptner C., Heid H., Fuchsbichler A., Hauser H., Mischinger H.-J., RA Zatloukal K., Denk H.; RT "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. RT Demonstration of p62 as major constituent."; RL Am. J. Pathol. 154:1701-1710(1999). RN [8] RP INTERACTION WITH LCK AND RASA1. RX PubMed=8618896; DOI=10.1073/pnas.92.26.12338; RA Park I., Chung J., Walsh C.T., Yun Y., Strominger J.L., Shin J.; RT "Phosphotyrosine-independent binding of a 62-kDa protein to the src RT homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of RT Ser-59 in the lck unique N-terminal region."; RL Proc. Natl. Acad. Sci. U.S.A. 92:12338-12342(1995). RN [9] RP INTERACTION WITH UBIQUITIN. RX PubMed=8702753; DOI=10.1074/jbc.271.34.20235; RA Vadlamudi R.K., Joung I., Strominger J.L., Shin J.; RT "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, RT belongs to a new class of ubiquitin-binding proteins."; RL J. Biol. Chem. 271:20235-20237(1996). RN [10] RP INTERACTION WITH NR2F2. RX PubMed=8910285; DOI=10.1074/jbc.271.44.27197; RA Marcus S.L., Winrow C.J., Capone J.P., Rachubinski R.A.; RT "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone RT receptor."; RL J. Biol. Chem. 271:27197-27200(1996). RN [11] RP INTERACTION WITH PRKCI AND PRKCZ, AND SUBCELLULAR LOCATION. RX PubMed=9566925; DOI=10.1128/mcb.18.5.3069; RA Sanchez P., De Carcer G., Sandoval I.V., Moscat J., Diaz-Meco M.T.; RT "Localization of atypical protein kinase C isoforms into lysosome-targeted RT endosomes through interaction with p62."; RL Mol. Cell. Biol. 18:3069-3080(1998). RN [12] RP INTERACTION WITH RIPK1; PRKCZ; PRKCI; IKBKB; TRADD AND TNFRSF1A, AND RP FUNCTION. RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044; RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.; RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB RT activation."; RL EMBO J. 18:3044-3053(1999). RN [13] RP INTERACTION WITH MAPKAPK5, AND SUBCELLULAR LOCATION. RX PubMed=10708586; DOI=10.1006/bbrc.2000.2333; RA Sudo T., Maruyama M., Osada H.; RT "p62 functions as a p38 MAP kinase regulator."; RL Biochem. Biophys. Res. Commun. 269:521-525(2000). RN [14] RP INTERACTION WITH TRAF6 AND RIPK1, DOMAIN, AND FUNCTION. RX PubMed=10747026; DOI=10.1093/emboj/19.7.1576; RA Sanz L., Diaz-Meco M.T., Nakano H., Moscat J.; RT "The atypical PKC-interacting protein p62 channels NF-kappaB activation by RT the IL-1-TRAF6 pathway."; RL EMBO J. 19:1576-1586(2000). RN [15] RP INTERACTION WITH NTRK1; TRAF6; NGFR AND PRKCZ, AND FUNCTION. RX PubMed=11244088; DOI=10.1074/jbc.c000869200; RA Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A., RA Moscat J.; RT "The atypical protein kinase C-interacting protein p62 is a scaffold for RT NF-kappaB activation by nerve growth factor."; RL J. Biol. Chem. 276:7709-7712(2001). RN [16] RP SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=11786419; DOI=10.1016/s0002-9440(10)64369-6; RA Zatloukal K., Stumptner C., Fuchsbichler A., Heid H., Schnoelzer M., RA Kenner L., Kleinert R., Prinz M., Aguzzi A., Denk H.; RT "p62 Is a common component of cytoplasmic inclusions in protein aggregation RT diseases."; RL Am. J. Pathol. 160:255-263(2002). RN [17] RP INTERACTION WITH PAWR AND PRKCZ. RX PubMed=11755531; DOI=10.1016/s0014-5793(01)03224-0; RA Chang S., Kim J.H., Shin J.; RT "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4- RT induced PKCzeta inhibition."; RL FEBS Lett. 510:57-61(2002). RN [18] RP SUBCELLULAR LOCATION. RX PubMed=11981755; DOI=10.1053/jhep.2002.32674; RA Stumptner C., Fuchsbichler A., Heid H., Zatloukal K., Denk H.; RT "Mallory body -- a disease-associated type of sequestosome."; RL Hepatology 35:1053-1062(2002). RN [19] RP INTERACTION WITH NTRK1; NTRK2 AND NTRK3, SUBCELLULAR LOCATION, AND RP FUNCTION. RX PubMed=12471037; DOI=10.1074/jbc.m208468200; RA Geetha T., Wooten M.W.; RT "Association of the atypical protein kinase C-interacting protein p62/ZIP RT with nerve growth factor receptor TrkA regulates receptor trafficking and RT Erk5 signaling."; RL J. Biol. Chem. 278:4730-4739(2003). RN [20] RP INTERACTION WITH PRKCI; PRKCZ; MAP2K5 AND NBR1, DOMAIN, MUTAGENESIS OF RP LYS-7; LYS-13; 21-ARG-ARG-22; TYR-67; ASP-69; ASP-71; ASP-73; ASP-80 AND RP GLU-82, AND DIMERIZATION. RX PubMed=12813044; DOI=10.1074/jbc.m303221200; RA Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A., RA Michaelsen E., Bjoerkoey G., Johansen T.; RT "Interaction codes within the family of mammalian Phox and Bem1p domain- RT containing proteins."; RL J. Biol. Chem. 278:34568-34581(2003). RN [21] RP INTERACTION WITH PRKCZ, DOMAIN, OLIGOMERIZATION, AND MUTAGENESIS OF LYS-7; RP ASP-69 AND ASP-73. RX PubMed=12887891; DOI=10.1016/s1097-2765(03)00246-6; RA Wilson M.I., Gill D.J., Perisic O., Quinn M.T., Williams R.L.; RT "PB1 domain-mediated heterodimerization in NADPH oxidase and signaling RT complexes of atypical protein kinase C with Par6 and p62."; RL Mol. Cell 12:39-50(2003). RN [22] RP INDUCTION. RX PubMed=12700667; DOI=10.1038/sj.onc.1206325; RA Thompson H.G.R., Harris J.W., Wold B.J., Lin F., Brody J.P.; RT "p62 overexpression in breast tumors and regulation by prostate-derived Ets RT factor in breast cancer cells."; RL Oncogene 22:2322-2333(2003). RN [23] RP SUBCELLULAR LOCATION. RX PubMed=15158159; DOI=10.1016/j.brainres.2004.03.029; RA Nakaso K., Yoshimoto Y., Nakano T., Takeshima T., Fukuhara Y., Yasui K., RA Araga S., Yanagawa T., Ishii T., Nakashima K.; RT "Transcriptional activation of p62/A170/ZIP during the formation of the RT aggregates: possible mechanisms and the role in Lewy body formation in RT Parkinson's disease."; RL Brain Res. 1012:42-51(2004). RN [24] RP INTERACTION WITH TRAF6; PSMC2 AND PSMD4, DOMAIN, MUTAGENESIS OF LEU-398; RP PHE-406; LEU-413; LEU-417 AND ILE-431, AND FUNCTION. RX PubMed=15340068; DOI=10.1128/mcb.24.18.8055-8068.2004; RA Seibenhener M.L., Babu J.R., Geetha T., Wong H.C., Krishna N.R., RA Wooten M.W.; RT "Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in RT ubiquitin proteasome degradation."; RL Mol. Cell. Biol. 24:8055-8068(2004). RN [25] RP FUNCTION. RX PubMed=16079148; DOI=10.1074/jbc.c500237200; RA Wooten M.W., Geetha T., Seibenhener M.L., Babu J.R., Diaz-Meco M.T., RA Moscat J.; RT "The p62 scaffold regulates nerve growth factor-induced NF-kappaB RT activation by influencing TRAF6 polyubiquitination."; RL J. Biol. Chem. 280:35625-35629(2005). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, HOMOOLIGOMERIZATION, INTERACTION WITH RP MAP1LC3B, POSSIBLE PROTECTIVE ROLE IN HD, AND MUTAGENESIS OF ASP-69 AND RP ILE-431. RX PubMed=16286508; DOI=10.1083/jcb.200507002; RA Bjorkoy G., Lamark T., Brech A., Outzen H., Perander M., Overvatn A., RA Stenmark H., Johansen T.; RT "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a RT protective effect on huntingtin-induced cell death."; RL J. Cell Biol. 171:603-614(2005). RN [27] RP INTERACTION WITH MAPT, DOMAIN, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x; RA Babu J.R., Geetha T., Wooten M.W.; RT "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal RT degradation."; RL J. Neurochem. 94:192-203(2005). RN [28] RP INTERACTION WITH AJUBA AND LIMD1. RX PubMed=15870274; DOI=10.1128/mcb.25.10.4010-4022.2005; RA Feng Y., Longmore G.D.; RT "The LIM protein Ajuba influences interleukin-1-induced NF-kappaB RT activation by affecting the assembly and activity of the protein kinase RT Czeta/p62/TRAF6 signaling complex."; RL Mol. Cell. Biol. 25:4010-4022(2005). RN [29] RP INDUCTION, AND FUNCTION. RX PubMed=15911346; DOI=10.1016/j.mcn.2005.02.011; RA Wang Z., Figueiredo-Pereira M.E.; RT "Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of RT ubiquitinated proteins induced by prostaglandin J2 without reducing its RT neurotoxicity."; RL Mol. Cell. Neurosci. 29:222-231(2005). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-148, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [31] RP INTERACTION WITH NBR1 AND TRIM55, PHOSPHORYLATION, DOMAIN, AND FUNCTION. RX PubMed=15802564; DOI=10.1126/science.1110463; RA Lange S., Xiang F., Yakovenko A., Vihola A., Hackman P., Rostkova E., RA Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson L.G., RA Hughes S.M., Marchand S., Sejersen T., Richard I., Edstroem L., Ehler E., RA Udd B., Gautel M.; RT "The kinase domain of titin controls muscle gene expression and protein RT turnover."; RL Science 308:1599-1603(2005). RN [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-332, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [34] RP FUNCTION, INTERACTION WITH GABARAP; GABARAPL1; GABARAPL2; MAP1LC3A AND RP MAP1LC3B, AND MUTAGENESIS OF 323-GLU-GLU-324; SER-332; 335-ASP--ASP-337; RP TRP-338 AND SER-342. RX PubMed=17580304; DOI=10.1074/jbc.m702824200; RA Pankiv S., Clausen T.H., Lamark T., Brech A., Bruun J.A., Outzen H., RA Overvatn A., Bjorkoy G., Johansen T.; RT "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of RT ubiquitinated protein aggregates by autophagy."; RL J. Biol. Chem. 282:24131-24145(2007). RN [35] RP PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION). RX PubMed=24331465; DOI=10.1016/j.chom.2013.11.003; RA Barnett T.C., Liebl D., Seymour L.M., Gillen C.M., Lim J.Y., Larock C.N., RA Davies M.R., Schulz B.L., Nizet V., Teasdale R.D., Walker M.J.; RT "The globally disseminated M1T1 clone of group A Streptococcus evades RT autophagy for intracellular replication."; RL Cell Host Microbe 14:675-682(2013). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-269 AND SER-272, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-328; SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [38] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [39] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [40] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-355 AND SER-361, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [41] RP FUNCTION, INTERACTION WITH WDFY3, AND SUBCELLULAR LOCATION. RX PubMed=20168092; DOI=10.4161/auto.6.3.11226; RA Clausen T.H., Lamark T., Isakson P., Finley K., Larsen K.B., Brech A., RA Overvatn A., Stenmark H., Bjorkoy G., Simonsen A., Johansen T.; RT "p62/SQSTM1 and ALFY interact to facilitate the formation of p62 RT bodies/ALIS and their degradation by autophagy."; RL Autophagy 6:330-344(2010). RN [42] RP INTERACTION WITH KEAP1. RX PubMed=20495340; DOI=10.4161/auto.6.5.12189; RA Fan W., Tang Z., Chen D., Moughon D., Ding X., Chen S., Zhu M., Zhong Q.; RT "Keap1 facilitates p62-mediated ubiquitin aggregate clearance via RT autophagy."; RL Autophagy 6:614-621(2010). RN [43] RP FUNCTION, INTERACTION WITH KEAP1, INDUCTION, AND MUTAGENESIS OF ASP-347; RP THR-350; GLY-351 AND GLU-352. RX PubMed=20452972; DOI=10.1074/jbc.m110.118976; RA Jain A., Lamark T., Sjoettem E., Larsen K.B., Awuh J.A., Oevervatn A., RA McMahon M., Hayes J.D., Johansen T.; RT "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a RT positive feedback loop by inducing antioxidant response element-driven gene RT transcription."; RL J. Biol. Chem. 285:22576-22591(2010). RN [44] RP INTERACTION WITH FHOD3. RX PubMed=21149568; DOI=10.1083/jcb.201005060; RA Iskratsch T., Lange S., Dwyer J., Kho A.L., dos Remedios C., Ehler E.; RT "Formin follows function: a muscle-specific isoform of FHOD3 is regulated RT by CK2 phosphorylation and promotes myofibril maintenance."; RL J. Cell Biol. 191:1159-1172(2010). RN [45] RP INTERACTION WITH TRIM5, AND SUBCELLULAR LOCATION. RX PubMed=20357094; DOI=10.1128/jvi.02412-09; RA O'Connor C., Pertel T., Gray S., Robia S.L., Bakowska J.C., Luban J., RA Campbell E.M.; RT "p62/sequestosome-1 associates with and sustains the expression of RT retroviral restriction factor TRIM5alpha."; RL J. Virol. 84:5997-6006(2010). RN [46] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; SER-207; SER-249; RP SER-266; SER-272 AND SER-332, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [47] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; ILE-153; LEU-228; RP LYS-238 DEL; PRO-318; CYS-321; PRO-370; LEU-392; SER-411 AND ARG-425. RX PubMed=22084127; DOI=10.1001/archneurol.2011.250; RA Fecto F., Yan J., Vemula S.P., Liu E., Yang Y., Chen W., Zheng J.G., RA Shi Y., Siddique N., Arrat H., Donkervoort S., Ajroud-Driss S., Sufit R.L., RA Heller S.L., Deng H.X., Siddique T.; RT "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."; RL Arch. Neurol. 68:1440-1446(2011). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [49] RP IDENTIFICATION IN A COMPLEX WITH ZFAND5 AND UBIQUITIN, AND SUBCELLULAR RP LOCATION. RX PubMed=21923101; DOI=10.1021/bi201137e; RA Garner T.P., Strachan J., Shedden E.C., Long J.E., Cavey J.R., Shaw B., RA Layfield R., Searle M.S.; RT "Independent interactions of ubiquitin-binding domains in a ubiquitin- RT mediated ternary complex."; RL Biochemistry 50:9076-9087(2011). RN [50] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-24; SER-207; RP THR-269; SER-272; SER-282; SER-332; SER-366 AND SER-403, AND MUTAGENESIS OF RP SER-403. RX PubMed=22017874; DOI=10.1016/j.molcel.2011.07.039; RA Matsumoto G., Wada K., Okuno M., Kurosawa M., Nukina N.; RT "Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic RT clearance of ubiquitinated proteins."; RL Mol. Cell 44:279-289(2011). RN [51] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-272, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [52] RP FUNCTION. RX PubMed=22622177; DOI=10.4161/auto.19381; RA Taillebourg E., Gregoire I., Viargues P., Jacomin A.C., Thevenon D., RA Faure M., Fauvarque M.O.; RT "The deubiquitinating enzyme USP36 controls selective autophagy activation RT by ubiquitinated proteins."; RL Autophagy 8:767-779(2012). RN [53] RP INTERACTION WITH TRIM13, AND SUBCELLULAR LOCATION. RX PubMed=22178386; DOI=10.1016/j.bbamcr.2011.11.015; RA Tomar D., Singh R., Singh A.K., Pandya C.D., Singh R.; RT "TRIM13 regulates ER stress induced autophagy and clonogenic ability of the RT cells."; RL Biochim. Biophys. Acta 1823:316-326(2012). RN [54] RP INTERACTION WITH MAP1LC3A. RX PubMed=22421968; DOI=10.1038/cdd.2012.30; RA Seillier M., Peuget S., Gayet O., Gauthier C., N'guessan P., Monte M., RA Carrier A., Iovanna J.L., Dusetti N.J.; RT "TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins RT through the LC3-interacting region (LIR) and promotes autophagy-dependent RT cell death."; RL Cell Death Differ. 19:1525-1535(2012). RN [55] RP INTERACTION WITH TRIM50, AND SUBCELLULAR LOCATION. RX PubMed=22792322; DOI=10.1371/journal.pone.0040440; RA Fusco C., Micale L., Egorov M., Monti M., D'Addetta E.V., Augello B., RA Cozzolino F., Calcagni A., Fontana A., Polishchuk R.S., Didelot G., RA Reymond A., Pucci P., Merla G.; RT "The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes RT the sequestration and clearance of ubiquitinated proteins into the RT aggresome."; RL PLoS ONE 7:E40440-E40440(2012). RN [56] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, ACETYLATION [LARGE SCALE RP ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS] RP (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [57] RP FUNCTION. RX PubMed=24128730; DOI=10.4161/auto.26085; RA Isakson P., Lystad A.H., Breen K., Koster G., Stenmark H., Simonsen A.; RT "TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody RT ring degradation by selective autophagy."; RL Autophagy 9:1955-1964(2013). RN [58] RP INTERACTION WITH SESN1 AND SESN2. RX PubMed=23274085; DOI=10.1016/j.cmet.2012.12.002; RA Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E., RA Kang D., Rhee S.G.; RT "Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation RT of Keap1 and prevent oxidative liver damage."; RL Cell Metab. 17:73-84(2013). RN [59] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-170; THR-269; SER-272; RP SER-332 AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [60] RP INVOLVEMENT IN FTDALS3, AND VARIANTS FTDALS3 VAL-33; VAL-381; LEU-387 AND RP LEU-392. RX PubMed=24042580; DOI=10.1001/jamaneurol.2013.3849; RG French Clinical and Genetic Research Network on FTD/FTD-ALS; RA Le Ber I., Camuzat A., Guerreiro R., Bouya-Ahmed K., Bras J., Nicolas G., RA Gabelle A., Didic M., De Septenville A., Millecamps S., Lenglet T., RA Latouche M., Kabashi E., Campion D., Hannequin D., Hardy J., Brice A.; RT "SQSTM1 mutations in French patients with frontotemporal dementia or RT frontotemporal dementia with amyotrophic lateral sclerosis."; RL JAMA Neurol. 70:1403-1410(2013). RN [61] RP LIR MOTIF. RX PubMed=23908376; DOI=10.1242/jcs.126128; RA Birgisdottir A.B., Lamark T., Johansen T.; RT "The LIR motif - crucial for selective autophagy."; RL J. Cell Sci. 126:3237-3247(2013). RN [62] RP INTERACTION WITH MAP1LC3B. RX PubMed=24089205; DOI=10.1038/nature12606; RA Tang Z., Lin M.G., Stowe T.R., Chen S., Zhu M., Stearns T., Franco B., RA Zhong Q.; RT "Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar RT satellites."; RL Nature 502:254-257(2013). RN [63] RP FUNCTION, INTERACTION WITH TNS2 AND IRS1, AND DEVELOPMENTAL STAGE. RX PubMed=25101860; DOI=10.1016/j.cellsig.2014.07.033; RA Koh A., Park D., Jeong H., Lee J., Lee M.N., Suh P.G., Ryu S.H.; RT "Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated RT sequestration and degradation."; RL Cell. Signal. 26:2470-2480(2014). RN [64] RP INTERACTION WITH TRIM5. RX PubMed=25127057; DOI=10.1016/j.devcel.2014.06.013; RA Mandell M.A., Jain A., Arko-Mensah J., Chauhan S., Kimura T., Dinkins C., RA Silvestri G., Munch J., Kirchhoff F., Simonsen A., Wei Y., Levine B., RA Johansen T., Deretic V.; RT "TRIM proteins regulate autophagy and can target autophagic substrates by RT direct recognition."; RL Dev. Cell 30:394-409(2014). RN [65] RP INTERACTION WITH SESN2 AND ULK1, AND PHOSPHORYLATION AT SER-403 BY ULK1. RX PubMed=25040165; DOI=10.1111/febs.12905; RA Ro S.H., Semple I.A., Park H., Park H., Park H.W., Kim M., Kim J.S., RA Lee J.H.; RT "Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of RT p62/sequestosome-1."; RL FEBS J. 281:3816-3827(2014). RN [66] RP INTERACTION WITH GABARAP, AND MUTAGENESIS OF TRP-338. RX PubMed=24668264; DOI=10.1002/embr.201338003; RA Lystad A.H., Ichimura Y., Takagi K., Yang Y., Pankiv S., Kanegae Y., RA Kageyama S., Suzuki M., Saito I., Mizushima T., Komatsu M., Simonsen A.; RT "Structural determinants in GABARAP required for the selective binding and RT recruitment of ALFY to LC3B-positive structures."; RL EMBO Rep. 15:557-565(2014). RN [67] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24; SER-176; SER-233; SER-306 RP AND SER-366, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [68] RP INTERACTION WITH UBD. RX PubMed=25422469; DOI=10.1073/pnas.1403383111; RA Theng S.S., Wang W., Mah W.C., Chan C., Zhuo J., Gao Y., Qin H., Lim L., RA Chong S.S., Song J., Lee C.G.; RT "Disruption of FAT10-MAD2 binding inhibits tumor progression."; RL Proc. Natl. Acad. Sci. U.S.A. 111:E5282-E5291(2014). RN [69] RP DISEASE, AND CHROMOSOMAL TRANSLOCATION WITH NU214. RX PubMed=20851865; DOI=10.3324/haematol.2010.029769; RA Gorello P., La Starza R., Di Giacomo D., Messina M., Puzzolo M.C., RA Crescenzi B., Santoro A., Chiaretti S., Mecucci C.; RT "SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic RT leukemia."; RL Haematologica 95:2161-2163(2010). RN [70] RP INVOLVEMENT IN FTDALS3, AND VARIANT FTDALS3 LYS-238 DEL. RX PubMed=25114083; DOI=10.3233/jad-141512; RA Boutoleau-Bretonniere C., Camuzat A., Le Ber I., Bouya-Ahmed K., RA Guerreiro R., Deruet A.L., Evrard C., Bras J., Lamy E., Auffray-Calvier E., RA Pallardy A., Hardy J., Brice A., Derkinderen P., Vercelletto M.; RT "A phenotype of atypical apraxia of speech in a family carrying SQSTM1 RT mutation."; RL J. Alzheimers Dis. 43:625-630(2015). RN [71] RP FUNCTION, AND INTERACTION WITH PEX5. RX PubMed=26344566; DOI=10.1038/ncb3230; RA Zhang J., Tripathi D.N., Jing J., Alexander A., Kim J., Powell R.T., RA Dere R., Tait-Mulder J., Lee J.H., Paull T.T., Pandita R.K., Charaka V.K., RA Pandita T.K., Kastan M.B., Walker C.L.; RT "ATM functions at the peroxisome to induce pexophagy in response to ROS."; RL Nat. Cell Biol. 17:1259-1269(2015). RN [72] RP INVOLVEMENT IN DMRV. RX PubMed=26208961; DOI=10.1212/wnl.0000000000001864; RA Bucelli R.C., Arhzaouy K., Pestronk A., Pittman S.K., Rojas L., Sue C.M., RA Evilae A., Hackman P., Udd B., Harms M.B., Weihl C.C.; RT "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."; RL Neurology 85:665-674(2015). RN [73] RP INVOLVEMENT IN NADGP. RX PubMed=27545679; DOI=10.1016/j.ajhg.2016.06.026; RA Haack T.B., Ignatius E., Calvo-Garrido J., Iuso A., Isohanni P., RA Maffezzini C., Loennqvist T., Suomalainen A., Gorza M., Kremer L.S., RA Graf E., Hartig M., Berutti R., Paucar M., Svenningsson P., Stranneheim H., RA Brandberg G., Wedell A., Kurian M.A., Hayflick S.A., Venco P., Tiranti V., RA Strom T.M., Dichgans M., Horvath R., Holinski-Feder E., Freyer C., RA Meitinger T., Prokisch H., Senderek J., Wredenberg A., Carroll C.J., RA Klopstock T.; RT "Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset RT neurodegeneration with ataxia, dystonia, and gaze palsy."; RL Am. J. Hum. Genet. 99:735-743(2016). RN [74] RP FUNCTION, AND UBIQUITINATION. RX PubMed=27368102; DOI=10.1016/j.cell.2016.05.078; RA Jongsma M.L., Berlin I., Wijdeven R.H., Janssen L., Janssen G.M., RA Garstka M.A., Janssen H., Mensink M., van Veelen P.A., Spaapen R.M., RA Neefjes J.; RT "An ER-associated pathway defines endosomal architecture for controlled RT cargo transport."; RL Cell 166:152-166(2016). RN [75] RP INTERACTION WITH TRIM11. RX PubMed=27498865; DOI=10.1016/j.celrep.2016.07.019; RA Liu T., Tang Q., Liu K., Xie W., Liu X., Wang H., Wang R.F., Cui J.; RT "TRIM11 suppresses AIM2 inflammasome by degrading AIM2 via p62-dependent RT selective autophagy."; RL Cell Rep. 16:1988-2002(2016). RN [76] RP UBIQUITINATION, AND FUNCTION. RX PubMed=27880896; DOI=10.1016/j.celrep.2016.11.005; RA Heath R.J., Goel G., Baxt L.A., Rush J.S., Mohanan V., Paulus G.L.C., RA Jani V., Lassen K.G., Xavier R.J.; RT "RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial RT Autophagy."; RL Cell Rep. 17:2183-2194(2016). RN [77] RP FUNCTION, UBIQUITINATION AT LYS-420, AND MUTAGENESIS OF LYS-420. RX PubMed=28380357; DOI=10.1016/j.celrep.2017.03.030; RA Lee Y., Chou T.F., Pittman S.K., Keith A.L., Razani B., Weihl C.C.; RT "Keap1/cullin3 modulates p62/SQSTM1 activity via UBA domain RT ubiquitination."; RL Cell Rep. 19:188-202(2017). RN [78] RP DOMAIN, AND UBIQUITINATION. RX PubMed=28322253; DOI=10.1038/cr.2017.40; RA Peng H., Yang J., Li G., You Q., Han W., Li T., Gao D., Xie X., Lee B.H., RA Du J., Hou J., Zhang T., Rao H., Huang Y., Li Q., Zeng R., Hui L., Wang H., RA Xia Q., Zhang X., He Y., Komatsu M., Dikic I., Finley D., Hu R.; RT "Ubiquitylation of p62/sequestosome1 activates its autophagy receptor RT function and controls selective autophagy upon ubiquitin stress."; RL Cell Res. 27:657-674(2017). RN [79] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-435, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [80] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-403, MUTAGENESIS OF RP SER-403, AND CHARACTERIZATION OF VARIANTS PDB3 THR-404 AND SER-411. RX PubMed=29507397; DOI=10.1038/s41422-018-0017-7; RA Sun D., Wu R., Zheng J., Li P., Yu L.; RT "Polyubiquitin chain-induced p62 phase separation drives autophagic cargo RT segregation."; RL Cell Res. 28:405-415(2018). RN [81] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=29343546; DOI=10.15252/embj.201798308; RA Zaffagnini G., Savova A., Danieli A., Romanov J., Tremel S., Ebner M., RA Peterbauer T., Sztacho M., Trapannone R., Tarafder A.K., Sachse C., RA Martens S.; RT "p62 filaments capture and present ubiquitinated cargos for autophagy."; RL EMBO J. 37:0-0(2018). RN [82] RP INTERACTION WITH TRIM16. RX PubMed=30143514; DOI=10.15252/embj.201798358; RA Jena K.K., Kolapalli S.P., Mehto S., Nath P., Das B., Sahoo P.K., Ahad A., RA Syed G.H., Raghav S.K., Senapati S., Chauhan S., Chauhan S.; RT "TRIM16 controls assembly and degradation of protein aggregates by RT modulating the p62-NRF2 axis and autophagy."; RL EMBO J. 37:0-0(2018). RN [83] RP INTERACTION WITH LRRC25. RX PubMed=29288164; DOI=10.15252/embj.201796781; RA Du Y., Duan T., Feng Y., Liu Q., Lin M., Cui J., Wang R.F.; RT "LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I RT for autophagic degradation."; RL EMBO J. 37:351-366(2018). RN [84] RP FUNCTION, INTERACTION WITH WDR81, AND DOMAIN. RX PubMed=28404643; DOI=10.1083/jcb.201608039; RA Liu X., Li Y., Wang X., Xing R., Liu K., Gan Q., Tang C., Gao Z., Jian Y., RA Luo S., Guo W., Yang C.; RT "The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote RT aggrephagy."; RL J. Cell Biol. 216:1301-1320(2017). RN [85] RP INTERACTION WITH TRIM23. RX PubMed=28871090; DOI=10.1038/s41564-017-0017-2; RA Sparrer K.M.J., Gableske S., Zurenski M.A., Parker Z.M., Full F., RA Baumgart G.J., Kato J., Pacheco-Rodriguez G., Liang C., Pornillos O., RA Moss J., Vaughan M., Gack M.U.; RT "TRIM23 mediates virus-induced autophagy via activation of TBK1."; RL Nat. Microbiol. 2:1543-1557(2017). RN [86] RP FUNCTION, PHOSPHORYLATION AT SER-403, AND MUTAGENESIS OF SER-403. RX PubMed=29496741; DOI=10.15252/embj.201797858; RA Prabakaran T., Bodda C., Krapp C., Zhang B.C., Christensen M.H., Sun C., RA Reinert L., Cai Y., Jensen S.B., Skouboe M.K., Nyengaard J.R., RA Thompson C.B., Lebbink R.J., Sen G.C., van Loo G., Nielsen R., Komatsu M., RA Nejsum L.N., Jakobsen M.R., Gyrd-Hansen M., Paludan S.R.; RT "Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent RT autophagy pathway activated by TBK1."; RL EMBO J. 37:0-0(2018). RN [87] RP INTERACTION WITH USP12. RX PubMed=30266909; DOI=10.1038/s41467-018-05653-z; RA Aron R., Pellegrini P., Green E.W., Maddison D.C., Opoku-Nsiah K., RA Oliveira A.O., Wong J.S., Daub A.C., Giorgini F., Muchowski P., RA Finkbeiner S.; RT "Deubiquitinase Usp12 functions noncatalytically to induce autophagy and RT confer neuroprotection in models of Huntington's disease."; RL Nat. Commun. 9:3191-3191(2018). RN [88] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, ACETYLATION AT LYS-420 AND LYS-435, RP AND MUTAGENESIS OF LYS-420 AND LYS-435. RX PubMed=31857589; DOI=10.1038/s41467-019-13718-w; RA You Z., Jiang W.X., Qin L.Y., Gong Z., Wan W., Li J., Wang Y., Zhang H., RA Peng C., Zhou T., Tang C., Liu W.; RT "Requirement for p62 acetylation in the aggregation of ubiquitylated RT proteins under nutrient stress."; RL Nat. Commun. 10:5792-5792(2019). RN [89] RP INTERACTION WITH ECSIT. RX PubMed=31281713; DOI=10.4110/in.2019.19.e16; RA Kim M.J., Min Y., Kwon J., Son J., Im J.S., Shin J., Lee K.Y.; RT "p62 Negatively Regulates TLR4 Signaling via Functional Regulation of the RT TRAF6-ECSIT Complex."; RL Immune Netw. 19:e16-e16(2019). RN [90] RP INTERACTION WITH CYLD. RX PubMed=32185393; DOI=10.1093/brain/awaa039; RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G., RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T., RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K., RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A., RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M., RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N., RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P., RA Kwok J.B.; RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral RT sclerosis."; RL Brain 143:783-799(2020). RN [91] RP FUNCTION, AND INTERACTION WITH MOAP1. RX PubMed=33393215; DOI=10.15252/embr.202050854; RA Tan C.T., Chang H.C., Zhou Q., Yu C., Fu N.Y., Sabapathy K., Yu V.C.; RT "MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and RT suppresses Nrf2 signaling."; RL EMBO Rep. 22:e50854-e50854(2021). RN [92] RP FUNCTION, AND UBIQUITINATION AT LYS-435. RX PubMed=33472082; DOI=10.1016/j.celrep.2020.108659; RA Cremer T., Jongsma M.L.M., Trulsson F., Vertegaal A.C.O., Neefjes J., RA Berlin I.; RT "The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal RT control over the endolysosomal pathway."; RL Cell Rep. 34:108659-108659(2021). RN [93] RP FUNCTION, AND DEUBIQUITINATION BY EPSTEIN-BARR VIRUS PROTEIN BPLF1 RP (MICROBIAL INFECTION). RX PubMed=33509017; DOI=10.1080/15548627.2021.1874660; RA Ylae-Anttila P., Gupta S., Masucci M.G.; RT "The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit RT selective autophagy."; RL Autophagy 17:3461-3474(2021). RN [94] RP SUBCELLULAR LOCATION, INTERACTION WITH TAX1BP1, AND FUNCTION. RX PubMed=34471133; DOI=10.1038/s41467-021-25572-w; RA Turco E., Savova A., Gere F., Ferrari L., Romanov J., Schuschnig M., RA Martens S.; RT "Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin RT condensate formation and autophagy initiation."; RL Nat. Commun. 12:5212-5212(2021). RN [95] RP INTERACTION WITH ASB6. RX PubMed=34164402; DOI=10.3389/fcell.2021.684885; RA Gong L., Wang K., Wang M., Hu R., Li H., Gao D., Lin M.; RT "CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to RT Regulate Cell Proliferation and Autophagy."; RL Front. Cell Dev. Biol. 9:684885-684885(2021). RN [96] RP FUNCTION. RX PubMed=34893540; DOI=10.1073/pnas.2107993118; RA Heo A.J., Kim S.B., Ji C.H., Han D., Lee S.J., Lee S.H., Lee M.J., RA Lee J.S., Ciechanover A., Kim B.Y., Kwon Y.T.; RT "The N-terminal cysteine is a dual sensor of oxygen and oxidative stress."; RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021). RN [97] RP FUNCTION, AND INTERACTION WITH GRB2. RX PubMed=35831301; DOI=10.1038/s41420-022-01106-1; RA Hou B., Huang H., Li Y., Liang J., Xi Z., Jiang X., Liu L., Li E.; RT "Grb2 interacts with necrosome components and is involved in rasfonin- RT induced necroptosis."; RL Cell. Death. Discov. 8:319-319(2022). RN [98] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-349; SER-403 AND RP SER-407, AND MUTAGENESIS OF SER-349; THR-350 AND 403-SER--SER-407. RX PubMed=37306101; DOI=10.15252/embj.2022113349; RA Ikeda R., Noshiro D., Morishita H., Takada S., Kageyama S., Fujioka Y., RA Funakoshi T., Komatsu-Hirota S., Arai R., Ryzhii E., Abe M., Koga T., RA Motohashi H., Nakao M., Sakimura K., Horii A., Waguri S., Ichimura Y., RA Noda N.N., Komatsu M.; RT "Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox- RT independent stress response."; RL EMBO J. 42:e113349-e113349(2023). RN [99] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-289 AND CYS-290, AND RP MUTAGENESIS OF 289-CYS-CYS-290. RX PubMed=37802024; DOI=10.1016/j.molcel.2023.09.004; RA Huang X., Yao J., Liu L., Chen J., Mei L., Huangfu J., Luo D., Wang X., RA Lin C., Chen X., Yang Y., Ouyang S., Wei F., Wang Z., Zhang S., Xiang T., RA Neculai D., Sun Q., Kong E., Tate E.W., Yang A.; RT "S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in RT mammalian autophagy."; RL Mol. Cell 83:3485-3501(2023). RN [100] RP INTERACTION WITH WDR83. RX PubMed=38103557; DOI=10.1016/j.molcel.2023.11.023; RA Abudu Y.P., Kournoutis A., Brenne H.B., Lamark T., Johansen T.; RT "MORG1 limits mTORC1 signaling by inhibiting Rag GTPases."; RL Mol. Cell 0:0-0(2023). RN [101] RP STRUCTURE BY NMR OF 387-436, CHARACTERIZATION OF VARIANT LEU-392, AND RP DOMAIN. RX PubMed=12857745; DOI=10.1074/jbc.m307416200; RA Ciani B., Layfield R., Cavey J.R., Sheppard P.W., Searle M.S.; RT "Structure of the ubiquitin-associated domain of p62 (SQSTM1) and RT implications for mutations that cause Paget's disease of bone."; RL J. Biol. Chem. 278:37409-37412(2003). RN [102] RP STRUCTURE BY NMR OF 387-436, AND INTERACTION WITH UBIQUITIN. RX PubMed=18083707; DOI=10.1074/jbc.m704973200; RA Long J., Gallagher T.R., Cavey J.R., Sheppard P.W., Ralston S.H., RA Layfield R., Searle M.S.; RT "Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a RT novel conformational switch."; RL J. Biol. Chem. 283:5427-5440(2008). RN [103] RP STRUCTURE BY NMR OF 387-436. RX PubMed=17932931; DOI=10.1002/prot.21692; RA Evans C.L., Long J.E., Gallagher T.R., Hirst J.D., Searle M.S.; RT "Conformation and dynamics of the three-helix bundle UBA domain of p62 from RT experiment and simulation."; RL Proteins 71:227-240(2008). RN [104] RP STRUCTURE BY NMR OF 387-436, SUBUNIT, FUNCTION, MUTAGENESIS OF GLU-409 AND RP GLY-410, AND CHARACTERIZATION OF VARIANT PDB3 ARG-425. RX PubMed=19931284; DOI=10.1016/j.jmb.2009.11.032; RA Long J., Garner T.P., Pandya M.J., Craven C.J., Chen P., Shaw B., RA Williamson M.P., Layfield R., Searle M.S.; RT "Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and RT regulates NF-kappaB signalling."; RL J. Mol. Biol. 396:178-194(2010). RN [105] RP VARIANT PDB3 LEU-392, AND VARIANTS VAL-117 AND GLN-274. RX PubMed=11992264; DOI=10.1086/340731; RA Laurin N., Brown J.P., Morissette J., Raymond V.; RT "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in RT Paget disease of bone."; RL Am. J. Hum. Genet. 70:1582-1588(2002). RN [106] RP VARIANT PDB3 LEU-392. RX PubMed=12374763; DOI=10.1093/hmg/11.22.2735; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Mangion J., Olavesen M., RA Cundy T., Nicholson G.C., Ward L., Bennett S.T., Wuyts W., Van Hul W., RA Ralston S.H.; RT "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and RT sporadic Paget's disease."; RL Hum. Mol. Genet. 11:2735-2739(2002). RN [107] RP VARIANT PDB3 LEU-387. RX PubMed=14584883; DOI=10.1359/jbmr.2003.18.10.1748; RA Johnson-Pais T.L., Wisdom J.H., Weldon K.S., Cody J.D., Hansen M.F., RA Singer F.R., Leach R.J.; RT "Three novel mutations in SQSTM1 identified in familial Paget's disease of RT bone."; RL J. Bone Miner. Res. 18:1748-1753(2003). RN [108] RP VARIANTS PDB3 LEU-392; PRO-399; THR-404 AND ARG-425. RX PubMed=15146436; DOI=10.1002/art.20224; RA Eekhoff E.W.M., Karperien M., Houtsma D., Zwinderman A.H., Dragoiescu C., RA Kneppers A.L.J., Papapoulos S.E.; RT "Familial Paget's disease in The Netherlands: occurrence, identification of RT new mutations in the sequestosome 1 gene, and their clinical RT associations."; RL Arthritis Rheum. 50:1650-1654(2004). RN [109] RP VARIANT PDB3 LEU-392. RX PubMed=15207768; DOI=10.1016/j.bone.2004.01.010; RA Good D.A., Busfield F., Fletcher B.H., Lovelock P.K., Duffy D.L., RA Kesting J.B., Andersen J., Shaw J.T.E.; RT "Identification of SQSTM1 mutations in familial Paget's disease in RT Australian pedigrees."; RL Bone 35:277-282(2004). RN [110] RP VARIANTS PDB3 LEU-392; VAL-404 AND ARG-425. RX PubMed=15125799; DOI=10.1359/jbmr.040203; RA Falchetti A., Di Stefano M., Marini F., Del Monte F., Mavilia C., RA Strigoli D., De Feo M.L., Isaia G., Masi L., Amedei A., Cioppi F., RA Ghinoi V., Maddali Bongi S., Di Fede G., Sferrazza C., Rini G.B., RA Melchiorre D., Matucci-Cerinic M., Brandi M.L.; RT "Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an RT Italian series of patients affected by Paget's disease of bone (PDB)."; RL J. Bone Miner. Res. 19:1013-1017(2004). RN [111] RP VARIANTS PDB3 VAL-404; SER-411 AND ARG-425, AND CHARACTERIZATION OF RP VARIANTS VAL-404; SER-411 AND ARG-425. RX PubMed=15176995; DOI=10.1359/jbmr.0403015; RA Hocking L.J., Lucas G.J.A., Daroszewska A., Cundy T., Nicholson G.C., RA Donath J., Walsh J.P., Finlayson C., Cavey J.R., Ciani B., Sheppard P.W., RA Searle M.S., Layfield R., Ralston S.H.; RT "Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype RT phenotype correlation, functional analysis, and structural consequences."; RL J. Bone Miner. Res. 19:1122-1127(2004). RN [112] RP VARIANT GLU-238, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17488105; DOI=10.1021/pr0700908; RA Bunger M.K., Cargile B.J., Sevinsky J.R., Deyanova E., Yates N.A., RA Hendrickson R.C., Stephenson J.L. Jr.; RT "Detection and validation of non-synonymous coding SNPs from orthogonal RT analysis of shotgun proteomics data."; RL J. Proteome Res. 6:2331-2340(2007). RN [113] RP INVOLVEMENT IN FTDALS3, VARIANTS FTDALS3 VAL-16; VAL-33; GLU-80; MET-90; RP TRP-107; ASN-129; CYS-212; VAL-219; PRO-226; LEU-228; THR-232; LYS-238 DEL; RP ASN-258; CYS-321; GLY-329; LEU-348; LEU-387; LEU-392 AND PRO-430, AND RP VARIANTS VAL-17; ARG-103; GLN-107; TYR-108; HIS-110; VAL-117; SER-118; RP GLY-119; SER-125; CYS-139; ILE-153; LEU-180; HIS-217; GLU-238; RP 265-SER-ARG-266 DELINS SER-ARG; ASP-274; ILE-278; VAL-308; LYS-319; GLY-334 RP DEL; THR-349 AND LEU-439. RX PubMed=24899140; DOI=10.1007/s00401-014-1298-7; RA van der Zee J., Van Langenhove T., Kovacs G.G., Dillen L., Deschamps W., RA Engelborghs S., Matej R., Vandenbulcke M., Sieben A., Dermaut B., Smets K., RA Van Damme P., Merlin C., Laureys A., Van Den Broeck M., Mattheijssens M., RA Peeters K., Benussi L., Binetti G., Ghidoni R., Borroni B., Padovani A., RA Archetti S., Pastor P., Razquin C., Ortega-Cubero S., Hernandez I., RA Boada M., Ruiz A., de Mendonca A., Miltenberger-Miltenyi G., do Couto F.S., RA Sorbi S., Nacmias B., Bagnoli S., Graff C., Chiang H.H., Thonberg H., RA Perneczky R., Diehl-Schmid J., Alexopoulos P., Frisoni G.B., Bonvicini C., RA Synofzik M., Maetzler W., vom Hagen J.M., Schoels L., Haack T.B., RA Strom T.M., Prokisch H., Dols-Icardo O., Clarimon J., Lleo A., Santana I., RA Almeida M.R., Santiago B., Heneka M.T., Jessen F., Ramirez A., RA Sanchez-Valle R., Llado A., Gelpi E., Sarafov S., Tournev I., Jordanova A., RA Parobkova E., Fabrizi G.M., Testi S., Salmon E., Stroebel T., Santens P., RA Robberecht W., De Jonghe P., Martin J.J., Cras P., Vandenberghe R., RA De Deyn P.P., Cruts M., Sleegers K., Van Broeckhoven C.; RT "Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar RT degeneration."; RL Acta Neuropathol. 128:397-410(2014). CC -!- FUNCTION: Molecular adapter required for selective macroautophagy CC (aggrephagy) by acting as a bridge between polyubiquitinated proteins CC and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, CC PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, CC PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the CC recruitment of ubiquitinated cargo proteins to autophagosomes via CC multiple domains that bridge proteins and organelles in different steps CC (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, CC PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, CC PubMed:37802024). SQSTM1 first mediates the assembly and removal of CC ubiquitinated proteins by undergoing liquid-liquid phase separation CC upon binding to ubiquitinated proteins via its UBA domain, leading to CC the formation of insoluble cytoplasmic inclusions, known as p62 bodies CC (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, CC PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). CC SQSTM1 then interacts with ATG8 family proteins on autophagosomes via CC its LIR motif, leading to p62 body recruitment to autophagosomes, CC followed by autophagic clearance of ubiquitinated proteins CC (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, CC PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself CC degraded along with its ubiquitinated cargos (PubMed:16286508, CC PubMed:17580304, PubMed:37802024). Also required to recruit CC ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). CC Also involved in autophagy of peroxisomes (pexophagy) in response to CC reactive oxygen species (ROS) by acting as a bridge between CC ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts CC as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: CC interaction inactivates the BCR(KEAP1) complex by sequestering the CC complex in inclusion bodies, promoting nuclear accumulation of CC NFE2L2/NRF2 and subsequent expression of cytoprotective genes CC (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). CC Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to CC autophagosomes (PubMed:29496741). Involved in endosome organization by CC retaining vesicles in the perinuclear cloud: following ubiquitination CC by RNF26, attracts specific vesicle-associated adapters, forming a CC molecular bridge that restrains cognate vesicles in the perinuclear CC region and organizes the endosomal pathway for efficient cargo CC transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 CC into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal CC degradation (PubMed:25101860). May regulate the activation of NFKB1 by CC TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, CC PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, CC PubMed:19931284). May play a role in titin/TTN downstream signaling in CC muscle cells (PubMed:15802564). Adapter that mediates the interaction CC between TRAF6 and CYLD (By similarity). {ECO:0000250|UniProtKB:Q64337, CC ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037, CC ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362, CC ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22622177, CC ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27368102, CC ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:28404643, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:33472082, CC ECO:0000269|PubMed:33509017, ECO:0000269|PubMed:34471133, CC ECO:0000269|PubMed:34893540, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. CC -!- SUBUNIT: Homooligomer or heterooligomer; may form homotypic arrays CC (PubMed:12887891, PubMed:19931284). Dimerization interferes with CC ubiquitin binding (PubMed:19931284). Component of a ternary complex CC with PAWR and PRKCZ (PubMed:11755531). Forms a complex with JUB/Ajuba, CC PRKCZ and TRAF6 (PubMed:15870274). Identified in a complex with TRAF6 CC and CYLD (By similarity). Identified in a heterotrimeric complex with CC ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the CC same ubiquitin molecule (PubMed:21923101). Interacts (via LIR motif) CC with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members, CC including GABARAP, GABARAPL1 and GABARAPL2; these interactions are CC necessary for the recruitment MAP1 LC3 family members to inclusion CC bodies containing polyubiquitinated protein aggregates and for their CC degradation by autophagy (PubMed:16286508, PubMed:17580304, CC PubMed:22421968, PubMed:24089205, PubMed:24668264). Interacts directly CC with PRKCI and PRKCZ (PubMed:10356400, PubMed:12813044, CC PubMed:12887891, PubMed:9566925). Interacts with EBI3, LCK, RASA1, CC NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5 (PubMed:10708586, CC PubMed:11244088, PubMed:12471037, PubMed:8551575, PubMed:8618896, CC PubMed:8650207, PubMed:8910285). Upon TNF stimulation, interacts with CC RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF- CC R1/TNFRSF1A, TRADD and RIPK1 (PubMed:10747026). Interacts with the CC proteasome subunits PSMD4 and PSMC2 (PubMed:15340068). Interacts with CC TRAF6 (PubMed:10747026). Interacts with 'Lys-63'-linked CC polyubiquitinated MAPT/TAU (PubMed:15953362). Interacts with FHOD3 CC (PubMed:21149568). Interacts with CYLD (PubMed:32185393). Interacts CC with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085, CC PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with CC UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct CC and regulates the interaction of SQSTM1 with ubiquitinated proteins CC (PubMed:28404643). Interacts with WDFY3; this interaction is required CC to recruit WDFY3 to cytoplasmic bodies and to PML bodies CC (PubMed:20168092). Interacts with LRRC25 (PubMed:29288164). Interacts CC with STING1; leading to relocalization of STING1 to autophagosomes CC (PubMed:29496741). Interacts (when phosphorylated at Ser-349) with CC KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex CC by sequestering KEAP1 in inclusion bodies, promoting its degradation CC (PubMed:20452972, PubMed:20495340, PubMed:37306101). Interacts with CC MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester CC KEAP1 (PubMed:33393215). Interacts with GBP1 (By similarity). Interacts CC with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5; CC specifically binds PEX5 ubiquitinated at 'Lys-209' in response to CC reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1 CC domain) with TNS2; the interaction leads to sequestration of TNS2 in CC cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and CC proteasomal degradation (PubMed:25101860). Interacts with IRS1; the CC interaction is disrupted by the presence of tensin TNS2 CC (PubMed:25101860). Interacts with TRIM5 (PubMed:20357094, CC PubMed:25127057). Interacts with TRIM11 (when ubiquitinated); promoting CC AIM2 recruitment to autophagosomes and autophagy-dependent degradation CC of AIM2 (PubMed:27498865). Interacts with TRIM13 (PubMed:22178386). CC Interacts with TRIM16 (PubMed:30143514). Interacts with TRIM23 CC (PubMed:28871090). Interacts with TRIM50 (PubMed:22792322). Interacts CC with TRIM55 (PubMed:15802564). Interacts with ECSIT; this interaction CC inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT CC complex (PubMed:31281713). Interacts with GABRR1, GABRR2 and GABRR3 (By CC similarity). Interacts with WDR83 (PubMed:38103557). Interacts with CC GRB2 (PubMed:35831301). Interacts with USP12; the interaction is CC independent of USP12 deubiquitinase activity and may be involved in CC regulation of autophagic flux (PubMed:30266909). Interacts with ASB6 CC (PubMed:34164402). {ECO:0000250|UniProtKB:O08623, CC ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400, CC ECO:0000269|PubMed:10708586, ECO:0000269|PubMed:10747026, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:11755531, CC ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:12813044, CC ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15870274, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:20495340, CC ECO:0000269|PubMed:21149568, ECO:0000269|PubMed:21923101, CC ECO:0000269|PubMed:22178386, ECO:0000269|PubMed:22421968, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:23274085, CC ECO:0000269|PubMed:24089205, ECO:0000269|PubMed:24668264, CC ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:25101860, CC ECO:0000269|PubMed:25127057, ECO:0000269|PubMed:25422469, CC ECO:0000269|PubMed:26344566, ECO:0000269|PubMed:27498865, CC ECO:0000269|PubMed:28404643, ECO:0000269|PubMed:28871090, CC ECO:0000269|PubMed:29288164, ECO:0000269|PubMed:29496741, CC ECO:0000269|PubMed:30143514, ECO:0000269|PubMed:30266909, CC ECO:0000269|PubMed:31281713, ECO:0000269|PubMed:32185393, CC ECO:0000269|PubMed:33393215, ECO:0000269|PubMed:34164402, CC ECO:0000269|PubMed:34471133, ECO:0000269|PubMed:35831301, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:38103557, CC ECO:0000269|PubMed:8551575, ECO:0000269|PubMed:8618896, CC ECO:0000269|PubMed:8650207, ECO:0000269|PubMed:8910285, CC ECO:0000269|PubMed:9566925}. CC -!- INTERACTION: CC Q13501; P05067: APP; NbExp=6; IntAct=EBI-307104, EBI-77613; CC Q13501; P54253: ATXN1; NbExp=4; IntAct=EBI-307104, EBI-930964; CC Q13501; O95817: BAG3; NbExp=3; IntAct=EBI-307104, EBI-747185; CC Q13501; Q16543: CDC37; NbExp=8; IntAct=EBI-307104, EBI-295634; CC Q13501; P57739: CLDN2; NbExp=4; IntAct=EBI-307104, EBI-751440; CC Q13501; P34972: CNR2; NbExp=5; IntAct=EBI-307104, EBI-2835940; CC Q13501; Q15038: DAZAP2; NbExp=4; IntAct=EBI-307104, EBI-724310; CC Q13501; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-307104, EBI-25840445; CC Q13501; O14682: ENC1; NbExp=7; IntAct=EBI-307104, EBI-6425462; CC Q13501; Q2V2M9: FHOD3; NbExp=6; IntAct=EBI-307104, EBI-6395541; CC Q13501; Q2V2M9-4: FHOD3; NbExp=4; IntAct=EBI-307104, EBI-6395505; CC Q13501; O95166: GABARAP; NbExp=17; IntAct=EBI-307104, EBI-712001; CC Q13501; Q9H0R8: GABARAPL1; NbExp=18; IntAct=EBI-307104, EBI-746969; CC Q13501; P60520: GABARAPL2; NbExp=25; IntAct=EBI-307104, EBI-720116; CC Q13501; P0DMV8: HSPA1A; NbExp=3; IntAct=EBI-307104, EBI-11052499; CC Q13501; P42858: HTT; NbExp=11; IntAct=EBI-307104, EBI-466029; CC Q13501; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-307104, EBI-81279; CC Q13501; Q14145: KEAP1; NbExp=21; IntAct=EBI-307104, EBI-751001; CC Q13501; Q5S007: LRRK2; NbExp=18; IntAct=EBI-307104, EBI-5323863; CC Q13501; Q9UDY8: MALT1; NbExp=2; IntAct=EBI-307104, EBI-1047372; CC Q13501; Q9H492: MAP1LC3A; NbExp=16; IntAct=EBI-307104, EBI-720768; CC Q13501; Q9GZQ8: MAP1LC3B; NbExp=31; IntAct=EBI-307104, EBI-373144; CC Q13501; Q9BXW4: MAP1LC3C; NbExp=8; IntAct=EBI-307104, EBI-2603996; CC Q13501; Q13163: MAP2K5; NbExp=5; IntAct=EBI-307104, EBI-307294; CC Q13501; Q14596: NBR1; NbExp=7; IntAct=EBI-307104, EBI-742698; CC Q13501; Q9BPW8: NIPSNAP1; NbExp=3; IntAct=EBI-307104, EBI-307125; CC Q13501; P04629: NTRK1; NbExp=2; IntAct=EBI-307104, EBI-1028226; CC Q13501; Q96CV9: OPTN; NbExp=7; IntAct=EBI-307104, EBI-748974; CC Q13501; P50542-3: PEX5; NbExp=2; IntAct=EBI-307104, EBI-12181987; CC Q13501; Q9UGJ0: PRKAG2; NbExp=3; IntAct=EBI-307104, EBI-2959705; CC Q13501; P41743: PRKCI; NbExp=11; IntAct=EBI-307104, EBI-286199; CC Q13501; Q12923: PTPN13; NbExp=2; IntAct=EBI-307104, EBI-355227; CC Q13501; P54725: RAD23A; NbExp=3; IntAct=EBI-307104, EBI-746453; CC Q13501; P58004: SESN2; NbExp=9; IntAct=EBI-307104, EBI-3939642; CC Q13501; Q96B97: SH3KBP1; NbExp=4; IntAct=EBI-307104, EBI-346595; CC Q13501; P84022: SMAD3; NbExp=3; IntAct=EBI-307104, EBI-347161; CC Q13501; P37840: SNCA; NbExp=3; IntAct=EBI-307104, EBI-985879; CC Q13501; Q13501: SQSTM1; NbExp=10; IntAct=EBI-307104, EBI-307104; CC Q13501; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-307104, EBI-357085; CC Q13501; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-307104, EBI-359276; CC Q13501; P07437: TUBB; NbExp=4; IntAct=EBI-307104, EBI-350864; CC Q13501; P0CG48: UBC; NbExp=5; IntAct=EBI-307104, EBI-3390054; CC Q13501; P11473: VDR; NbExp=4; IntAct=EBI-307104, EBI-286357; CC Q13501; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-307104, EBI-11141397; CC Q13501; Q8IZQ1: WDFY3; NbExp=7; IntAct=EBI-307104, EBI-1569256; CC Q13501; P19544-6: WT1; NbExp=3; IntAct=EBI-307104, EBI-11745701; CC Q13501; P17028: ZNF24; NbExp=3; IntAct=EBI-307104, EBI-707773; CC Q13501; A8K2U6; NbExp=3; IntAct=EBI-307104, EBI-25877771; CC Q13501; P38182: ATG8; Xeno; NbExp=3; IntAct=EBI-307104, EBI-2684; CC Q13501; Q9Z2X8: Keap1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-647110; CC Q13501; P12709: PGI1; Xeno; NbExp=3; IntAct=EBI-307104, EBI-7238; CC Q13501; P28700: Rxra; Xeno; NbExp=3; IntAct=EBI-307104, EBI-346715; CC Q13501; O70405: Ulk1; Xeno; NbExp=2; IntAct=EBI-307104, EBI-8390771; CC Q13501; P12504: vif; Xeno; NbExp=2; IntAct=EBI-307104, EBI-779991; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, autophagosome CC {ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16286508, CC ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:20168092, CC ECO:0000269|PubMed:37802024}. Preautophagosomal structure CC {ECO:0000269|PubMed:34471133}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:11786419, ECO:0000269|PubMed:11981755, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:21923101, ECO:0000269|PubMed:22017874, CC ECO:0000269|PubMed:22792322, ECO:0000269|PubMed:29343546, CC ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, CC ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024}. Nucleus, PML CC body {ECO:0000269|PubMed:20168092}. Late endosome CC {ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:9566925}. Lysosome CC {ECO:0000269|PubMed:9566925}. Nucleus {ECO:0000269|PubMed:10708586}. CC Endoplasmic reticulum {ECO:0000269|PubMed:22178386}. Cytoplasm, CC myofibril, sarcomere {ECO:0000250|UniProtKB:O08623}. Note=In cardiac CC muscle, localizes to the sarcomeric band (By similarity). Localizes to CC cytoplasmic membraneless inclusion bodies, known as p62 bodies, CC containing polyubiquitinated protein aggregates (PubMed:11786419, CC PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397, CC PubMed:31857589, PubMed:37306101, PubMed:37802024). In CC neurodegenerative diseases, detected in Lewy bodies in Parkinson CC disease, neurofibrillary tangles in Alzheimer disease, and HTT CC aggregates in Huntington disease (PubMed:15158159). In protein CC aggregate diseases of the liver, found in large amounts in Mallory CC bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in CC hepatocellular carcinoma, and in SERPINA1 aggregates (PubMed:11981755). CC Enriched in Rosenthal fibers of pilocytic astrocytoma CC (PubMed:11786419). In the cytoplasm, observed in both membrane-free CC ubiquitin-containing protein aggregates (sequestosomes) and membrane- CC surrounded autophagosomes (PubMed:15953362, PubMed:17580304). CC Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum CC (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies CC (PubMed:20357094). When nuclear export is blocked by treatment with CC leptomycin B, accumulates in PML bodies (PubMed:20168092). CC {ECO:0000250|UniProtKB:O08623, ECO:0000269|PubMed:11786419, CC ECO:0000269|PubMed:11981755, ECO:0000269|PubMed:15158159, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:17580304, CC ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22178386, CC ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29507397, CC ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:37306101, CC ECO:0000269|PubMed:37802024}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13501-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13501-2; Sequence=VSP_015841; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {ECO:0000269|PubMed:8650207}. CC -!- DEVELOPMENTAL STAGE: During myogenesis, there is a marked increase in CC levels in fully differentiated myotubes compared to undifferentiated CC myoblasts. {ECO:0000269|PubMed:25101860}. CC -!- INDUCTION: By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at CC protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is CC directly activated by NFE2L2/NRF2; creating a positive feedback loop CC (PubMed:20452972). {ECO:0000269|PubMed:12700667, CC ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:9762895}. CC -!- DOMAIN: The UBA domain binds specifically 'Lys-63'-linked polyubiquitin CC chains of polyubiquitinated substrates (PubMed:12857745, CC PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the CC interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains CC are necessary and sufficient for the localization into the ubiquitin- CC containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12857745, ECO:0000269|PubMed:15340068, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28322253, CC ECO:0000269|PubMed:31857589}. CC -!- DOMAIN: The PB1 domain mediates homooligomerization and interactions CC with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044, CC PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and CC UBA domains are necessary and sufficient for the localization into the CC ubiquitin-containing inclusion bodies (PubMed:15802564). CC {ECO:0000269|PubMed:12813044, ECO:0000269|PubMed:12887891, CC ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:28404643}. CC -!- DOMAIN: The ZZ-type zinc finger mediates the interaction with RIPK1. CC {ECO:0000269|PubMed:10747026}. CC -!- DOMAIN: The LIR (LC3-interacting region) motif mediates the interaction CC with ATG8 family proteins. {ECO:0000269|PubMed:23908376}. CC -!- PTM: Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer CC interface and increases binding affinity to ubiquitinated proteins (By CC similarity). Phosphorylation at Ser-407 also primes for subsequent CC phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 CC by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing CC the affinity between the UBA domain and polyubiquitin chains CC (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1 CC is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by CC TBK1, leading to promote relocalization of 'Lys-63'-linked CC ubiquitinated STING1 to autophagosomes (PubMed:29496741). CC Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and CC inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear CC accumulation and expression of phase II detoxifying enzymes CC (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564). CC {ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:15802564, CC ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:25040165, CC ECO:0000269|PubMed:29496741, ECO:0000269|PubMed:37306101}. CC -!- PTM: Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 CC attracts specific vesicle-associated adapters, forming a molecular CC bridge that restrains cognate vesicles in the perinuclear region and CC organizes the endosomal pathway for efficient cargo transport CC (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 CC increases its ability to bind polyubiquitin chains by destabilizing the CC UBA dimer interface (PubMed:28322253). Deubiquitination by USP15 CC releases target vesicles for fast transport into the cell periphery CC (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, CC increasing SQSTM1 sequestering activity and promoting its degradation CC (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked CC polyubiquitination leading to xenophagic targeting of bacteria and CC inhibition of their replication (PubMed:27880896). CC {ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:27880896, CC ECO:0000269|PubMed:28322253, ECO:0000269|PubMed:28380357, CC ECO:0000269|PubMed:33472082}. CC -!- PTM: Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity CC by destabilizing the UBA dimer interface and increases binding affinity CC to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 CC (PubMed:31857589). {ECO:0000269|PubMed:31857589}. CC -!- PTM: Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for CC efficient autophagic degradation of SQSTM1-cargo complexes by promoting CC affinity for ATG8 proteins and recruitment of p62 bodies to CC autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 CC by LYPLA1 (PubMed:37802024). {ECO:0000269|PubMed:37802024}. CC -!- PTM: (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading CC to its degradation (PubMed:24331465). Degradation by SpeB prevents CC autophagy, promoting to S.pyogenes intracellular replication CC (PubMed:24331465). {ECO:0000269|PubMed:24331465}. CC -!- PTM: (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; CC leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1- CC positive structures. {ECO:0000269|PubMed:33509017}. CC -!- DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of CC bone remodeling characterized by increased bone turnover affecting one CC or more sites throughout the skeleton, primarily the axial skeleton. CC Osteoclastic overactivity followed by compensatory osteoblastic CC activity leads to a structurally disorganized mosaic of bone (woven CC bone), which is mechanically weaker, larger, less compact, more CC vascular, and more susceptible to fracture than normal adult lamellar CC bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, CC ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, CC ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, CC ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284, CC ECO:0000269|PubMed:29507397}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=In a cell model for Huntington disease (HD), appears to CC form a shell surrounding aggregates of mutant HTT that may protect CC cells from apoptosis, possibly by recruiting autophagosomal components CC to the polyubiquitinated protein aggregates. CC {ECO:0000269|PubMed:16286508}. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 CC (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by CC frontotemporal dementia and/or amyotrophic lateral sclerosis in CC affected individuals. There is high intrafamilial variation. CC Frontotemporal dementia is characterized by frontal and temporal lobe CC atrophy associated with neuronal loss, gliosis, and dementia. Patients CC exhibit progressive changes in social, behavioral, and/or language CC function. Amyotrophic lateral sclerosis is characterized by the death CC of motor neurons in the brain, brainstem, and spinal cord, resulting in CC fatal paralysis. Some FTDALS3 patients may also develop Paget disease CC of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, CC ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy, CC childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder CC characterized by gait abnormalities, ataxia, dysarthria, dystonia, CC vertical gaze palsy, and cognitive decline. Disease onset is in CC childhood or adolescence. NADGP transmission pattern is consistent with CC autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An CC autosomal dominant myopathy with adult onset, characterized by muscle CC weakness of the distal upper and lower limbs, walking difficulties, and CC proximal weakness of the shoulder girdle muscles. Muscle biopsy shows CC rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=A chromosomal aberration involving SQSTM1 is found in a CC form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) CC with NUP214. {ECO:0000269|PubMed:20851865}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U41806; AAA93299.1; -; mRNA. DR EMBL; U46751; AAC52070.1; -; mRNA. DR EMBL; AK098077; BAG53577.1; -; mRNA. DR EMBL; AK312451; BAG35358.1; -; mRNA. DR EMBL; AC008393; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000951; AAH00951.1; -; mRNA. DR EMBL; BC001874; AAH01874.1; -; mRNA. DR EMBL; BC003139; AAH03139.1; -; mRNA. DR EMBL; BC017222; AAH17222.1; -; mRNA. DR EMBL; BC019111; AAH19111.1; -; mRNA. DR EMBL; AF060494; AAC64516.1; -; Genomic_DNA. DR CCDS; CCDS34317.1; -. [Q13501-1] DR CCDS; CCDS47355.1; -. [Q13501-2] DR RefSeq; NP_001135770.1; NM_001142298.2. [Q13501-2] DR RefSeq; NP_001135771.1; NM_001142299.2. [Q13501-2] DR RefSeq; NP_003891.1; NM_003900.5. [Q13501-1] DR PDB; 1Q02; NMR; -; A=387-436. DR PDB; 2JY7; NMR; -; A=387-436. DR PDB; 2JY8; NMR; -; A=387-436. DR PDB; 2K0B; NMR; -; X=387-436. DR PDB; 2KNV; NMR; -; A/B=387-436. DR PDB; 4MJS; X-ray; 2.50 A; B/D/F/H/J/L/N/P/R/T/V/X=3-102. DR PDB; 4UF8; EM; 10.90 A; A/B/C/I=3-102. DR PDB; 4UF9; EM; 10.30 A; A/B/D=1-122. DR PDB; 5YP7; X-ray; 1.42 A; A/D=126-180. DR PDB; 5YP8; X-ray; 1.45 A; A/B=126-180. DR PDB; 5YPA; X-ray; 2.50 A; A/B=126-180. DR PDB; 5YPB; X-ray; 2.90 A; A/B/C/D=126-180. DR PDB; 5YPC; X-ray; 1.96 A; A/B/C/D=126-180. DR PDB; 5YPE; X-ray; 2.85 A; A/B/C/D=126-180. DR PDB; 5YPF; X-ray; 2.95 A; A/B/C/D=126-180. DR PDB; 5YPG; X-ray; 2.20 A; A/B=126-180. DR PDB; 5YPH; X-ray; 1.63 A; A/B=126-180. DR PDB; 6JM4; X-ray; 3.20 A; A/B/C/D=1-102. DR PDB; 6KHZ; X-ray; 2.80 A; A/B/C/D=125-169. DR PDB; 6MIU; X-ray; 1.90 A; A/B=120-171. DR PDB; 6MJ7; X-ray; 1.41 A; A=120-171. DR PDB; 6TGY; EM; 3.50 A; A=1-122. DR PDB; 6TH3; EM; 4.00 A; A/B/C=1-122. DR PDB; 7R1O; X-ray; 2.20 A; AAA/BBB/CCC/DDD=120-172. DR PDBsum; 1Q02; -. DR PDBsum; 2JY7; -. DR PDBsum; 2JY8; -. DR PDBsum; 2K0B; -. DR PDBsum; 2KNV; -. DR PDBsum; 4MJS; -. DR PDBsum; 4UF8; -. DR PDBsum; 4UF9; -. DR PDBsum; 5YP7; -. DR PDBsum; 5YP8; -. DR PDBsum; 5YPA; -. DR PDBsum; 5YPB; -. DR PDBsum; 5YPC; -. DR PDBsum; 5YPE; -. DR PDBsum; 5YPF; -. DR PDBsum; 5YPG; -. DR PDBsum; 5YPH; -. DR PDBsum; 6JM4; -. DR PDBsum; 6KHZ; -. DR PDBsum; 6MIU; -. DR PDBsum; 6MJ7; -. DR PDBsum; 6TGY; -. DR PDBsum; 6TH3; -. DR PDBsum; 7R1O; -. DR AlphaFoldDB; Q13501; -. DR BMRB; Q13501; -. DR EMDB; EMD-10501; -. DR EMDB; EMD-10502; -. DR EMDB; EMD-2936; -. DR EMDB; EMD-2937; -. DR SMR; Q13501; -. DR BioGRID; 114397; 1356. DR CORUM; Q13501; -. DR DIP; DIP-34443N; -. DR ELM; Q13501; -. DR FunCoup; Q13501; 2230. DR IntAct; Q13501; 311. DR MINT; Q13501; -. DR STRING; 9606.ENSP00000374455; -. DR BindingDB; Q13501; -. DR ChEMBL; CHEMBL4295816; -. DR GuidetoPHARMACOLOGY; 3213; -. DR MoonDB; Q13501; Predicted. DR GlyGen; Q13501; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13501; -. DR PhosphoSitePlus; Q13501; -. DR SwissPalm; Q13501; -. DR BioMuta; SQSTM1; -. DR DMDM; 74735628; -. DR jPOST; Q13501; -. DR MassIVE; Q13501; -. DR PaxDb; 9606-ENSP00000374455; -. DR PeptideAtlas; Q13501; -. DR ProteomicsDB; 59496; -. [Q13501-1] DR ProteomicsDB; 59497; -. [Q13501-2] DR Pumba; Q13501; -. DR Antibodypedia; 761; 1362 antibodies from 49 providers. DR DNASU; 8878; -. DR YCharOS; Q13501; Tested 18 antibodies from 6 manufacturers. DR Ensembl; ENST00000360718.5; ENSP00000353944.5; ENSG00000161011.21. [Q13501-2] DR Ensembl; ENST00000389805.9; ENSP00000374455.4; ENSG00000161011.21. [Q13501-1] DR Ensembl; ENST00000640444.2; ENSP00000491834.2; ENSG00000284099.3. [Q13501-1] DR Ensembl; ENST00000643389.2; ENSP00000495843.2; ENSG00000284099.3. [Q13501-1] DR GeneID; 8878; -. DR KEGG; hsa:8878; -. DR MANE-Select; ENST00000389805.9; ENSP00000374455.4; NM_003900.5; NP_003891.1. DR UCSC; uc003mkw.5; human. [Q13501-1] DR AGR; HGNC:11280; -. DR ClinPGx; PA36109; -. DR CTD; 8878; -. DR DisGeNET; 8878; -. DR GeneCards; SQSTM1; -. DR HGNC; HGNC:11280; SQSTM1. DR HPA; ENSG00000161011; Tissue enhanced (skeletal). DR MalaCards; SQSTM1; -. DR MIM; 167250; phenotype. DR MIM; 601530; gene. DR MIM; 616437; phenotype. DR MIM; 617145; phenotype. DR MIM; 617158; phenotype. DR OpenTargets; ENSG00000161011; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 603; Distal myopathy, Welander type. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR VEuPathDB; HostDB:ENSG00000161011; -. DR eggNOG; KOG4582; Eukaryota. DR GeneTree; ENSGT00390000002781; -. DR HOGENOM; CLU_038011_1_0_1; -. DR InParanoid; Q13501; -. DR OMA; NCNGWLT; -. DR OrthoDB; 441278at2759; -. DR PAN-GO; Q13501; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13501; -. DR PathwayCommons; Q13501; -. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes. DR Reactome; R-HSA-209560; NF-kB is activated and signals survival. DR Reactome; R-HSA-5205685; PINK1-PRKN Mediated Mitophagy. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-9664873; Pexophagy. DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2. DR SignaLink; Q13501; -. DR SIGNOR; Q13501; -. DR Agora; ENSG00000161011; -. DR BioGRID-ORCS; 8878; 28 hits in 1166 CRISPR screens. DR CD-CODE; 1822EB5E; Synthetic Condensate 000092. DR CD-CODE; 5D6181E1; Synthetic Condensate 000293. DR CD-CODE; 718A9EC3; P62 body. DR CD-CODE; 98C8800A; Synthetic Condensate 000338. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; EF6CBD8C; Synthetic Condensate 000070. DR CD-CODE; F17BA747; P62 cluster. DR CD-CODE; F5639AB0; Synthetic Condensate 000096. DR ChiTaRS; SQSTM1; human. DR EvolutionaryTrace; Q13501; -. DR GeneWiki; Sequestosome_1; -. DR GenomeRNAi; 8878; -. DR Pharos; Q13501; Tbio. DR PRO; PR:Q13501; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q13501; protein. DR Bgee; ENSG00000161011; Expressed in right adrenal gland cortex and 177 other cell types or tissues. DR ExpressionAtlas; Q13501; baseline and differential. DR GO; GO:0016235; C:aggresome; IBA:GO_Central. DR GO; GO:0044753; C:amphisome; IDA:ParkinsonsUK-UCL. DR GO; GO:0044754; C:autolysosome; IDA:ParkinsonsUK-UCL. DR GO; GO:0005776; C:autophagosome; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0043232; C:intracellular membraneless organelle; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell. DR GO; GO:0097413; C:Lewy body; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0000932; C:P-body; IDA:UniProtKB. DR GO; GO:0000407; C:phagophore assembly site; IEA:UniProtKB-SubCell. DR GO; GO:0016605; C:PML body; IDA:UniProtKB. DR GO; GO:0030017; C:sarcomere; IEA:UniProtKB-SubCell. DR GO; GO:0097225; C:sperm midpiece; IEA:Ensembl. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0035255; F:ionotropic glutamate receptor binding; ISS:ARUK-UCL. DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:UniProtKB. DR GO; GO:0140313; F:molecular sequestering activity; IDA:UniProt. DR GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB. DR GO; GO:0005080; F:protein kinase C binding; IPI:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; TAS:ProtInc. DR GO; GO:0042169; F:SH2 domain binding; IDA:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; IDA:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IDA:UniProt. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0035973; P:aggrephagy; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0006914; P:autophagy; IDA:UniProtKB. DR GO; GO:0000422; P:autophagy of mitochondrion; NAS:ParkinsonsUK-UCL. DR GO; GO:0070342; P:brown fat cell proliferation; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0033554; P:cellular response to stress; IDA:UniProt. DR GO; GO:0016197; P:endosomal transport; TAS:UniProtKB. DR GO; GO:0007032; P:endosome organization; IDA:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; IEA:Ensembl. DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW. DR GO; GO:0008104; P:intracellular protein localization; TAS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IDA:UniProtKB. DR GO; GO:0140694; P:membraneless organelle assembly; IDA:UniProtKB. DR GO; GO:0000423; P:mitophagy; IGI:ParkinsonsUK-UCL. DR GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0000425; P:pexophagy; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt. DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:ARUK-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; TAS:UniProtKB. DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:1905719; P:protein localization to perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0071211; P:protein targeting to vacuole involved in autophagy; IDA:UniProtKB. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0010821; P:regulation of mitochondrion organization; NAS:ParkinsonsUK-UCL. DR GO; GO:0061635; P:regulation of protein complex stability; IDA:UniProtKB. DR GO; GO:0046578; P:regulation of Ras protein signal transduction; NAS:UniProtKB. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0098780; P:response to mitochondrial depolarisation; IGI:ParkinsonsUK-UCL. DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc. DR CDD; cd06402; PB1_p62; 1. DR CDD; cd14320; UBA_SQSTM; 1. DR CDD; cd02340; ZZ_NBR1_like; 1. DR DisProt; DP01111; -. DR FunFam; 1.10.8.10:FF:000034; Sequestosome 1; 1. DR FunFam; 3.10.20.90:FF:000169; Sequestosome 1; 1. DR FunFam; 3.30.60.90:FF:000012; Sequestosome 1; 1. DR Gene3D; 3.30.60.90; -; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1. DR IDEAL; IID00383; -. DR InterPro; IPR052260; Autophagy_Rcpt_SigReg. DR InterPro; IPR053793; PB1-like. DR InterPro; IPR000270; PB1_dom. DR InterPro; IPR034866; PB1_p62. DR InterPro; IPR033741; SQSTM_UBA. DR InterPro; IPR015940; UBA. DR InterPro; IPR009060; UBA-like_sf. DR InterPro; IPR000433; Znf_ZZ. DR InterPro; IPR043145; Znf_ZZ_sf. DR PANTHER; PTHR15090; SEQUESTOSOME 1-RELATED; 1. DR PANTHER; PTHR15090:SF0; SEQUESTOSOME-1; 1. DR Pfam; PF00564; PB1; 1. DR Pfam; PF16577; UBA_5; 1. DR Pfam; PF00569; ZZ; 1. DR SMART; SM00666; PB1; 1. DR SMART; SM00165; UBA; 1. DR SMART; SM00291; ZnF_ZZ; 1. DR SUPFAM; SSF54277; CAD & PB1 domains; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR PROSITE; PS51745; PB1; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS01357; ZF_ZZ_1; 1. DR PROSITE; PS50135; ZF_ZZ_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; KW Amyotrophic lateral sclerosis; Apoptosis; Autophagy; Cytoplasm; KW Cytoplasmic vesicle; Differentiation; Direct protein sequencing; KW Disease variant; Endoplasmic reticulum; Endosome; Immunity; KW Isopeptide bond; Lipoprotein; Lysosome; Metal-binding; Neurodegeneration; KW Nucleus; Palmitate; Phosphoprotein; Proteomics identification; KW Reference proteome; Ubl conjugation; Zinc; Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT CHAIN 2..440 FT /note="Sequestosome-1" FT /id="PRO_0000072176" FT DOMAIN 3..102 FT /note="PB1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01081" FT DOMAIN 389..434 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT ZN_FING 123..173 FT /note="ZZ-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT REGION 2..50 FT /note="Interaction with LCK" FT /evidence="ECO:0000269|PubMed:8650207" FT REGION 43..107 FT /note="Interaction with PRKCZ and dimerization" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 50..80 FT /note="Interaction with PAWR" FT /evidence="ECO:0000269|PubMed:11755531" FT REGION 122..224 FT /note="Interaction with GABRR3" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 170..220 FT /note="LIM protein-binding (LB)" FT REGION 196..235 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 264..390 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 269..440 FT /note="Interaction with NTRK1" FT /evidence="ECO:0000250|UniProtKB:O08623" FT REGION 321..342 FT /note="MAP1LC3B-binding" FT /evidence="ECO:0000269|PubMed:17580304" FT REGION 347..352 FT /note="Interaction with KEAP1" FT /evidence="ECO:0000269|PubMed:20452972" FT MOTIF 228..233 FT /note="TRAF6-binding" FT MOTIF 336..341 FT /note="LIR" FT COMPBIAS 283..296 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 310..324 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 337..347 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 351..373 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 128 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 131 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 142 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 145 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 151 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 154 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 160 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT BINDING 163 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228" FT SITE 252..253 FT /note="Breakpoint for translocation to form the NUP214- FT SQSTM1 fusion protein" FT /evidence="ECO:0000269|PubMed:20851865" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 24 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:24275569" FT MOD_RES 148 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 170 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 176 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 207 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:20068231" FT MOD_RES 233 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 249 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 266 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 269 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163" FT MOD_RES 272 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 282 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874" FT MOD_RES 306 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 328 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 332 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 349 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 355 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 361 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 365 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q64337" FT MOD_RES 366 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 403 FT /note="Phosphoserine; by CK2, ULK1 and TBK1" FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:25040165, ECO:0000269|PubMed:29496741, FT ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:37306101" FT MOD_RES 407 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:37306101" FT MOD_RES 420 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT MOD_RES 435 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:31857589" FT LIPID 289 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT LIPID 290 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:37802024" FT CROSSLNK 91 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 189 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27880896" FT CROSSLNK 420 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:28380357" FT CROSSLNK 435 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000269|PubMed:33472082, FT ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..84 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015841" FT VARIANT 16 FT /note="A -> V (in FTDALS3; dbSNP:rs1554162295)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073899" FT VARIANT 17 FT /note="A -> V (in dbSNP:rs141502868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073900" FT VARIANT 33 FT /note="A -> V (in FTDALS3; dbSNP:rs200396166)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_073901" FT VARIANT 80 FT /note="D -> E (in FTDALS3; dbSNP:rs148366738)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073902" FT VARIANT 90 FT /note="V -> M (in FTDALS3; dbSNP:rs181263868)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073903" FT VARIANT 103 FT /note="K -> R (in dbSNP:rs748170760)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073904" FT VARIANT 107 FT /note="R -> Q" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073905" FT VARIANT 107 FT /note="R -> W (in FTDALS3; dbSNP:rs771903158)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073906" FT VARIANT 108 FT /note="D -> Y" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073907" FT VARIANT 110 FT /note="R -> H (in dbSNP:rs1267306593)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073908" FT VARIANT 117 FT /note="A -> V (in dbSNP:rs147810437)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:24899140" FT /id="VAR_023590" FT VARIANT 118 FT /note="P -> S (in dbSNP:rs200152247)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073909" FT VARIANT 119 FT /note="R -> G (in dbSNP:rs548787835)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073910" FT VARIANT 125 FT /note="N -> S (in dbSNP:rs769325755)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073911" FT VARIANT 129 FT /note="D -> N (in FTDALS3; dbSNP:rs753212399)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073912" FT VARIANT 139 FT /note="R -> C (in dbSNP:rs750256905)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073913" FT VARIANT 153 FT /note="V -> I (in FTDALS3; dbSNP:rs145056421)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073914" FT VARIANT 180 FT /note="S -> L (in dbSNP:rs1582008478)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073915" FT VARIANT 212 FT /note="R -> C (in FTDALS3; dbSNP:rs201263163)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073916" FT VARIANT 217 FT /note="R -> H (in dbSNP:rs761822261)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073917" FT VARIANT 219 FT /note="G -> V (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073918" FT VARIANT 226 FT /note="S -> P (in FTDALS3; dbSNP:rs765200636)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073919" FT VARIANT 228 FT /note="P -> L (in FTDALS3; dbSNP:rs151191977)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073920" FT VARIANT 232 FT /note="P -> T (in FTDALS3; dbSNP:rs1225746517)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073921" FT VARIANT 238 FT /note="K -> E (confirmed at protein level; FT dbSNP:rs11548633)" FT /evidence="ECO:0000269|PubMed:17488105, FT ECO:0000269|PubMed:24899140" FT /id="VAR_068915" FT VARIANT 238 FT /note="Missing (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083" FT /id="VAR_073922" FT VARIANT 258 FT /note="D -> N (in FTDALS3; dbSNP:rs774986849)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073923" FT VARIANT 265..266 FT /note="RS -> SR" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073924" FT VARIANT 274 FT /note="E -> D (in dbSNP:rs55793208)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_061707" FT VARIANT 274 FT /note="E -> Q" FT /evidence="ECO:0000269|PubMed:11992264" FT /id="VAR_023591" FT VARIANT 278 FT /note="T -> I (in dbSNP:rs200445838)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073925" FT VARIANT 308 FT /note="A -> V (in dbSNP:rs541356917)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073926" FT VARIANT 318 FT /note="S -> P (in FTDALS3)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073927" FT VARIANT 319 FT /note="E -> K (in dbSNP:rs61748794)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073928" FT VARIANT 321 FT /note="R -> C (in FTDALS3; likely benign; FT dbSNP:rs140226523)" FT /evidence="ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24899140" FT /id="VAR_073929" FT VARIANT 329 FT /note="D -> G (in FTDALS3; dbSNP:rs148294622)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073930" FT VARIANT 334 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073931" FT VARIANT 348 FT /note="P -> L (in FTDALS3; dbSNP:rs772889843)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073932" FT VARIANT 349 FT /note="S -> T (in dbSNP:rs774512680)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073933" FT VARIANT 370 FT /note="S -> P (in FTDALS3; dbSNP:rs143956614)" FT /evidence="ECO:0000269|PubMed:22084127" FT /id="VAR_073934" FT VARIANT 381 FT /note="A -> V (in FTDALS3; dbSNP:rs772122047)" FT /evidence="ECO:0000269|PubMed:24042580" FT /id="VAR_073935" FT VARIANT 387 FT /note="P -> L (in PDB3 and FTDALS3; dbSNP:rs776749939)" FT /evidence="ECO:0000269|PubMed:14584883, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023592" FT VARIANT 392 FT /note="P -> L (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; dbSNP:rs104893941)" FT /evidence="ECO:0000269|PubMed:11992264, FT ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:12857745, FT ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:22084127, FT ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140" FT /id="VAR_023593" FT VARIANT 399 FT /note="S -> P (in PDB3; dbSNP:rs1561609625)" FT /evidence="ECO:0000269|PubMed:15146436" FT /id="VAR_023594" FT VARIANT 404 FT /note="M -> T (in PDB3; decreased ability to undergo FT liquid-liquid phase separation and formation of p62 body; FT dbSNP:rs1247551175)" FT /evidence="ECO:0000269|PubMed:15146436, FT ECO:0000269|PubMed:29507397" FT /id="VAR_023595" FT VARIANT 404 FT /note="M -> V (in PDB3; loss of polyubiquitin-binding; FT dbSNP:rs771966860)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15176995" FT /id="VAR_023596" FT VARIANT 411 FT /note="G -> S (in PDB3 and FTDALS3; no effect on FT polyubiquitin-binding; decreased ability to undergo liquid- FT liquid phase separation and formation of p62 body; FT dbSNP:rs143511494)" FT /evidence="ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:29507397" FT /id="VAR_023597" FT VARIANT 425 FT /note="G -> R (in PDB3 and FTDALS3; loss of polyubiquitin- FT binding and increased activation of NF-kappa-B; FT dbSNP:rs757212984)" FT /evidence="ECO:0000269|PubMed:15125799, FT ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, FT ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:22084127" FT /id="VAR_023598" FT VARIANT 430 FT /note="T -> P (in FTDALS3; dbSNP:rs770118706)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073936" FT VARIANT 439 FT /note="P -> L (in dbSNP:rs199854262)" FT /evidence="ECO:0000269|PubMed:24899140" FT /id="VAR_073937" FT MUTAGEN 7 FT /note="K->A: Loss of interactions with PRKCZ, PRCKI and FT NBR1. Loss of dimerization; when associated with A-69." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 9 FT /note="Y->F: No effect on interaction with LCK." FT /evidence="ECO:0000269|PubMed:8650207" FT MUTAGEN 13 FT /note="K->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 21..22 FT /note="RR->AA: Loss of interaction with PRKCI. Alters FT dimerization." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 67 FT /note="Y->A: No effect on interaction with PRKCZ." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 69 FT /note="D->A: No effect on interactions with PRKCZ, PRKCI FT and NBR1. Loss of localization in cytoplasmic inclusion FT bodies. Loss of dimerization; when associated with A-7." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891, ECO:0000269|PubMed:16286508" FT MUTAGEN 71 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 73 FT /note="D->A: No effect on interactions with PRKCZ and FT PRKCI." FT /evidence="ECO:0000269|PubMed:12813044, FT ECO:0000269|PubMed:12887891" FT MUTAGEN 80 FT /note="D->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 82 FT /note="E->A: No effect on interaction with PRKCI." FT /evidence="ECO:0000269|PubMed:12813044" FT MUTAGEN 289..290 FT /note="CC->SS: Abolished palmitoylation." FT /evidence="ECO:0000269|PubMed:37802024" FT MUTAGEN 323..324 FT /note="EE->AA: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 332 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 335..337 FT /note="DDD->ADA: 75% decrease in MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 338 FT /note="W->A: Strong decrease in MAP1LC3B-binding, disrupts FT interaction with GABARAP." FT /evidence="ECO:0000269|PubMed:17580304, FT ECO:0000269|PubMed:24668264" FT MUTAGEN 342 FT /note="S->A: No effect on MAP1LC3B-binding." FT /evidence="ECO:0000269|PubMed:17580304" FT MUTAGEN 347 FT /note="D->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 349 FT /note="S->A: Impaired phosphorylation by ULK1, leading to FT decreased p62 body formation." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 350 FT /note="T->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972, FT ECO:0000269|PubMed:37306101" FT MUTAGEN 351 FT /note="G->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 352 FT /note="E->A: Strongly decreased interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:20452972" FT MUTAGEN 398 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 403..407 FT /note="SMGFS->EMGFE: Mimics phosphorylation; increased FT phosphorylation at S-349." FT /evidence="ECO:0000269|PubMed:37306101" FT MUTAGEN 403 FT /note="S->A: Abolished phosphorylation by CK2, leading to FT decreased affinity for ubiquitinated proteins. Abolished FT ability to promote relocalization of 'Lys-63'-linked FT ubiquitinated STING1 to autophagosomes." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29496741" FT MUTAGEN 403 FT /note="S->E: Mimmics phosphorylation; increased affinity FT for ubiquitinated proteins, leading to increased p62 body FT formation and autophagic degradation." FT /evidence="ECO:0000269|PubMed:22017874, FT ECO:0000269|PubMed:29507397" FT MUTAGEN 406 FT /note="F->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 409 FT /note="E->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 410 FT /note="G->K: Decreased activation of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:19931284" FT MUTAGEN 413 FT /note="L->V: No effect on polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 417 FT /note="L->V: Loss of polyubiquitin-binding." FT /evidence="ECO:0000269|PubMed:15340068" FT MUTAGEN 420 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-435." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 420 FT /note="K->R: Decreased ubiquitination by the BCR(KEAP1) FT complex, leading to decreased sequestering activity. FT Strongly reduced acetylation; when associated with R-435." FT /evidence="ECO:0000269|PubMed:28380357, FT ECO:0000269|PubMed:31857589" FT MUTAGEN 431 FT /note="I->V: Partial loss of polyubiquitin-binding. Loss of FT localization to cytoplasmic inclusion bodies." FT /evidence="ECO:0000269|PubMed:15340068, FT ECO:0000269|PubMed:16286508" FT MUTAGEN 435 FT /note="K->Q: Mimics acetylation; leading to increased FT ability to bind ubiquitinated proteins; when associated FT with Q-420." FT /evidence="ECO:0000269|PubMed:31857589" FT MUTAGEN 435 FT /note="K->R: Strongly reduced acetylation; when associated FT with R-420." FT /evidence="ECO:0000269|PubMed:31857589" FT CONFLICT 321 FT /note="R -> A (in Ref. 1; AAA93299)" FT /evidence="ECO:0000305" FT STRAND 5..10 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 13..15 FT /evidence="ECO:0007829|PDB:6TGY" FT STRAND 19..24 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 36..39 FT /evidence="ECO:0007829|PDB:6TGY" FT HELIX 43..54 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 62..64 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 74..76 FT /evidence="ECO:0007829|PDB:4MJS" FT HELIX 80..88 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 92..101 FT /evidence="ECO:0007829|PDB:4MJS" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 129..131 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:6KHZ" FT STRAND 139..147 FT /evidence="ECO:0007829|PDB:6MJ7" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:6MJ7" FT TURN 157..162 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 165..168 FT /evidence="ECO:0007829|PDB:6MJ7" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 392..402 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:2JY7" FT STRAND 409..411 FT /evidence="ECO:0007829|PDB:2JY7" FT HELIX 412..419 FT /evidence="ECO:0007829|PDB:1Q02" FT TURN 420..422 FT /evidence="ECO:0007829|PDB:1Q02" FT HELIX 424..431 FT /evidence="ECO:0007829|PDB:1Q02" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:2JY8" FT INIT_MET Q13501-2:1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES Q13501-2:2 FT /note="N-acetylalanine" FT /evidence="ECO:0007744|PubMed:22814378" SQ SEQUENCE 440 AA; 47687 MW; 462D94C171F337CD CRC64; MASLTVKAYL LGKEDAAREI RRFSFCCSPE PEAEAEAAAG PGPCERLLSR VAALFPALRP GGFQAHYRDE DGDLVAFSSD EELTMAMSYV KDDIFRIYIK EKKECRRDHR PPCAQEAPRN MVHPNVICDG CNGPVVGTRY KCSVCPDYDL CSVCEGKGLH RGHTKLAFPS PFGHLSEGFS HSRWLRKVKH GHFGWPGWEM GPPGNWSPRP PRAGEARPGP TAESASGPSE DPSVNFLKNV GESVAAALSP LGIEVDIDVE HGGKRSRLTP VSPESSSTEE KSSSQPSSCC SDPSKPGGNV EGATQSLAEQ MRKIALESEG RPEEQMESDN CSGGDDDWTH LSSKEVDPST GELQSLQMPE SEGPSSLDPS QEGPTGLKEA ALYPHLPPEA DPRLIESLSQ MLSMGFSDEG GWLTRLLQTK NYDIGAALDT IQYSKHPPPL // ID T106B_HUMAN Reviewed; 274 AA. AC Q9NUM4; A4D108; Q53FL9; Q8N4L0; DT 27-JUN-2006, integrated into UniProtKB/Swiss-Prot. DT 27-JUN-2006, sequence version 2. DT 28-JAN-2026, entry version 162. DE RecName: Full=Transmembrane protein 106B {ECO:0000305}; GN Name=TMEM106B {ECO:0000312|HGNC:HGNC:22407}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-185. 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Gastric mucosa; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D., RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., RA Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, 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 [8] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-183. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [9] RP INVOLVEMENT IN FTD2. RX PubMed=20154673; DOI=10.1038/ng.536; RA Van Deerlin V.M., Sleiman P.M., Martinez-Lage M., Chen-Plotkin A., RA Wang L.S., Graff-Radford N.R., Dickson D.W., Rademakers R., Boeve B.F., RA Grossman M., Arnold S.E., Mann D.M., Pickering-Brown S.M., Seelaar H., RA Heutink P., van Swieten J.C., Murrell J.R., Ghetti B., Spina S., RA Grafman J., Hodges J., Spillantini M.G., Gilman S., Lieberman A.P., RA Kaye J.A., Woltjer R.L., Bigio E.H., Mesulam M., Al-Sarraj S., Troakes C., RA Rosenberg R.N., White C.L. III, Ferrer I., Llado A., Neumann M., RA Kretzschmar H.A., Hulette C.M., Welsh-Bohmer K.A., Miller B.L., RA Alzualde A., de Munain A.L., McKee A.C., Gearing M., Levey A.I., Lah J.J., RA Hardy J., Rohrer J.D., Lashley T., Mackenzie I.R., Feldman H.H., RA Hamilton R.L., Dekosky S.T., van der Zee J., Kumar-Singh S., RA Van Broeckhoven C., Mayeux R., Vonsattel J.P., Troncoso J.C., Kril J.J., RA Kwok J.B., Halliday G.M., Bird T.D., Ince P.G., Shaw P.J., Cairns N.J., RA Morris J.C., McLean C.A., DeCarli C., Ellis W.G., Freeman S.H., RA Frosch M.P., Growdon J.H., Perl D.P., Sano M., Bennett D.A., RA Schneider J.A., Beach T.G., Reiman E.M., Woodruff B.K., Cummings J., RA Vinters H.V., Miller C.A., Chui H.C., Alafuzoff I., Hartikainen P., RA Seilhean D., Galasko D., Masliah E., Cotman C.W., Tunon M.T., RA Martinez M.C., Munoz D.G., Carroll S.L., Marson D., Riederer P.F., RA Bogdanovic N., Schellenberg G.D., Hakonarson H., Trojanowski J.Q., RA Lee V.M.; RT "Common variants at 7p21 are associated with frontotemporal lobar RT degeneration with TDP-43 inclusions."; RL Nat. Genet. 42:234-239(2010). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [11] RP INVOLVEMENT IN FTD2. RX PubMed=21178100; DOI=10.1212/wnl.0b013e31820a0e3b; RA Finch N., Carrasquillo M.M., Baker M., Rutherford N.J., Coppola G., RA Dejesus-Hernandez M., Crook R., Hunter T., Ghidoni R., Benussi L., RA Crook J., Finger E., Hantanpaa K.J., Karydas A.M., Sengdy P., Gonzalez J., RA Seeley W.W., Johnson N., Beach T.G., Mesulam M., Forloni G., Kertesz A., RA Knopman D.S., Uitti R., White C.L. III, Caselli R., Lippa C., Bigio E.H., RA Wszolek Z.K., Binetti G., Mackenzie I.R., Miller B.L., Boeve B.F., RA Younkin S.G., Dickson D.W., Petersen R.C., Graff-Radford N.R., RA Geschwind D.H., Rademakers R.; RT "TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN RT mutation carriers."; RL Neurology 76:467-474(2011). RN [12] RP SUBCELLULAR LOCATION, TOPOLOGY, AND GLYCOSYLATION AT ASN-145; ASN-151; RP ASN-164; ASN-183 AND ASN-256. RX PubMed=22511793; DOI=10.1074/jbc.m112.365098; RA Lang C.M., Fellerer K., Schwenk B.M., Kuhn P.H., Kremmer E., Edbauer D., RA Capell A., Haass C.; RT "Membrane orientation and subcellular localization of transmembrane protein RT 106B (TMEM106B), a major risk factor for frontotemporal lobar RT degeneration."; RL J. Biol. Chem. 287:19355-19365(2012). RN [13] RP INVOLVEMENT IN FTD2. RX PubMed=22895706; DOI=10.1523/jneurosci.0521-12.2012; RA Chen-Plotkin A.S., Unger T.L., Gallagher M.D., Bill E., Kwong L.K., RA Volpicelli-Daley L., Busch J.I., Akle S., Grossman M., Van Deerlin V., RA Trojanowski J.Q., Lee V.M.; RT "TMEM106B, the risk gene for frontotemporal dementia, is regulated by the RT microRNA-132/212 cluster and affects progranulin pathways."; RL J. Neurosci. 32:11213-11227(2012). RN [14] RP SUBCELLULAR LOCATION, TOPOLOGY, AND HOMOMERIZATION. RX PubMed=23136129; DOI=10.1093/hmg/dds475; RA Brady O.A., Zheng Y., Murphy K., Huang M., Hu F.; RT "The frontotemporal lobar degeneration risk factor, TMEM106B, regulates RT lysosomal morphology and function."; RL Hum. Mol. Genet. 22:685-695(2013). RN [15] RP INVOLVEMENT IN FTD2, VARIANT SER-185, SUBCELLULAR LOCATION, AND RP GLYCOSYLATION AT ASN-183. RX PubMed=23742080; DOI=10.1111/jnc.12329; RA Nicholson A.M., Finch N.A., Wojtas A., Baker M.C., Perkerson R.B., RA Castanedes-Casey M., Rousseau L., Benussi L., Binetti G., Ghidoni R., RA Hsiung G.Y., Mackenzie I.R., Finger E., Boeve B.F., Ertekin-Taner N., RA Graff-Radford N.R., Dickson D.W., Rademakers R.; RT "TMEM106B p.T185S regulates TMEM106B protein levels: implications for RT frontotemporal dementia."; RL J. Neurochem. 126:781-791(2013). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [17] RP INVOLVEMENT IN FTDALS1. RX PubMed=24488309; DOI=10.1007/s00401-014-1249-3; RA Deming Y., Cruchaga C.; RT "TMEM106B: a strong FTLD disease modifier."; RL Acta Neuropathol. 127:419-422(2014). RN [18] RP INVOLVEMENT IN FTDALS1. RX PubMed=24442578; DOI=10.1007/s00401-013-1239-x; RA Gallagher M.D., Suh E., Grossman M., Elman L., McCluskey L., RA Van Swieten J.C., Al-Sarraj S., Neumann M., Gelpi E., Ghetti B., RA Rohrer J.D., Halliday G., Van Broeckhoven C., Seilhean D., Shaw P.J., RA Frosch M.P., Alafuzoff I., Antonell A., Bogdanovic N., Brooks W., RA Cairns N.J., Cooper-Knock J., Cotman C., Cras P., Cruts M., De Deyn P.P., RA Decarli C., Dobson-Stone C., Engelborghs S., Fox N., Galasko D., RA Gearing M., Gijselinck I., Grafman J., Hartikainen P., Hatanpaa K.J., RA Highley J.R., Hodges J., Hulette C., Ince P.G., Jin L.W., Kirby J., RA Kofler J., Kril J., Kwok J.B., Levey A., Lieberman A., Llado A., RA Martin J.J., Masliah E., McDermott C.J., McKee A., McLean C., Mead S., RA Miller C.A., Miller J., Munoz D.G., Murrell J., Paulson H., Piguet O., RA Rossor M., Sanchez-Valle R., Sano M., Schneider J., Silbert L.C., Spina S., RA van der Zee J., Van Langenhove T., Warren J., Wharton S.B., White Iii C.L., RA Woltjer R.L., Trojanowski J.Q., Lee V.M., Van Deerlin V., RA Chen-Plotkin A.S.; RT "TMEM106B is a genetic modifier of frontotemporal lobar degeneration with RT C9orf72 hexanucleotide repeat expansions."; RL Acta Neuropathol. 127:407-418(2014). RN [19] RP INVOLVEMENT IN FTDALS1. RX PubMed=24385136; DOI=10.1007/s00401-013-1240-4; RA van Blitterswijk M., Mullen B., Nicholson A.M., Bieniek K.F., Heckman M.G., RA Baker M.C., Dejesus-Hernandez M., Finch N.A., Brown P.H., Murray M.E., RA Hsiung G.Y., Stewart H., Karydas A.M., Finger E., Kertesz A., Bigio E.H., RA Weintraub S., Mesulam M., Hatanpaa K.J., White Iii C.L., Strong M.J., RA Beach T.G., Wszolek Z.K., Lippa C., Caselli R., Petrucelli L., RA Josephs K.A., Parisi J.E., Knopman D.S., Petersen R.C., Mackenzie I.R., RA Seeley W.W., Grinberg L.T., Miller B.L., Boylan K.B., Graff-Radford N.R., RA Boeve B.F., Dickson D.W., Rademakers R.; RT "TMEM106B protects C9ORF72 expansion carriers against frontotemporal RT dementia."; RL Acta Neuropathol. 127:397-406(2014). RN [20] RP INTERACTION WITH MAP6. RX PubMed=24357581; DOI=10.1002/embj.201385857; RA Schwenk B.M., Lang C.M., Hogl S., Tahirovic S., Orozco D., Rentzsch K., RA Lichtenthaler S.F., Hoogenraad C.C., Capell A., Haass C., Edbauer D.; RT "The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of RT lysosomes."; RL EMBO J. 33:450-467(2014). RN [21] RP FUNCTION, INTERACTION WITH AP2M1; CLTC AND TMEM106C, HOMOMERIZATION, RP SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=25066864; DOI=10.1016/j.mcn.2014.07.006; RA Stagi M., Klein Z.A., Gould T.J., Bewersdorf J., Strittmatter S.M.; RT "Lysosome size, motility and stress response regulated by fronto-temporal RT dementia modifier TMEM106B."; RL Mol. Cell. Neurosci. 61:226-240(2014). RN [22] RP MYRISTOYLATION AT GLY-2, CLEAVAGE OF INITIATOR METHIONINE, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=25255805; DOI=10.1038/ncomms5919; RA Thinon E., Serwa R.A., Broncel M., Brannigan J.A., Brassat U., Wright M.H., RA Heal W.P., Wilkinson A.J., Mann D.J., Tate E.W.; RT "Global profiling of co- and post-translationally N-myristoylated proteomes RT in human cells."; RL Nat. Commun. 5:4919-4919(2014). RN [23] RP INTERACTION WITH ATP6AP1. RX PubMed=28728022; DOI=10.1016/j.neuron.2017.06.026; RA Klein Z.A., Takahashi H., Ma M., Stagi M., Zhou M., Lam T.T., RA Strittmatter S.M.; RT "Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related RT phenotypes in progranulin-deficient mice."; RL Neuron 95:281-296(2017). RN [24] RP FUNCTION (MICROBIAL INFECTION). RX PubMed=33333024; DOI=10.1016/j.cell.2020.12.004; RA Wang R., Simoneau C.R., Kulsuptrakul J., Bouhaddou M., Travisano K.A., RA Hayashi J.M., Carlson-Stevermer J., Zengel J.R., Richards C.M., Fozouni P., RA Oki J., Rodriguez L., Joehnk B., Walcott K., Holden K., Sil A., RA Carette J.E., Krogan N.J., Ott M., Puschnik A.S.; RT "Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold RT Coronaviruses."; RL Cell 184:106-119(2021). RN [25] RP FUNCTION (MICROBIAL INFECTION), AND TISSUE SPECIFICITY. RX PubMed=33686287; DOI=10.1038/s41588-021-00805-2; RA Baggen J., Persoons L., Vanstreels E., Jansen S., Van Looveren D., RA Boeckx B., Geudens V., De Man J., Jochmans D., Wauters J., Wauters E., RA Vanaudenaerde B.M., Lambrechts D., Neyts J., Dallmeier K., Thibaut H.J., RA Jacquemyn M., Maes P., Daelemans D.; RT "Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor RT for SARS-CoV-2."; RL Nat. Genet. 53:435-444(2021). RN [26] {ECO:0007744|PDB:7U10, ECO:0007744|PDB:7U11, ECO:0007744|PDB:7U12, ECO:0007744|PDB:7U13, ECO:0007744|PDB:7U14, ECO:0007744|PDB:7U15, ECO:0007744|PDB:7U16, ECO:0007744|PDB:7U17} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF 120-254, AGGREGATION RP IN NEURODEGENERATIVE DISEASES, AND TISSUE SPECIFICITY. RX PubMed=35247328; DOI=10.1016/j.cell.2022.02.026; RA Chang A., Xiang X., Wang J., Lee C., Arakhamia T., Simjanoska M., Wang C., RA Carlomagno Y., Zhang G., Dhingra S., Thierry M., Perneel J., Heeman B., RA Forgrave L.M., DeTure M., DeMarco M.L., Cook C.N., Rademakers R., RA Dickson D.W., Petrucelli L., Stowell M.H.B., Mackenzie I.R.A., RA Fitzpatrick A.W.P.; RT "Homotypic fibrillization of TMEM106B across diverse neurodegenerative RT diseases."; RL Cell 185:1346-1355(2022). RN [27] {ECO:0007744|PDB:7SAQ, ECO:0007744|PDB:7SAR, ECO:0007744|PDB:7SAS} RP STRUCTURE BY ELECTRON MICROSCOPY (2.90 ANGSTROMS) OF 120-254, AND RP AGGREGATION IN NEURODEGENERATIVE DISEASES. RX PubMed=35344984; DOI=10.1038/s41586-022-04670-9; RA Jiang Y.X., Cao Q., Sawaya M.R., Abskharon R., Ge P., DeTure M., RA Dickson D.W., Fu J.Y., Ogorzalek Loo R.R., Loo J.A., Loo J.A., RA Eisenberg D.S.; RT "Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43."; RL Nature 605:304-309(2022). RN [28] {ECO:0007744|PDB:7QVC, ECO:0007744|PDB:7QVF, ECO:0007744|PDB:7QWG, ECO:0007744|PDB:7QWL, ECO:0007744|PDB:7QWM} RP STRUCTURE BY ELECTRON MICROSCOPY (2.64 ANGSTROMS) OF 120-254, AGGREGATION RP IN NEURODEGENERATIVE DISEASES, AND TISSUE SPECIFICITY. RX PubMed=35344985; DOI=10.1038/s41586-022-04650-z; RA Schweighauser M., Arseni D., Bacioglu M., Huang M., Lovestam S., Shi Y., RA Yang Y., Zhang W., Kotecha A., Garringer H.J., Vidal R., Hallinan G.I., RA Newell K.L., Tarutani A., Murayama S., Miyazaki M., Saito Y., Yoshida M., RA Hasegawa K., Lashley T., Revesz T., Kovacs G.G., van Swieten J., Takao M., RA Hasegawa M., Ghetti B., Spillantini M.G., Ryskeldi-Falcon B., Murzin A.G., RA Goedert M., Scheres S.H.W.; RT "Age-dependent formation of TMEM106B amyloid filaments in human brains."; RL Nature 605:310-314(2022). RN [29] RP STRUCTURE BY ELECTRON MICROSCOPY (2.59 ANGSTROMS) OF 118-261, FUNCTION RP (MICROBIAL INFECTION), INTERACTION WITH SARS-COV-2 SPIKE GLYCOPROTEIN RP (MICROBIAL INFECTION), SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 210-MET--PHE-213; MET-210 AND PHE-213. RX PubMed=37421949; DOI=10.1016/j.cell.2023.06.005; RA Baggen J., Jacquemyn M., Persoons L., Vanstreels E., Pye V.E., Wrobel A.G., RA Calvaresi V., Martin S.R., Roustan C., Cronin N.B., Reading E., RA Thibaut H.J., Vercruysse T., Maes P., De Smet F., Yee A., Nivitchanyong T., RA Roell M., Franco-Hernandez N., Rhinn H., Mamchak A.A., Ah Young-Chapon M., RA Brown E., Cherepanov P., Daelemans D.; RT "TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry."; RL Cell 186:1-16(2023). RN [30] RP INVOLVEMENT IN HLD16, AND VARIANT HLD16 ASN-252. RX PubMed=29186371; DOI=10.1093/brain/awx314; RA Simons C., Dyment D., Bent S.J., Crawford J., D'Hooghe M., RA Kohlschuetter A., Venkateswaran S., Helman G., Poll-The B.T., RA Makowski C.C., Ito Y., Kernohan K., Hartley T., Waisfisz Q., Taft R.J., RA van der Knaap M.S., Wolf N.I.; RT "A recurrent de novo mutation in TMEM106B causes hypomyelinating RT leukodystrophy."; RL Brain 140:3105-3111(2017). RN [31] RP INVOLVEMENT IN HLD16, AND VARIANT HLD16 ASN-252. RX PubMed=29444210; DOI=10.1093/brain/awy029; RA Yan H., Kubisiak T., Ji H., Xiao J., Wang J., Burmeister M.; RT "The recurrent mutation in TMEM106B also causes hypomyelinating RT leukodystrophy in China and is a CpG hotspot."; RL Brain 141:E36-E36(2018). CC -!- FUNCTION: In neurons, involved in the transport of late CC endosomes/lysosomes (PubMed:25066864). May be involved in dendrite CC morphogenesis and maintenance by regulating lysosomal trafficking CC (PubMed:25066864). May act as a molecular brake for retrograde CC transport of late endosomes/lysosomes, possibly via its interaction CC with MAP6 (By similarity). In motoneurons, may mediate the axonal CC transport of lysosomes and axonal sorting at the initial segment (By CC similarity). It remains unclear whether TMEM106B affects the transport CC of moving lysosomes in the anterograde or retrograde direction in CC neurites and whether it is important in the sorting of lysosomes in CC axons or in dendrites (By similarity). In neurons, may also play a role CC in the regulation of lysosomal size and responsiveness to stress CC (PubMed:25066864). Required for proper lysosomal acidification (By CC similarity). {ECO:0000250|UniProtKB:Q6AYA5, CC ECO:0000250|UniProtKB:Q80X71, ECO:0000269|PubMed:25066864}. CC -!- FUNCTION: (Microbial infection) Plays a role in human coronavirus SARS- CC CoV-2 infection, but not in common cold coronaviruses HCoV-229E and CC HCoV-OC43 infections. Involved in ACE2-independent SARS-CoV-2 cell CC entry. Required for post-endocytic stage of virus entry, facilitates CC spike-mediated membrane fusion. Virus attachment and endocytosis can CC also be mediated by other cell surface receptors. CC {ECO:0000269|PubMed:33333024, ECO:0000269|PubMed:33686287, CC ECO:0000269|PubMed:37421949}. CC -!- SUBUNIT: Can form homomers (PubMed:23136129, PubMed:25066864). CC Interacts (via N-terminus) with MAP6 (via C-terminus) CC (PubMed:24357581). Interacts (via C-terminus) with the vacuolar-type CC ATPase subunit ATP6AP1 (PubMed:28728022). Interacts (via N-terminus) CC with AP2M1 and CLTC (PubMed:25066864). Interacts with TMEM106C CC (PubMed:25066864). {ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:24357581, ECO:0000269|PubMed:25066864, CC ECO:0000269|PubMed:28728022}. CC -!- SUBUNIT: (Microbial infection) Interacts with SARS coronavirus-2/SARS- CC CoV-2 spike protein (via RBD domain). {ECO:0000269|PubMed:37421949}. CC -!- INTERACTION: CC Q9NUM4; P42858: HTT; NbExp=3; IntAct=EBI-10490807, EBI-466029; CC Q9NUM4; Q9BVX2: TMEM106C; NbExp=4; IntAct=EBI-10490807, EBI-2821497; CC -!- SUBCELLULAR LOCATION: Late endosome membrane CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:25066864}; Single-pass type II membrane protein CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:25066864}. Lysosome membrane CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:25066864, CC ECO:0000269|PubMed:37421949}; Single-pass type II membrane protein CC {ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23136129, CC ECO:0000269|PubMed:25066864}. Cell membrane CC {ECO:0000269|PubMed:37421949}; Single-pass type II membrane protein CC {ECO:0000255}. Note=Colocalizes with LAMP1. A small fraction resides on CC the cell surface (PubMed:37421949). {ECO:0000269|PubMed:22511793, CC ECO:0000269|PubMed:25066864, ECO:0000269|PubMed:37421949}. CC -!- TISSUE SPECIFICITY: Expressed in the brain, including in the frontal CC cortex (at protein level) (PubMed:35247328, PubMed:35344985). Expressed CC in lung epithelial cells (PubMed:33686287). CC {ECO:0000269|PubMed:33686287, ECO:0000269|PubMed:35247328, CC ECO:0000269|PubMed:35344985}. CC -!- DISEASE: Frontotemporal dementia 2 (FTD2) [MIM:607485]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. Gestural apraxia, CC parkinsonism, visual loss, and visual hallucinations are present in 25 CC to 40% of patients. {ECO:0000269|PubMed:20154673, CC ECO:0000269|PubMed:21178100, ECO:0000269|PubMed:22895706, CC ECO:0000269|PubMed:23742080}. Note=The gene represented in this entry CC may act as a disease modifier. Risk alleles confer genetic CC susceptibility by increasing gene expression (PubMed:20154673, CC PubMed:21178100). Increased expression may be the result of down- CC regulation of microRNA miR-132 and miR-212, that repress TMEM106B CC expression (PubMed:22895706). Thr-185 is a risk allele associated with CC lower GRN protein levels and early age at onset in GRN FTD2 mutation CC carriers: it presents slower protein degradation that leads to higher CC steady-state TMEM106B levels, leading to alterations in the CC intracellular versus extracellular partitioning of GRN CC (PubMed:23742080). {ECO:0000269|PubMed:20154673, CC ECO:0000269|PubMed:21178100, ECO:0000269|PubMed:22895706, CC ECO:0000269|PubMed:23742080}. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 CC (FTDALS1) [MIM:105550]: An autosomal dominant neurodegenerative CC disorder characterized by adult onset of frontotemporal dementia and/or CC amyotrophic lateral sclerosis in an affected individual. There is high CC intrafamilial variation. Frontotemporal dementia is characterized by CC frontal and temporal lobe atrophy associated with neuronal loss, CC gliosis, and dementia. Patients exhibit progressive changes in social, CC behavioral, and/or language function. Amyotrophic lateral sclerosis is CC characterized by the death of motor neurons in the brain, brainstem, CC and spinal cord, resulting in fatal paralysis. CC {ECO:0000269|PubMed:24385136, ECO:0000269|PubMed:24442578, CC ECO:0000303|PubMed:24488309}. Note=The gene represented in this entry CC acts as a disease modifier. CC -!- DISEASE: Leukodystrophy, hypomyelinating, 16 (HLD16) [MIM:617964]: An CC autosomal dominant disorder characterized by hypomyelination, CC leukodystrophy, and thin corpus callosum observed on brain imaging. CC Clinical features include hypotonia, nystagmus, and mildly delayed CC motor development with onset in infancy, ataxic or broad-based gait, CC hyperreflexia, intention tremor, dysmetria, and a mild pyramidal CC syndrome. Some patients have cognitive impairment, whereas others may CC have normal cognition or mild intellectual disability with speech CC difficulties. {ECO:0000269|PubMed:29186371, CC ECO:0000269|PubMed:29444210}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Note=A TMEM106B truncated C-terminal fragment (residues 120 CC through 254) was found to aggregate into stable amyloid fibrils in the CC brain of patients suffering from diverse genetic and sporadic CC tauopathies, amyloid-beta amyloidoses, synucleinopathies and TDP-43 CC proteinopathies. It is currently unclear whether TMEM106B fibrils are CC associated with a pathogenic process or represents a non-specific CC secondary phenomenon, a general downstream marker of lysosomal stress CC for instance (PubMed:35247328, PubMed:35344984, PubMed:35344985). CC TMEM106B amyloid filaments form in an age-dependent manner in human CC brains, however fibrillization of TMEM106B seems substantially greater CC in patients with known neurodegeneration compared to age-matched CC unaffected individuals (PubMed:35344985). {ECO:0000269|PubMed:35247328, CC ECO:0000269|PubMed:35344984, ECO:0000269|PubMed:35344985}. CC -!- SIMILARITY: Belongs to the TMEM106 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; AK002135; BAA92099.1; -; mRNA. DR EMBL; AK223263; BAD96983.1; -; mRNA. DR EMBL; AC007321; AAQ96840.1; -; Genomic_DNA. DR EMBL; CH236948; EAL24296.1; -; Genomic_DNA. DR EMBL; CH471073; EAW93638.1; -; Genomic_DNA. DR EMBL; BC033901; AAH33901.1; -; mRNA. DR EMBL; BC039741; AAH39741.1; -; mRNA. DR CCDS; CCDS5358.1; -. DR RefSeq; NP_001127704.1; NM_001134232.2. DR RefSeq; NP_060844.2; NM_018374.3. DR PDB; 7QVC; EM; 2.64 A; A/B/C=120-254. DR PDB; 7QVF; EM; 3.64 A; A/B/C/D/E/F=120-254. DR PDB; 7QWG; EM; 3.38 A; A/B/C=120-254. DR PDB; 7QWL; EM; 3.47 A; A/B/C=120-254. DR PDB; 7QWM; EM; 2.76 A; A/B/C=120-254. DR PDB; 7SAQ; EM; 2.90 A; A/B/C/D/E=120-254. DR PDB; 7SAR; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J=120-254. DR PDB; 7SAS; EM; 3.70 A; A/B/C/D/E/F/G/H/I/J=120-254. DR PDB; 7TMC; EM; 3.25 A; A/B/C=1-274. DR PDB; 7U10; EM; 3.00 A; A/B/C=120-254. DR PDB; 7U11; EM; 3.20 A; A/B/C=120-254. DR PDB; 7U12; EM; 3.50 A; A/B/C=120-254. DR PDB; 7U13; EM; 2.90 A; A/B/C=120-254. DR PDB; 7U14; EM; 4.50 A; A/B/C=120-254. DR PDB; 7U15; EM; 3.00 A; A/B/C=120-254. DR PDB; 7U16; EM; 2.70 A; A/B/C=120-254. DR PDB; 7U17; EM; 3.00 A; A/B/C=120-254. DR PDB; 7U18; EM; 2.70 A; A/B/C=120-254. DR PDB; 7X83; EM; 3.40 A; A/B/C=1-274. DR PDB; 7X84; EM; 3.00 A; A/B/C=120-254. DR PDB; 8B7D; X-ray; 2.59 A; A=118-274. DR PDB; 8F9K; EM; 3.40 A; A/B/C/D/E/F=1-274. DR PDB; 8J7N; EM; 3.00 A; A/B/C=1-274. DR PDB; 8J7P; EM; 3.40 A; A/B/C=1-274. DR PDB; 8OTD; EM; 2.60 A; A/B/C/D=1-274. DR PDB; 8OTE; EM; 3.60 A; A/B/C/D/E/F/G/H=1-274. DR PDB; 8X5H; EM; 3.47 A; A/B/C=1-274. DR PDB; 9FNB; EM; 2.64 A; A/B/C/D=120-254. DR PDBsum; 7QVC; -. DR PDBsum; 7QVF; -. DR PDBsum; 7QWG; -. DR PDBsum; 7QWL; -. DR PDBsum; 7QWM; -. DR PDBsum; 7SAQ; -. DR PDBsum; 7SAR; -. DR PDBsum; 7SAS; -. DR PDBsum; 7TMC; -. DR PDBsum; 7U10; -. DR PDBsum; 7U11; -. DR PDBsum; 7U12; -. DR PDBsum; 7U13; -. DR PDBsum; 7U14; -. DR PDBsum; 7U15; -. DR PDBsum; 7U16; -. DR PDBsum; 7U17; -. DR PDBsum; 7U18; -. DR PDBsum; 7X83; -. DR PDBsum; 7X84; -. DR PDBsum; 8B7D; -. DR PDBsum; 8F9K; -. DR PDBsum; 8J7N; -. DR PDBsum; 8J7P; -. DR PDBsum; 8OTD; -. DR PDBsum; 8OTE; -. DR PDBsum; 8X5H; -. DR PDBsum; 9FNB; -. DR AlphaFoldDB; Q9NUM4; -. DR EMDB; EMD-14174; -. DR EMDB; EMD-14176; -. DR EMDB; EMD-14187; -. DR EMDB; EMD-14188; -. DR EMDB; EMD-14189; -. DR EMDB; EMD-17170; -. DR EMDB; EMD-17175; -. DR EMDB; EMD-17176; -. DR EMDB; EMD-24953; -. DR EMDB; EMD-24954; -. DR EMDB; EMD-24955; -. DR EMDB; EMD-25995; -. DR EMDB; EMD-26273; -. DR EMDB; EMD-26274; -. DR EMDB; EMD-26275; -. DR EMDB; EMD-26276; -. DR EMDB; EMD-26277; -. DR EMDB; EMD-26278; -. DR EMDB; EMD-26279; -. DR EMDB; EMD-28943; -. DR EMDB; EMD-33054; -. DR EMDB; EMD-33055; -. DR EMDB; EMD-36043; -. DR EMDB; EMD-36045; -. DR EMDB; EMD-38069; -. DR EMDB; EMD-50587; -. DR SMR; Q9NUM4; -. DR BioGRID; 120093; 371. DR FunCoup; Q9NUM4; 1015. DR IntAct; Q9NUM4; 76. DR MINT; Q9NUM4; -. DR STRING; 9606.ENSP00000379901; -. DR TCDB; 9.B.23.1.1; the tmem106 (tmem106) family. DR GlyConnect; 1849; 19 N-Linked glycans (2 sites). DR GlyCosmos; Q9NUM4; 6 sites, 20 glycans. DR GlyGen; Q9NUM4; 8 sites, 28 N-linked glycans (3 sites), 1 O-linked glycan (1 site). DR iPTMnet; Q9NUM4; -. DR PhosphoSitePlus; Q9NUM4; -. DR SwissPalm; Q9NUM4; -. DR BioMuta; TMEM106B; -. DR DMDM; 109895058; -. DR jPOST; Q9NUM4; -. DR MassIVE; Q9NUM4; -. DR PaxDb; 9606-ENSP00000379901; -. DR PeptideAtlas; Q9NUM4; -. DR ProteomicsDB; 82695; -. DR Pumba; Q9NUM4; -. DR Antibodypedia; 43908; 126 antibodies from 30 providers. DR DNASU; 54664; -. DR YCharOS; Q9NUM4; Tested 6 antibodies from 5 manufacturers. DR Ensembl; ENST00000396667.7; ENSP00000379901.2; ENSG00000106460.21. DR Ensembl; ENST00000396668.8; ENSP00000379902.3; ENSG00000106460.21. DR Ensembl; ENST00000444443.6; ENSP00000401302.2; ENSG00000106460.21. DR Ensembl; ENST00000704455.1; ENSP00000515905.1; ENSG00000106460.21. DR GeneID; 54664; -. DR KEGG; hsa:54664; -. DR MANE-Select; ENST00000396668.8; ENSP00000379902.3; NM_001134232.2; NP_001127704.1. DR UCSC; uc003ssh.4; human. DR AGR; HGNC:22407; -. DR ClinPGx; PA142670756; -. DR CTD; 54664; -. DR DisGeNET; 54664; -. DR GeneCards; TMEM106B; -. DR HGNC; HGNC:22407; TMEM106B. DR HPA; ENSG00000106460; Low tissue specificity. DR MalaCards; TMEM106B; -. DR MIM; 105550; phenotype. DR MIM; 607485; phenotype. DR MIM; 613413; gene. DR MIM; 617964; phenotype. DR NIAGADS; ENSG00000106460; -. DR OpenTargets; ENSG00000106460; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000106460; -. DR eggNOG; ENOG502QQRZ; Eukaryota. DR GeneTree; ENSGT00940000158360; -. DR HOGENOM; CLU_089337_2_0_1; -. DR InParanoid; Q9NUM4; -. DR OMA; FGHSEQT; -. DR OrthoDB; 508875at2759; -. DR PAN-GO; Q9NUM4; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q9NUM4; -. DR PathwayCommons; Q9NUM4; -. DR SignaLink; Q9NUM4; -. DR Agora; ENSG00000106460; -. DR BioGRID-ORCS; 54664; 25 hits in 1169 CRISPR screens. DR ChiTaRS; TMEM106B; human. DR GeneWiki; TMEM106B; -. DR GenomeRNAi; 54664; -. DR Pharos; Q9NUM4; Tbio. DR PRO; PR:Q9NUM4; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q9NUM4; protein. DR Bgee; ENSG00000106460; Expressed in cauda epididymis and 213 other cell types or tissues. DR ExpressionAtlas; Q9NUM4; baseline and differential. DR GO; GO:0005768; C:endosome; IDA:HPA. DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0051117; F:ATPase binding; IPI:MGI. DR GO; GO:0048813; P:dendrite morphogenesis; IMP:UniProtKB. DR GO; GO:0007042; P:lysosomal lumen acidification; IEA:Ensembl. DR GO; GO:1905146; P:lysosomal protein catabolic process; IEA:Ensembl. DR GO; GO:0007041; P:lysosomal transport; IBA:GO_Central. DR GO; GO:0032418; P:lysosome localization; IMP:UniProtKB. DR GO; GO:0007040; P:lysosome organization; IBA:GO_Central. DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl. DR GO; GO:1900006; P:positive regulation of dendrite development; IEA:Ensembl. DR GO; GO:1905671; P:regulation of lysosome organization; IEA:Ensembl. DR DisProt; DP02543; -. DR InterPro; IPR009790; TMEM106. DR InterPro; IPR048509; TMEM106_C. DR InterPro; IPR048511; TMEM106_N. DR PANTHER; PTHR28556; TRANSMEMBRANE PROTEIN 106B; 1. DR PANTHER; PTHR28556:SF1; TRANSMEMBRANE PROTEIN 106B; 1. DR Pfam; PF07092; TMEM106; 1. DR Pfam; PF21002; TMEM106_N; 1. DR SUPFAM; SSF117070; LEA14-like; 1. PE 1: Evidence at protein level; KW 3D-structure; Amyotrophic lateral sclerosis; Cell membrane; KW Disease variant; Disulfide bond; Endosome; Glycoprotein; Leukodystrophy; KW Lipoprotein; Lysosome; Membrane; Myristate; Neurodegeneration; KW Phosphoprotein; Proteomics identification; Reference proteome; KW Signal-anchor; Transmembrane; Transmembrane helix; Transport. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:25255805" FT CHAIN 2..274 FT /note="Transmembrane protein 106B" FT /id="PRO_0000242650" FT TOPO_DOM 2..96 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:22511793, FT ECO:0000269|PubMed:23136129, ECO:0000269|PubMed:25066864" FT TRANSMEM 97..117 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 118..274 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:22511793, FT ECO:0000269|PubMed:23136129, ECO:0000269|PubMed:25066864" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..11 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 33 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT LIPID 2 FT /note="N-myristoyl glycine" FT /evidence="ECO:0000269|PubMed:25255805" FT CARBOHYD 145 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT CARBOHYD 151 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT CARBOHYD 164 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT CARBOHYD 183 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:22511793, ECO:0000269|PubMed:23742080" FT CARBOHYD 256 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22511793" FT DISULFID 214..253 FT /evidence="ECO:0000269|PubMed:35344984" FT VARIANT 185 FT /note="T -> S (in dbSNP:rs3173615)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:23742080" FT /id="VAR_026849" FT VARIANT 252 FT /note="D -> N (in HLD16; dbSNP:rs1554310600)" FT /evidence="ECO:0000269|PubMed:29186371, FT ECO:0000269|PubMed:29444210" FT /id="VAR_081068" FT MUTAGEN 210..213 FT /note="MYDF->AYDA: Highly decreased number of infected FT cells by SARS-CoV-2. No effect on infection with HCoV- FT 229E." FT /evidence="ECO:0000269|PubMed:37421949" FT MUTAGEN 210 FT /note="M->A: Decreased number of infected cells by SARS- FT CoV-2. No effect on infection with HCoV-229E." FT /evidence="ECO:0000269|PubMed:37421949" FT MUTAGEN 213 FT /note="F->A: Decreased number of infected cells by SARS- FT CoV-2. No effect on infection with HCoV-229E." FT /evidence="ECO:0000269|PubMed:37421949" FT CONFLICT 50 FT /note="Y -> C (in Ref. 2; BAD96983)" FT /evidence="ECO:0000305" FT CONFLICT 106 FT /note="L -> P (in Ref. 2; BAD96983)" FT /evidence="ECO:0000305" FT CONFLICT 197 FT /note="Y -> N (in Ref. 2; BAD96983)" FT /evidence="ECO:0000305" FT STRAND 122..136 FT /evidence="ECO:0007829|PDB:8B7D" FT TURN 137..140 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 141..153 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 156..158 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 160..171 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 174..183 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 184..187 FT /evidence="ECO:0007829|PDB:7QWM" FT STRAND 192..203 FT /evidence="ECO:0007829|PDB:8B7D" FT HELIX 205..208 FT /evidence="ECO:0007829|PDB:8B7D" FT HELIX 209..214 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 216..220 FT /evidence="ECO:0007829|PDB:7QVC" FT STRAND 223..236 FT /evidence="ECO:0007829|PDB:8B7D" FT STRAND 239..252 FT /evidence="ECO:0007829|PDB:8B7D" SQ SEQUENCE 274 AA; 31127 MW; 906C923986DC04E6 CRC64; MGKSLSHLPL HSSKEDAYDG VTSENMRNGL VNSEVHNEDG RNGDVSQFPY VEFTGRDSVT CPTCQGTGRI PRGQENQLVA LIPYSDQRLR PRRTKLYVMA SVFVCLLLSG LAVFFLFPRS IDVKYIGVKS AYVSYDVQKR TIYLNITNTL NITNNNYYSV EVENITAQVQ FSKTVIGKAR LNNITIIGPL DMKQIDYTVP TVIAEEMSYM YDFCTLISIK VHNIVLMMQV TVTTTYFGHS EQISQERYQY VDCGRNTTYQ LGQSEYLNVL QPQQ // ID TAU_HUMAN Reviewed; 758 AA. AC P10636; P18518; Q14799; Q15549; Q15550; Q15551; Q1RMF6; Q53YB1; Q5CZI7; AC Q5XWF0; Q6QT54; Q9UDJ3; Q9UMH0; Q9UQ96; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 31-MAY-2011, sequence version 5. DT 28-JAN-2026, entry version 293. DE RecName: Full=Microtubule-associated protein tau {ECO:0000305}; DE AltName: Full=Neurofibrillary tangle protein; DE AltName: Full=Paired helical filament-tau; DE Short=PHF-tau; GN Name=MAPT {ECO:0000312|HGNC:HGNC:6893}; Synonyms=MAPTL, MTBT1, TAU; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FETAL-TAU). RC TISSUE=Brain; RX PubMed=3131773; DOI=10.1073/pnas.85.11.4051; RA Goedert M., Wischik C., Crowther R., Walker J., Klug A.; RT "Cloning and sequencing of the cDNA encoding a core protein of the paired RT helical filament of Alzheimer disease: identification as the microtubule- RT associated protein tau."; RL Proc. Natl. Acad. Sci. U.S.A. 85:4051-4055(1988). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TAU-D). RC TISSUE=Brain; RX PubMed=2498079; DOI=10.1002/j.1460-2075.1989.tb03390.x; RA Goedert M., Spillantini M.G., Potier M.-C., Ulrich J., Crowther R.A.; RT "Cloning and sequencing of the cDNA encoding an isoform of microtubule- RT associated protein tau containing four tandem repeats: differential RT expression of tau protein mRNAs in human brain."; RL EMBO J. 8:393-399(1989). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TAU-A AND FETAL-TAU). RC TISSUE=Fetal brain; RX PubMed=2516729; DOI=10.1016/0896-6273(89)90050-0; RA Lee G., Neve R.L., Kosik K.S.; RT "The microtubule binding domain of tau protein."; RL Neuron 2:1615-1624(1989). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TAU-B; TAU-C; TAU-E AND TAU-F), AND RP ASSOCIATION WITH ALZHEIMER DISEASE. RC TISSUE=Brain; RX PubMed=2484340; DOI=10.1016/0896-6273(89)90210-9; RA Goedert M., Spillantini M.G., Jakes R., Rutherford D., Crowther R.A.; RT "Multiple isoforms of human microtubule-associated protein tau: sequences RT and localization in neurofibrillary tangles of Alzheimer's disease."; RL Neuron 3:519-526(1989). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS PNS-TAU; FETAL-TAU AND TAU-F), RP ALTERNATIVE SPLICING, AND VARIANT HIS-441. RX PubMed=1420178; DOI=10.1021/bi00158a027; RA Andreadis A., Brown W.M., Kosik K.S.; RT "Structure and novel exons of the human tau gene."; RL Biochemistry 31:10626-10633(1992). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TAU-E). RA Chun J., Kwon T., Lee E.-J., Hyun S.-H., Kang S.S.; RT "Cloning of tau-related genes."; RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM FETAL-TAU). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS FETAL-TAU AND TAU-D). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP PROTEIN SEQUENCE OF 2-73; 103-381; 468-497; 508-571; 577-583; 592-607; RP 616-634; 639-657; 661-664; 671-700 AND 703-758, CLEAVAGE OF INITIATOR RP METHIONINE, ACETYLATION AT ALA-2, AND DEAMIDATION AT ASN-484 AND ASN-596. RC TISSUE=Brain; RX PubMed=1512244; DOI=10.1016/s0021-9258(18)41890-x; RA Hasegawa M., Morishima-Kawashima M., Takio K., Suzuki M., Titani K., RA Ihara Y.; RT "Protein sequence and mass spectrometric analyses of tau in the Alzheimer's RT disease brain."; RL J. Biol. Chem. 267:17047-17054(1992). RN [11] RP PROTEIN SEQUENCE OF 25-44; 529-538; 560-571 AND 671-686, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 466-740 (ISOFORMS RP TAU-A/TAU-B/TAU-C/FETAL-TAU). RA Han J., Zhang J., Dong X.-P.; RT "Molecular interactions of recombinant neural protein tau with recombinant RT and native PrP proteins in vitro."; RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases. RN [13] RP PROTEIN SEQUENCE OF 543-551; 560-574; 576-584 AND 623-634, PHOSPHORYLATION RP AT SER-531; THR-534; THR-548; SER-552; SER-554; SER-579; SER-713 AND RP SER-739, UBIQUITINATION AT LYS-571; LYS-628 AND LYS-670, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RX PubMed=16443603; DOI=10.1074/jbc.m512786200; RA Cripps D., Thomas S.N., Jeng Y., Yang F., Davies P., Yang A.J.; RT "Alzheimer disease-specific conformation of hyperphosphorylated paired RT helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 RT ubiquitin conjugation."; RL J. Biol. Chem. 281:10825-10838(2006). RN [14] RP PROTEIN SEQUENCE OF 577-584; 608-611; 616-628; 639-648 AND 671-686, RP PHOSPHORYLATION AT SER-579; SER-610; SER-622; SER-641 AND SER-673, RP MUTAGENESIS, AND DOMAIN. RX PubMed=7706316; DOI=10.1074/jbc.270.13.7679; RA Drewes G., Trinczek B., Illenberger S., Biernat J., Schmitt-Ulms G., RA Meyer H.E., Mandelkow E.-M., Mandelkow E.; RT "Microtubule-associated protein/microtubule affinity-regulating kinase RT (p110mark). A novel protein kinase that regulates tau-microtubule RT interactions and dynamic instability by phosphorylation at the Alzheimer- RT specific site serine 262."; RL J. Biol. Chem. 270:7679-7688(1995). RN [15] RP NUCLEOTIDE SEQUENCE [MRNA] OF 592-622 (ISOFORMS PNS-TAU/TAU-D/TAU-E/TAU-F). RC TISSUE=Brain; RX PubMed=2495000; DOI=10.1016/0006-291x(89)92240-7; RA Mori H., Hamada Y., Kawaguchi M., Honda T., Kondo J., Ihara Y.; RT "A distinct form of tau is selectively incorporated into Alzheimer's paired RT helical filaments."; RL Biochem. Biophys. Res. Commun. 159:1221-1226(1989). RN [16] RP PROTEIN SEQUENCE OF 379-392 AND 568-581, AND PHOSPHORYLATION AT SER-713. RX PubMed=1899488; DOI=10.1126/science.1899488; RA Lee V.M., Balin B.J., Otvos L. Jr., Trojanowski J.Q.; RT "A68: a major subunit of paired helical filaments and derivatized forms of RT normal Tau."; RL Science 251:675-678(1991). RN [17] RP PROTEIN SEQUENCE OF 616-712. RX PubMed=1915258; DOI=10.1002/j.1460-2075.1991.tb07820.x; RA Jakes R., Novak M., Davison M., Wischik C.M.; RT "Identification of 3- and 4-repeat tau isoforms within the PHF in RT Alzheimer's disease."; RL EMBO J. 10:2725-2729(1991). RN [18] RP IDENTIFICATION (ISOFORM TAU-G), AND VARIANT HIS-441. RX PubMed=15365985; DOI=10.1002/humu.20086; RA Rademakers R., Cruts M., van Broeckhoven C.; RT "The role of tau (MAPT) in frontotemporal dementia and related RT tauopathies."; RL Hum. Mutat. 24:277-295(2004). RN [19] RP REVIEW. RX PubMed=1713721; DOI=10.1016/0166-2236(91)90105-4; RA Goedert M., Crowther R.A., Garner C.C.; RT "Molecular characterization of microtubule-associated proteins tau and RT MAP2."; RL Trends Neurosci. 14:193-199(1991). RN [20] RP PHOSPHORYLATION AT SER-554; SER-579; SER-602; SER-622 AND SER-669. RX PubMed=8999860; DOI=10.1016/s0021-9258(19)67481-8; RA Paudel H.K.; RT "The regulatory Ser262 of microtubule-associated protein tau is RT phosphorylated by phosphorylase kinase."; RL J. Biol. Chem. 272:1777-1785(1997). RN [21] RP GLYCATION AT LYS-87; LYS-383; LYS-467; LYS-480; LYS-491; LYS-542; LYS-551; RP LYS-576; LYS-597; LYS-598; LYS-664; LYS-670 AND LYS-686, AND LACK OF RP GLYCATION AT LYS-24; LYS-44; LYS-67; LYS-381; LYS-391; LYS-392; LYS-394; RP LYS-465; LYS-497; LYS-507; LYS-541; LYS-557; LYS-571; LYS-574; LYS-584; RP LYS-591; LYS-607; LYS-611; LYS-615; LYS-628; LYS-634; LYS-638; LYS-648; RP LYS-657; LYS-660; LYS-687; LYS-692; LYS-700; LYS-702; LYS-712 AND LYS-755. RX PubMed=9326300; DOI=10.1046/j.1471-4159.1997.69041709.x; RA Nacharaju P., Ko L., Yen S.H.; RT "Characterization of in vitro glycation sites of tau."; RL J. Neurochem. 69:1709-1719(1997). RN [22] RP PHOSPHORYLATION, AND MUTAGENESIS. RX PubMed=9735171; DOI=10.1006/abbi.1998.0813; RA Sengupta A., Kabat J., Novak M., Wu Q., Grundke-Iqbal I., Iqbal K.; RT "Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal RT inhibition of its binding to microtubules."; RL Arch. Biochem. Biophys. 357:299-309(1998). RN [23] RP PHOSPHORYLATION AT THR-470; SER-516; SER-519; THR-529; SER-531; SER-552; RP SER-579; SER-713; SER-721 AND SER-739, AND MUTAGENESIS. RX PubMed=9614189; DOI=10.1091/mbc.9.6.1495; RA Illenberger S., Zheng-Fischhofer Q., Preuss U., Stamer K., Baumann K., RA Trinczek B., Biernat J., Godemann R., Mandelkow E.-M., Mandelkow E.; RT "The endogenous and cell cycle-dependent phosphorylation of tau protein in RT living cells: implications for Alzheimer's disease."; RL Mol. Biol. Cell 9:1495-1512(1998). RN [24] RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION. RX PubMed=10747907; DOI=10.1074/jbc.m000389200; RA Maas T., Eidenmueller J., Brandt R.; RT "Interaction of tau with the neural membrane cortex is regulated by RT phosphorylation at sites that are modified in paired helical filaments."; RL J. Biol. Chem. 275:15733-15740(2000). RN [25] RP PHOSPHORYLATION AT SER-519; THR-522; SER-713 AND SER-721 BY CSNK1D/CK1, AND RP INTERACTION WITH CSNK1D. RX PubMed=14761950; DOI=10.1074/jbc.m314116200; RA Li G., Yin H., Kuret J.; RT "Casein kinase 1 delta phosphorylates tau and disrupts its binding to RT microtubules."; RL J. Biol. Chem. 279:15938-15945(2004). RN [26] RP PHOSPHORYLATION AT THR-548 BY GSK3B. RX PubMed=14690523; DOI=10.1111/j.1471-4159.2004.02155.x; RA Cho J.H., Johnson G.V.; RT "Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta RT (GSK3beta) plays a critical role in regulating tau's ability to bind and RT stabilize microtubules."; RL J. Neurochem. 88:349-358(2004). RN [27] RP PHOSPHORYLATION AT TYR-18 BY FYN. RX PubMed=14999081; DOI=10.1523/jneurosci.4162-03.2004; RA Lee G., Thangavel R., Sharma V.M., Litersky J.M., Bhaskar K., Fang S.M., RA Do L.H., Andreadis A., Van Hoesen G., Ksiezak-Reding H.; RT "Phosphorylation of tau by fyn: implications for Alzheimer's disease."; RL J. Neurosci. 24:2304-2312(2004). RN [28] RP INTERACTION WITH SQSTM1, UBIQUITINATION, AND PROTEASOMAL DEGRADATION. RX PubMed=15953362; DOI=10.1111/j.1471-4159.2005.03181.x; RA Babu J.R., Geetha T., Wooten M.W.; RT "Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal RT degradation."; RL J. Neurochem. 94:192-203(2005). RN [29] RP PHOSPHORYLATION AT THR-498; SER-516; SER-519; THR-522; THR-529; SER-531; RP THR-548; SER-552; SER-579; SER-713; SER-721 AND SER-726, AND RP DEPHOSPHORYLATION AT THR-498; SER-516; SER-519; THR-522; THR-529; SER-531; RP THR-548; SER-552; SER-579; SER-713; SER-721 AND SER-726 BY PPP5C. RX PubMed=15546861; DOI=10.1074/jbc.m410775200; RA Liu F., Iqbal K., Grundke-Iqbal I., Rossie S., Gong C.X.; RT "Dephosphorylation of tau by protein phosphatase 5: impairment in RT Alzheimer's disease."; RL J. Biol. Chem. 280:1790-1796(2005). RN [30] RP PHOSPHORYLATION AT TYR-514; SER-515; SER-516; SER-519; SER-733; SER-739 AND RP THR-744. RX PubMed=16923168; DOI=10.1111/j.1471-4159.2006.04059.x; RA Sato S., Cerny R.L., Buescher J.L., Ikezu T.; RT "Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is RT involved in tau phosphorylation and aggregation."; RL J. Neurochem. 98:1573-1584(2006). RN [31] RP PHOSPHORYLATION AT SER-214 BY SGK1, AND INTERACTION WITH SGK1. RX PubMed=16982696; DOI=10.1128/mcb.01017-06; RA Yang Y.C., Lin C.H., Lee E.H.; RT "Serum- and glucocorticoid-inducible kinase 1 (SGK1) increases neurite RT formation through microtubule depolymerization by SGK1 and by SGK1 RT phosphorylation of tau."; RL Mol. Cell. Biol. 26:8357-8370(2006). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [33] RP PHOSPHORYLATION BY CSNK1D/CK1. RX PubMed=17562708; DOI=10.1074/jbc.m703269200; RA Hanger D.P., Byers H.L., Wray S., Leung K.-Y., Saxton M.J., Seereeram A., RA Reynolds C.H., Ward M.A., Anderton B.H.; RT "Novel phosphorylation sites in tau from Alzheimer brain support a role for RT casein kinase 1 in disease pathogenesis."; RL J. Biol. Chem. 282:23645-23654(2007). RN [34] RP PHOSPHORYLATION AT THR-529 BY DYRK2. RX PubMed=18599021; DOI=10.1016/j.bcp.2008.05.021; RA Yoshida K.; RT "Role for DYRK family kinases on regulation of apoptosis."; RL Biochem. Pharmacol. 76:1389-1394(2008). RN [35] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [36] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [37] RP GLYCOSYLATION, PHOSPHORYLATION AT SER-516; SER-519; THR-522; THR-529; RP SER-531; THR-534; SER-579; SER-713; SER-721 AND SER-739, AND ASSOCIATION RP WITH ALZHEIMER DISEASE. RX PubMed=19451179; DOI=10.1093/brain/awp099; RA Liu F., Shi J., Tanimukai H., Gu J., Gu J., Grundke-Iqbal I., Iqbal K., RA Gong C.X.; RT "Reduced O-GlcNAcylation links lower brain glucose metabolism and tau RT pathology in Alzheimer's disease."; RL Brain 132:1820-1832(2009). RN [38] RP INTERACTION WITH EPM2A. RX PubMed=19542233; DOI=10.1074/jbc.m109.009688; RA Puri R., Suzuki T., Yamakawa K., Ganesh S.; RT "Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an RT animal model for Lafora disease."; RL J. Biol. Chem. 284:22657-22663(2009). RN [39] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-713; SER-717; SER-721 AND RP SER-726, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [41] RP GLYCOSYLATION AT SER-525; SER-555 AND SER-717, PHOSPHORYLATION AT SER-519; RP SER-713 SER-717 AND SER-721, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=21327254; DOI=10.1039/c0mb00337a; RA Smet-Nocca C., Broncel M., Wieruszeski J.M., Tokarski C., Hanoulle X., RA Leroy A., Landrieu I., Rolando C., Lippens G., Hackenberger C.P.; RT "Identification of O-GlcNAc sites within peptides of the Tau protein and RT their impact on phosphorylation."; RL Mol. Biosyst. 7:1420-1429(2011). RN [42] RP FUNCTION, AND PHOSPHORYLATION AT THR-529 AND SER-579. RX PubMed=21985311; DOI=10.1111/j.1471-4159.2011.07523.x; RA Yoshida H., Goedert M.; RT "Phosphorylation of microtubule-associated protein tau by AMPK-related RT kinases."; RL J. Neurochem. 120:165-176(2012). RN [43] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519; THR-548; SER-552; RP SER-713 AND SER-721, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [44] RP INTERACTION WITH MARK1; MARK2; MARK3 AND MARK4, SUBCELLULAR LOCATION, AND RP PHOSPHORYLATION AT SER-579. RX PubMed=23666762; DOI=10.1007/s12017-013-8232-3; RA Gu G.J., Lund H., Wu D., Blokzijl A., Classon C., von Euler G., RA Landegren U., Sunnemark D., Kamali-Moghaddam M.; RT "Role of individual MARK isoforms in phosphorylation of tau at Ser262 in RT Alzheimer's disease."; RL NeuroMolecular Med. 15:458-469(2013). RN [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-519, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [46] RP INTERACTION WITH LRRK2, AND SUBCELLULAR LOCATION. RX PubMed=26014385; DOI=10.1007/s12035-015-9209-z; RA Guerreiro P.S., Gerhardt E., Lopes da Fonseca T., Baehr M., Outeiro T.F., RA Eckermann K.; RT "LRRK2 Promotes Tau Accumulation, Aggregation and Release."; RL Mol. Neurobiol. 53:3124-3135(2016). RN [47] RP INTERACTION WITH LRP1. RX PubMed=32296178; DOI=10.1038/s41586-020-2156-5; RA Rauch J.N., Luna G., Guzman E., Challis C., Sibih Y.E., Leshuk C., RA Hernandez I., Wegmann S., Hyman B.T., Gradinaru V., Kampmann M., RA Kosik K.S.; RT "LRP1 is a master regulator of tau uptake and spread."; RL Nature 580:381-385(2020). RN [48] RP STRUCTURE BY NMR OF 542-554 IN COMPLEX WITH PIN1. RX PubMed=11313338; DOI=10.1074/jbc.m010327200; RA Wintjens R., Wieruszeski J.-M., Drobecq H., Rousselot-Pailley P., Buee L., RA Lippens G., Landrieu I.; RT "1H NMR study on the binding of Pin1 Trp-Trp domain with phosphothreonine RT peptides."; RL J. Biol. Chem. 276:25150-25156(2001). RN [49] RP SUBCELLULAR LOCATION. RX PubMed=32272059; DOI=10.1016/j.cell.2020.03.031; RA Zhang M., Liu L., Lin X., Wang Y., Li Y., Guo Q., Li S., Sun Y., Tao X., RA Zhang D., Lv X., Zheng L., Ge L.; RT "A Translocation Pathway for Vesicle-Mediated Unconventional Protein RT Secretion."; RL Cell 181:637-652(2020). RN [50] RP REVIEW ON VARIANTS. RX PubMed=10899436; DOI=10.1016/s0925-4439(00)00037-5; RA Goedert M., Spillantini M.G.; RT "Tau mutations in frontotemporal dementia FTDP-17 and their relevance for RT Alzheimer's disease."; RL Biochim. Biophys. Acta 1502:110-121(2000). RN [51] RP VARIANT FTD1 MET-654, VARIANTS ASN-285; ALA-289; HIS-441 AND PRO-447, AND RP INVOLVEMENT IN FTD1. RX PubMed=9629852; DOI=10.1002/ana.410430617; RA Poorkaj P., Bird T.D., Wijsman E., Nemens E., Garruto R.M., Anderson L., RA Andreadis A., Wiederholt W.C., Raskind M., Schellenberg G.D.; RT "Tau is a candidate gene for chromosome 17 frontotemporal dementia."; RL Ann. Neurol. 43:815-825(1998). RN [52] RP ERRATUM OF PUBMED:9629852. RA Poorkaj P., Bird T.D., Wijsman E., Nemens E., Garruto R.M., Anderson L., RA Andreadis A., Wiederholt W.C., Raskind M., Schellenberg G.D.; RL Ann. Neurol. 44:428-428(1998). RN [53] RP VARIANT FTD1 LEU-618. RX PubMed=9736786; DOI=10.1093/hmg/7.11.1825; RA Dumanchin C., Camuzat A., Campion D., Verpillat P., Hannequin D., RA Dubois B., Saugier-Veber P., Martin C., Penet C., Charbonnier F., Agid Y., RA Frebourg T., Brice A.; RT "Segregation of a missense mutation in the microtubule-associated protein RT tau gene with familial frontotemporal dementia and parkinsonism."; RL Hum. Mol. Genet. 7:1825-1829(1998). RN [54] RP VARIANTS FTD1 VAL-589; LEU-618 AND TRP-723. RX PubMed=9641683; DOI=10.1038/31508; RA Hutton M., Lendon C.L., Rizzu P., Baker M., Froelich S., Houlden H., RA Pickering-Brown S., Chakraverty S., Isaacs A., Grover A., Hackett J., RA Adamson J., Lincoln S., Dickson D., Davies P., Petersen R.C., Stevens M., RA de Graaff E., Wauters E., van Baren J., Hillebrand M., Joosse M., RA Kwon J.M., Nowotny P., Che L.K., Norton J., Morris J.C., Reed L.A., RA Trojanowski J., Basun H., Lannfelt L., Neystat M., Fahn S., Dark F., RA Tannenberg T., Dodd P.R., Hayward N., Kwok J.B.J., Schofield P.R., RA Andreadis A., Snowden J., Craufurd D., Neary D., Owen F., Oostra B.A., RA Hardy J., Goate A., van Swieten J., Mann D., Lynch T., Heutink P.; RT "Association of missense and 5'-splice-site mutations in tau with the RT inherited dementia FTDP-17."; RL Nature 393:702-705(1998). RN [55] RP VARIANTS FTD1 LYS-596 AND LEU-618. RX PubMed=9789048; DOI=10.1073/pnas.95.22.13103; RA Clark L.N., Poorkaj P., Wszolek Z., Geschwind D.H., Nasreddine Z.S., RA Miller B., Li D., Payami H., Awert F., Markopoulou K., Andreadis A., RA D'Souza I., Lee V.M.-Y., Reed L., Trojanowski J.Q., Zhukareva V., Bird T., RA Schellenberg G., Wilhelmsen K.C.; RT "Pathogenic implications of mutations in the tau gene in pallido-ponto- RT nigral degeneration and related neurodegenerative disorders linked to RT chromosome 17."; RL Proc. Natl. Acad. Sci. U.S.A. 95:13103-13107(1998). RN [56] RP VARIANT PPND LYS-596. RX PubMed=10412802; DOI=10.1007/s004010051052; RA Delisle M.-B., Murrell J.R., Richardson R., Trofatter J.A., Rascol O., RA Soulages X., Mohr M., Calvas P., Ghetti B.; RT "A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a RT tauopathy with dementia and supranuclear palsy."; RL Acta Neuropathol. 98:62-77(1999). RN [57] RP VARIANTS FTD1 VAL-589; LYS-597 DEL; LEU-618 AND TRP-723. RX PubMed=9973279; DOI=10.1086/302256; RA Rizzu P., Van Swieten J.C., Joosse M., Hasegawa M., Stevens M., Tibben A., RA Niermeijer M.F., Hillebrand M., Ravid R., Oostra B.A., Goedert M., RA van Duijn C.M., Heutink P.; RT "High prevalence of mutations in the microtubule-associated protein tau in RT a population study of frontotemporal dementia in the Netherlands."; RL Am. J. Hum. Genet. 64:414-421(1999). RN [58] RP VARIANT FTD1 SER-618. RX PubMed=10553987; RX DOI=10.1002/1531-8249(199911)46:5<708::aid-ana5>3.0.co;2-k; RA Sperfeld A.D., Collatz M.B., Baier H., Palmbach M., Storch A., Schwarz J., RA Tatsch K., Reske S., Joosse M., Heutink P., Ludolph A.C.; RT "FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures RT caused by a novel mutation."; RL Ann. Neurol. 46:708-715(1999). RN [59] RP VARIANTS FTD1 LEU-618; MET-654 AND TRP-723. RX PubMed=10214944; DOI=10.1016/s0014-5793(99)00294-x; RA Nacharaju P., Lewis J., Easson C., Yen S., Hackett J., Hutton M., Yen S.H.; RT "Accelerated filament formation from tau protein with specific FTDP-17 RT missense mutations."; RL FEBS Lett. 447:195-199(1999). RN [60] RP VARIANT FTD1/CBD SER-618. RX PubMed=10374757; DOI=10.1097/00005072-199906000-00011; RA Bugiani O., Murrell J.R., Giaccone G., Hasegawa M., Ghigo G., Tabaton M., RA Morbin M., Primavera A., Carella F., Solaro C., Grisoli M., Savoiardo M., RA Spillantini M.G., Tagliavini F., Goedert M., Ghetti B.; RT "Frontotemporal dementia and corticobasal degeneration in a family with a RT P301S mutation in tau."; RL J. Neuropathol. Exp. Neurol. 58:667-677(1999). RN [61] RP VARIANT PIDB ARG-706. RX PubMed=10604746; DOI=10.1097/00005072-199912000-00002; RA Murrell J.R., Spillantini M.G., Zolo P., Guazzelli M., Smith M.J., RA Hasegawa M., Redi F., Crowther R.A., Pietrini P., Ghetti B., Goedert M.; RT "Tau gene mutation G389R causes a tauopathy with abundant pick body-like RT inclusions and axonal deposits."; RL J. Neuropathol. Exp. Neurol. 58:1207-1226(1999). RN [62] RP VARIANT FTD1 LYS-596. RX PubMed=10489057; DOI=10.1212/wnl.53.4.864; RA Yasuda M., Kawamata T., Komure O., Kuno S., D'Souza I., Poorkaj P., RA Kawai J., Tanimukai S., Yamamoto Y., Hasegawa H., Sasahara M., Hazama F., RA Schellenberg G.D., Tanaka C.; RT "A mutation in the microtubule-associated protein tau in pallido-nigro- RT luysian degeneration."; RL Neurology 53:864-868(1999). RN [63] RP VARIANTS PSNP1 ASN-285 AND ALA-289. RX PubMed=10534245; DOI=10.1212/wnl.53.7.1421; RA Higgins J.J., Adler R.L., Loveless J.M.; RT "Mutational analysis of the tau gene in progressive supranuclear palsy."; RL Neurology 53:1421-1424(1999). RN [64] RP VARIANT FTD1 ASN-622. RX PubMed=10208578; DOI=10.1097/00001756-199902250-00010; RA Iijima M., Tabira T., Poorkaj P., Schellenberg G.D., Trojanowski J.Q., RA Lee V.M.-Y., Schmidt M.L., Takahashi K., Nabika T., Matsumoto T., RA Yamashita Y., Yoshioka S., Ishino H.; RT "A distinct familial presenile dementia with a novel missense mutation in RT the tau gene."; RL NeuroReport 10:497-501(1999). RN [65] RP VARIANT FTD1 VAL-659. RX PubMed=11117541; RX DOI=10.1002/1531-8249(200012)48:6<850::aid-ana5>3.3.co;2-m; RA Lippa C.F., Zhukareva V., Kawarai T., Uryu K., Shafiq M., Nee L.E., RA Grafman J., Liang Y., St George-Hyslop P.H., Trojanowski J.Q., Lee V.M.-Y.; RT "Frontotemporal dementia with novel tau pathology and a Glu342Val tau RT mutation."; RL Ann. Neurol. 48:850-858(2000). RN [66] RP VARIANTS PIDB THR-574 AND ARG-706, AND CHARACTERIZATION OF VARIANTS PIDB RP THR-574 AND ARG-706. RX PubMed=11117542; RX DOI=10.1002/1531-8249(200012)48:6<859::aid-ana6>3.3.co;2-t; RA Pickering-Brown S., Baker M., Yen S.-H., Liu W.-K., Hasegawa M., Cairns N., RA Lantos P.L., Rossor M., Iwatsubo T., Davies Y., Allsop D., Furlong R., RA Owen F., Hardy J., Mann D., Hutton M.; RT "Pick's disease is associated with mutations in the tau gene."; RL Ann. Neurol. 48:859-867(2000). RN [67] RP VARIANT PIDB THR-574. RX PubMed=11089577; DOI=10.1093/jnen/59.11.990; RA Rizzini C., Goedert M., Hodges J.R., Smith M.J., Jakes R., Hills R., RA Xuereb J.H., Crowther R.A., Spillantini M.G.; RT "Tau gene mutation K257T causes a tauopathy similar to Pick's disease."; RL J. Neuropathol. Exp. Neurol. 59:990-1001(2000). RN [68] RP VARIANT FTD1 LYS-596. RX PubMed=10802785; DOI=10.1212/wnl.54.9.1787; RA Arima K., Kowalska A., Hasegawa M., Mukoyama M., Watanabe R., Kawai M., RA Takahashi K., Iwatsubo T., Tabira T., Sunohara N.; RT "Two brothers with frontotemporal dementia and parkinsonism with an N279K RT mutation of the tau gene."; RL Neurology 54:1787-1795(2000). RN [69] RP VARIANT FTD1 SER-618. RX PubMed=11071507; DOI=10.1212/wnl.55.8.1224; RA Yasuda M., Yokoyama K., Nakayasu T., Nishimura Y., Matsui M., Yokoyama T., RA Miyoshi K., Tanaka C.; RT "A Japanese patient with frontotemporal dementia and parkinsonism by a tau RT P301S mutation."; RL Neurology 55:1224-1227(2000). RN [70] RP VARIANT FTD1 HIS-613. RX PubMed=11585254; DOI=10.1007/s004010000333; RA Iseki E., Matsumura T., Marui W., Hino H., Odawara T., Sugiyama N., RA Suzuki K., Sawada H., Arai T., Kosaka K.; RT "Familial frontotemporal dementia and parkinsonism with a novel N296H RT mutation in exon 10 of the tau gene and a widespread tau accumulation in RT the glial cells."; RL Acta Neuropathol. 102:285-292(2001). RN [71] RP VARIANT PSNP1 ASN-613 DEL. RX PubMed=11220749; RX DOI=10.1002/1531-8249(20010201)49:2<263::aid-ana50>3.0.co;2-k; RA Pastor P., Pastor E., Carnero C., Vela R., Garcia T., Amer G., Tolosa E., RA Oliva R.; RT "Familial atypical progressive supranuclear palsy associated with RT homozygosity for the delN296 mutation in the tau gene."; RL Ann. Neurol. 49:263-267(2001). RN [72] RP VARIANT PIDB ILE-686, AND CHARACTERIZATION OF VARIANT PIDB ILE-686. RX PubMed=11601501; DOI=10.1002/ana.1223; RA Neumann M., Schulz-Schaeffer W., Crowther R.A., Smith M.J., RA Spillantini M.G., Goedert M., Kretzschmar H.A.; RT "Pick's disease associated with the novel Tau gene mutation K369I."; RL Ann. Neurol. 50:503-513(2001). RN [73] RP CHARACTERIZATION OF VARIANT FTD1 TRP-723. RX PubMed=11278002; DOI=10.1016/s0014-5793(01)02267-0; RA Connell J.W., Gibb G.M., Betts J.C., Blackstock W.P., Gallo J.-M., RA Lovestone S., Hutton M., Anderton B.H.; RT "Effects of FTDP-17 mutations on the in vitro phosphorylation of tau by RT glycogen synthase kinase 3beta identified by mass spectrometry demonstrate RT certain mutations exert long-range conformational changes."; RL FEBS Lett. 493:40-44(2001). RN [74] RP VARIANT FTD1 LYS-596. RX PubMed=12473774; DOI=10.1212/01.wnl.0000038909.49164.4b; RA Tsuboi Y., Baker M., Hutton M.L., Uitti R.J., Rascol O., Delisle M.-B., RA Soulages X., Murrell J.R., Ghetti B., Yasuda M., Komure O., Kuno S., RA Arima K., Sunohara N., Kobayashi T., Mizuno Y., Wszolek Z.K.; RT "Clinical and genetic studies of families with the tau N279K mutation RT (FTDP-17)."; RL Neurology 59:1791-1793(2002). RN [75] RP VARIANT PIDB PHE-637, AND CHARACTERIZATION OF VARIANT PIDB PHE-637. RX PubMed=11891833; DOI=10.1002/ana.10140; RA Rosso S.M., Van Herpen E., Deelen W., Kamphorst W., Severijnen L.-A., RA Willemsen R., Ravid R., Niermeijer M.F., Dooijes D., Smith M.J., RA Goedert M., Heutink P., Van Swieten J.C.; RT "A novel tau mutation, S320F, causes a tauopathy with inclusions similar to RT those in Pick's disease."; RL Ann. Neurol. 51:373-376(2002). RN [76] RP VARIANT FTD1 HIS-5, AND CHARACTERIZATION OF VARIANT FTD1 HIS-5. RX PubMed=11921059; DOI=10.1002/ana.10163; RA Hayashi S., Toyoshima Y., Hasegawa M., Umeda Y., Wakabayashi K., RA Tokiguchi S., Iwatsubo T., Takahashi H.; RT "Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene RT mutation."; RL Ann. Neurol. 51:525-530(2002). RN [77] RP VARIANT PSNP1 LEU-5, AND CHARACTERIZATION OF VARIANT PSNP1 LEU-5. RX PubMed=12325083; DOI=10.1002/ana.10340; RA Poorkaj P., Muma N.A., Zhukareva V., Cochran E.J., Shannon K.M., Hurtig H., RA Koller W.C., Bird T.D., Trojanowski J.Q., Lee V.M.-Y., Schellenberg G.D.; RT "An R5L tau mutation in a subject with a progressive supranuclear palsy RT phenotype."; RL Ann. Neurol. 52:511-516(2002). RN [78] RP CHARACTERIZATION OF VARIANTS FTD1 ASN-613 DEL AND HIS-613. RX PubMed=11906000; DOI=10.1046/j.0022-3042.2001.00729.x; RA Yoshida H., Crowther R.A., Goedert M.; RT "Functional effects of tau gene mutations deltaN296 and N296H."; RL J. Neurochem. 80:548-551(2002). RN [79] RP VARIANT FTD1 TRP-723. RX PubMed=11889249; DOI=10.1212/wnl.58.5.811; RA Saito Y., Geyer A., Sasaki R., Kuzuhara S., Nanba E., Miyasaka T., RA Suzuki K., Murayama S.; RT "Early-onset, rapidly progressive familial tauopathy with R406W mutation."; RL Neurology 58:811-813(2002). RN [80] RP VARIANT FTD1 VAL-583, AND CHARACTERIZATION OF VARIANT FTD1 VAL-583. RX PubMed=12509859; DOI=10.1002/ana.10447; RA Kobayashi T., Ota S., Tanaka K., Ito Y., Hasegawa M., Umeda Y., Motoi Y., RA Takanashi M., Yasuhara M., Anno M., Mizuno Y., Mori H.; RT "A novel L266V mutation of the tau gene causes frontotemporal dementia with RT a unique tau pathology."; RL Ann. Neurol. 53:133-137(2003). RN [81] RP VARIANT FATAL RESPIRATORY HYPOVENTILATION LEU-669, AND CHARACTERIZATION OF RP VARIANT FATAL RESPIRATORY HYPOVENTILATION LEU-669. RX PubMed=14595660; DOI=10.1002/ana.10747; RA Nicholl D.J., Greenstone M.A., Clarke C.E., Rizzu P., Crooks D., Crowe A., RA Trojanowski J.Q., Lee V.M.-Y., Heutink P.; RT "An English kindred with a novel recessive tauopathy and respiratory RT failure."; RL Ann. Neurol. 54:682-686(2003). RN [82] RP VARIANT FTD1/ALZHEIMER DISEASE TRP-723, AND INVOLVEMENT IN ALZHEIMER RP DISEASE. RX PubMed=14517953; DOI=10.1002/humu.10269; RA Rademakers R., Dermaut B., Peeters K., Cruts M., Heutink P., Goate A., RA Van Broeckhoven C.; RT "Tau (MAPT) mutation arg406trp presenting clinically with Alzheimer disease RT does not share a common founder in western Europe."; RL Hum. Mutat. 22:409-411(2003). RN [83] RP VARIANT ATYPICAL PSNP1 ASN-613 DEL. RX PubMed=14991829; DOI=10.1002/ana.20006; RA Rossi G., Gasparoli E., Pasquali C., Di Fede G., Testa D., Albanese A., RA Bracco F., Tagliavini F.; RT "Progressive supranuclear palsy and Parkinson's disease in a family with a RT new mutation in the tau gene."; RL Ann. Neurol. 55:448-448(2004). RN [84] RP VARIANT PSNP1/ATYPICAL PSNP1 ASN-613 DEL. RX PubMed=14991828; DOI=10.1002/ana.20025; RA Oliva R., Pastor P.; RT "Tau gene delN296 mutation, Parkinson's disease, and atypical supranuclear RT palsy."; RL Ann. Neurol. 55:448-449(2004). RN [85] RP VARIANT FTD1 SER-618. RX PubMed=16240366; DOI=10.1002/ana.20668; RA Yasuda M., Nakamura Y., Kawamata T., Kaneyuki H., Maeda K., Komure O.; RT "Phenotypic heterogeneity within a new family with the MAPT P301S RT mutation."; RL Ann. Neurol. 58:920-928(2005). RN [86] RP VARIANT PSNP1 VAL-620. RX PubMed=16157753; DOI=10.1001/archneur.62.9.1444; RA Ros R., Thobois S., Streichenberger N., Kopp N., Sanchez M.P., Perez M., RA Hoenicka J., Avila J., Honnorat J., de Yebenes J.G.; RT "A new mutation of the tau gene, G303V, in early-onset familial progressive RT supranuclear palsy."; RL Arch. Neurol. 62:1444-1450(2005). RN [87] RP VARIANT FTD1 MET-634. RX PubMed=15883319; DOI=10.1212/01.wnl.0000160116.65034.12; RA Zarranz J.J., Ferrer I., Lezcano E., Forcadas M.I., Eizaguirre B., RA Atares B., Puig B., Gomez-Esteban J.C., Fernandez-Maiztegui C., Rouco I., RA Perez-Concha T., Fernandez M., Rodriguez O., Rodriguez-Martinez A.B., RA de Pancorbo M.M., Pastor P., Perez-Tur J.; RT "A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron RT disease."; RL Neurology 64:1578-1585(2005). RN [88] RP VARIANTS MET-17; ALA-30 AND ILE-617. RX PubMed=20020531; DOI=10.1002/humu.21152; RA Guerreiro R.J., Washecka N., Hardy J., Singleton A.; RT "A thorough assessment of benign genetic variability in GRN and MAPT."; RL Hum. Mutat. 31:E1126-E1140(2010). RN [89] RP VARIANT FTD1/ALZHEIMER DISEASE TRP-723. RX PubMed=26086902; DOI=10.1016/j.gene.2015.06.033; RA Behnam M., Ghorbani F., Shin J.H., Kim D.S., Jang H., Nouri N., Sedghi M., RA Salehi M., Ansari B., Basiri K.; RT "Homozygous MAPT R406W mutation causing FTDP phenotype: A unique instance RT of a unique mutation."; RL Gene 570:150-152(2015). RN [90] RP VARIANT FTD1 ARG-590, CHARACTERIZATION OF VARIANT FTD1 ARG-590, AND RP FUNCTION. RX PubMed=32961270; DOI=10.1016/j.nbd.2020.105079; RA Sandberg A., Ling H., Gearing M., Dombroski B., Cantwell L., R'Bibo L., RA Levey A., Schellenberg G.D., Hardy J., Wood N., Fernius J., Nystroem S., RA Svensson S., Thor S., Hammarstroem P., Revesz T., Mok K.Y.; RT "Fibrillation and molecular characteristics are coherent with clinical and RT pathological features of 4-repeat tauopathy caused by MAPT variant G273R."; RL Neurobiol. Dis. 146:105079-105079(2020). CC -!- FUNCTION: Promotes microtubule assembly and stability, and might be CC involved in the establishment and maintenance of neuronal polarity CC (PubMed:21985311). The C-terminus binds axonal microtubules while the CC N-terminus binds neural plasma membrane components, suggesting that tau CC functions as a linker protein between both (PubMed:21985311, CC PubMed:32961270). Axonal polarity is predetermined by TAU/MAPT CC localization (in the neuronal cell) in the domain of the cell body CC defined by the centrosome. The short isoforms allow plasticity of the CC cytoskeleton whereas the longer isoforms may preferentially play a role CC in its stabilization. {ECO:0000269|PubMed:21985311, CC ECO:0000269|PubMed:32961270}. CC -!- SUBUNIT: Interacts with MARK1, MARK2, MARK3 and MARK4 CC (PubMed:23666762). Interacts with PSMC2 through SQSTM1 (By similarity). CC Interacts with SQSTM1 when polyubiquitinated (PubMed:15953362). CC Interacts with FKBP4 (By similarity). Binds to CSNK1D CC (PubMed:14761950). Interacts with SGK1 (PubMed:16982696). Interacts CC with EPM2A; the interaction dephosphorylates MAPT at Ser-396 CC (PubMed:19542233). Interacts with PIN1 (PubMed:11313338). Interacts CC with LRRK2 (PubMed:26014385). Interacts with LRP1, leading to CC endocytosis; this interaction is reduced in the presence of LRPAP1/RAP CC (PubMed:32296178). {ECO:0000250|UniProtKB:P10637, CC ECO:0000250|UniProtKB:P19332, ECO:0000269|PubMed:11313338, CC ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:15953362, CC ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:19542233, CC ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:26014385, CC ECO:0000269|PubMed:32296178}. CC -!- INTERACTION: CC P10636; P31749: AKT1; NbExp=2; IntAct=EBI-366182, EBI-296087; CC P10636; PRO_0000001987 [P02649]: APOE; NbExp=3; IntAct=EBI-366182, EBI-9209835; CC P10636; P05067: APP; NbExp=8; IntAct=EBI-366182, EBI-77613; CC P10636; PRO_0000000092 [P05067]: APP; NbExp=5; IntAct=EBI-366182, EBI-821758; CC P10636; Q9HC96: CAPN10; NbExp=3; IntAct=EBI-366182, EBI-3915761; CC P10636; Q9NR30: DDX21; NbExp=3; IntAct=EBI-366182, EBI-357942; CC P10636; O43583: DENR; NbExp=2; IntAct=EBI-366182, EBI-716083; CC P10636; Q92608-2: DOCK2; NbExp=3; IntAct=EBI-366182, EBI-25875570; CC P10636; P06241: FYN; NbExp=3; IntAct=EBI-366182, EBI-515315; CC P10636; P49841: GSK3B; NbExp=4; IntAct=EBI-366182, EBI-373586; CC P10636; P11142: HSPA8; NbExp=6; IntAct=EBI-366182, EBI-351896; CC P10636; Q8TCE9: LGALS14; NbExp=3; IntAct=EBI-366182, EBI-10274069; CC P10636; Q9UPY8: MAPRE3; NbExp=3; IntAct=EBI-366182, EBI-726739; CC P10636; P10636: MAPT; NbExp=3; IntAct=EBI-366182, EBI-366182; CC P10636; P04156: PRNP; NbExp=2; IntAct=EBI-366182, EBI-977302; CC P10636; P46779: RPL28; NbExp=4; IntAct=EBI-366182, EBI-366357; CC P10636; P43004: SLC1A2; NbExp=4; IntAct=EBI-366182, EBI-3440986; CC P10636; Q9UNE7: STUB1; NbExp=2; IntAct=EBI-366182, EBI-357085; CC P10636; Q9UNE7-1: STUB1; NbExp=5; IntAct=EBI-366182, EBI-15687717; CC P10636; O15195-2: VILL; NbExp=3; IntAct=EBI-366182, EBI-21845957; CC P10636; P63104: YWHAZ; NbExp=8; IntAct=EBI-366182, EBI-347088; CC P10636; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-366182, EBI-25850811; CC P10636-2; P06241: FYN; NbExp=2; IntAct=EBI-7796412, EBI-515315; CC P10636-2; Q5S007: LRRK2; NbExp=3; IntAct=EBI-7796412, EBI-5323863; CC P10636-2; P31947: SFN; NbExp=2; IntAct=EBI-7796412, EBI-476295; CC P10636-2; P63104: YWHAZ; NbExp=2; IntAct=EBI-7796412, EBI-347088; CC P10636-3; P63104: YWHAZ; NbExp=9; IntAct=EBI-7145070, EBI-347088; CC P10636-5; P06241: FYN; NbExp=2; IntAct=EBI-21313635, EBI-515315; CC P10636-6; P02649: APOE; NbExp=3; IntAct=EBI-7796455, EBI-1222467; CC P10636-6; Q14203-5: DCTN1; NbExp=3; IntAct=EBI-7796455, EBI-25840379; CC P10636-6; Q92608-2: DOCK2; NbExp=3; IntAct=EBI-7796455, EBI-25875570; CC P10636-6; P06241: FYN; NbExp=3; IntAct=EBI-7796455, EBI-515315; CC P10636-6; P11142: HSPA8; NbExp=3; IntAct=EBI-7796455, EBI-351896; CC P10636-6; O60260-5: PRKN; NbExp=3; IntAct=EBI-7796455, EBI-21251460; CC P10636-6; P37840: SNCA; NbExp=3; IntAct=EBI-7796455, EBI-985879; CC P10636-6; Q9C0A1: ZFHX2; NbExp=3; IntAct=EBI-7796455, EBI-25850811; CC P10636-7; O00499-1: BIN1; NbExp=5; IntAct=EBI-6926270, EBI-6926280; CC P10636-8; P07355: ANXA2; NbExp=10; IntAct=EBI-366233, EBI-352622; CC P10636-8; P08133: ANXA6; NbExp=5; IntAct=EBI-366233, EBI-352541; CC P10636-8; P05067: APP; NbExp=4; IntAct=EBI-366233, EBI-77613; CC P10636-8; O00499-1: BIN1; NbExp=6; IntAct=EBI-366233, EBI-6926280; CC P10636-8; Q14203: DCTN1; NbExp=9; IntAct=EBI-366233, EBI-724352; CC P10636-8; P26196: DDX6; NbExp=10; IntAct=EBI-366233, EBI-351257; CC P10636-8; Q02790: FKBP4; NbExp=7; IntAct=EBI-366233, EBI-1047444; CC P10636-8; Q13451: FKBP5; NbExp=8; IntAct=EBI-366233, EBI-306914; CC P10636-8; P06241: FYN; NbExp=9; IntAct=EBI-366233, EBI-515315; CC P10636-8; P49840: GSK3A; NbExp=2; IntAct=EBI-366233, EBI-1044067; CC P10636-8; P49841: GSK3B; NbExp=12; IntAct=EBI-366233, EBI-373586; CC P10636-8; P08238: HSP90AB1; NbExp=18; IntAct=EBI-366233, EBI-352572; CC P10636-8; P14625: HSP90B1; NbExp=5; IntAct=EBI-366233, EBI-359129; CC P10636-8; Q92743: HTRA1; NbExp=9; IntAct=EBI-366233, EBI-352256; CC P10636-8; Q5S007: LRRK2; NbExp=9; IntAct=EBI-366233, EBI-5323863; CC P10636-8; P10636-8: MAPT; NbExp=6; IntAct=EBI-366233, EBI-366233; CC P10636-8; O43347: MSI1; NbExp=2; IntAct=EBI-366233, EBI-726515; CC P10636-8; Q96DH6: MSI2; NbExp=4; IntAct=EBI-366233, EBI-2462339; CC P10636-8; P07237: P4HB; NbExp=6; IntAct=EBI-366233, EBI-395883; CC P10636-8; Q12765: SCRN1; NbExp=5; IntAct=EBI-366233, EBI-2690712; CC P10636-8; P31947: SFN; NbExp=10; IntAct=EBI-366233, EBI-476295; CC P10636-8; P37840: SNCA; NbExp=12; IntAct=EBI-366233, EBI-985879; CC P10636-8; Q71U36: TUBA1A; NbExp=7; IntAct=EBI-366233, EBI-302552; CC P10636-8; P07437: TUBB; NbExp=4; IntAct=EBI-366233, EBI-350864; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:10747907, CC ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:26014385}. Cell CC membrane {ECO:0000269|PubMed:10747907}; Peripheral membrane protein CC {ECO:0000269|PubMed:10747907}; Cytoplasmic side CC {ECO:0000269|PubMed:10747907}. Cytoplasm, cytoskeleton CC {ECO:0000269|PubMed:10747907}. Cell projection, axon CC {ECO:0000269|PubMed:10747907}. Cell projection, dendrite CC {ECO:0000269|PubMed:23666762}. Secreted {ECO:0000269|PubMed:32272059}. CC Note=Mostly found in the axons of neurons, in the cytosol and in CC association with plasma membrane components (PubMed:10747907). Can be CC secreted; the secretion is dependent on protein unfolding and CC facilitated by the cargo receptor TMED10; it results in protein CC translocation from the cytoplasm into the ERGIC (endoplasmic reticulum- CC Golgi intermediate compartment) followed by vesicle entry and secretion CC (PubMed:32272059). {ECO:0000269|PubMed:10747907, CC ECO:0000269|PubMed:32272059}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=9; CC Comment=Additional isoforms seem to exist. Isoforms differ from each CC other by the presence or absence of up to 5 of the 15 exons. One of CC these optional exons contains the additional tau/MAP repeat.; CC Name=PNS-tau; CC IsoId=P10636-1; Sequence=Displayed; CC Name=Fetal-tau; Synonyms=0N3R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-2; Sequence=VSP_003176, VSP_003177, VSP_003179, CC VSP_003180, VSP_003181; CC Name=Tau-A; CC IsoId=P10636-3; Sequence=VSP_003175, VSP_003176, VSP_003177, CC VSP_003178, VSP_003179, VSP_003180, CC VSP_003181; CC Name=Tau-B; Synonyms=1N3R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-4; Sequence=VSP_003177, VSP_003179, VSP_003180, CC VSP_003181; CC Name=Tau-C; Synonyms=Tau-3, 2N3R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-5; Sequence=VSP_003179, VSP_003180, VSP_003181; CC Name=Tau-D; Synonyms=0N4R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-6; Sequence=VSP_003176, VSP_003177, VSP_003179, CC VSP_003180; CC Name=Tau-E; Synonyms=1N4R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-7; Sequence=VSP_003177, VSP_003179, VSP_003180; CC Name=Tau-F; Synonyms=Tau-4, 2N4R {ECO:0000303|PubMed:9789048}; CC IsoId=P10636-8; Sequence=VSP_003179, VSP_003180; CC Name=Tau-G; CC IsoId=P10636-9; Sequence=VSP_026780; CC -!- TISSUE SPECIFICITY: Expressed in neurons. Isoform PNS-tau is expressed CC in the peripheral nervous system while the others are expressed in the CC central nervous system. CC -!- DEVELOPMENTAL STAGE: Four-repeat (type II) TAU/MAPT is expressed in an CC adult-specific manner and is not found in fetal brain, whereas three- CC repeat (type I) TAU/MAPT is found in both adult and fetal brain. CC -!- DOMAIN: The tau/MAP repeat binds to tubulin. Type I isoforms contain 3 CC repeats while type II isoforms contain 4 repeats. CC -!- PTM: Phosphorylation at serine and threonine residues in S-P or T-P CC motifs by proline-directed protein kinases (PDPK1, CDK1, CDK5, GSK3, CC MAPK) (only 2-3 sites per protein in interphase, seven-fold increase in CC mitosis, and in the form associated with paired helical filaments (PHF- CC tau)), and at serine residues in K-X-G-S motifs by MAP/microtubule CC affinity-regulating kinase (MARK1, MARK2, MARK3 or MARK4), causing CC detachment from microtubules, and their disassembly (PubMed:23666762, CC PubMed:7706316). Phosphorylation decreases with age. Phosphorylation CC within tau/MAP's repeat domain or in flanking regions seems to reduce CC tau/MAP's interaction with, respectively, microtubules or plasma CC membrane components (PubMed:7706316). Phosphorylation on Ser-610, Ser- CC 622, Ser-641 and Ser-673 in several isoforms during mitosis. CC Phosphorylation at Ser-548 by GSK3B reduces ability to bind and CC stabilize microtubules. Phosphorylation at Ser-579 by BRSK1 and BRSK2 CC in neurons affects ability to bind microtubules and plays a role in CC neuron polarization. Phosphorylated at Ser-554, Ser-579, Ser-602, Ser- CC 606 and Ser-669 by PHK. Phosphorylation at Ser-214 by SGK1 mediates CC microtubule depolymerization and neurite formation in hippocampal CC neurons. There is a reciprocal down-regulation of phosphorylation and CC O-GlcNAcylation. Phosphorylation on Ser-717 completely abolishes the O- CC GlcNAcylation on this site, while phosphorylation on Ser-713 and Ser- CC 721 reduces glycosylation by a factor of 2 and 4 respectively. CC Phosphorylation on Ser-721 is reduced by about 41.5% by GlcNAcylation CC on Ser-717. Dephosphorylated at several serine and threonine residues CC by the serine/threonine phosphatase PPP5C. CC {ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:14761950, CC ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603, CC ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:19451179, CC ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:21985311, CC ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:7706316, CC ECO:0000269|PubMed:8999860, ECO:0000269|PubMed:9614189}. CC -!- PTM: Polyubiquitinated. Requires functional TRAF6 and may provoke CC SQSTM1-dependent degradation by the proteasome (By similarity). PHF-tau CC can be modified by three different forms of polyubiquitination. 'Lys- CC 48'-linked polyubiquitination is the major form, 'Lys-6'-linked and CC 'Lys-11'-linked polyubiquitination also occur. {ECO:0000250, CC ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16443603}. CC -!- PTM: O-glycosylated. O-GlcNAcylation content is around 8.2%. There is CC reciprocal down-regulation of phosphorylation and O-GlcNAcylation. CC Phosphorylation on Ser-717 completely abolishes the O-GlcNAcylation on CC this site, while phosphorylation on Ser-713 and Ser-721 reduces O- CC GlcNAcylation by a factor of 2 and 4 respectively. O-GlcNAcylation on CC Ser-717 decreases the phosphorylation on Ser-721 by about 41.5%. CC {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:15546861, CC ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179, CC ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189}. CC -!- PTM: Glycation of PHF-tau, but not normal brain TAU/MAPT. Glycation is CC a non-enzymatic post-translational modification that involves a CC covalent linkage between a sugar and an amino group of a protein CC molecule forming ketoamine. Subsequent oxidation, fragmentation and/or CC cross-linking of ketoamine leads to the production of advanced CC glycation endproducts (AGES). Glycation may play a role in stabilizing CC PHF aggregation leading to tangle formation in AD. CC -!- DISEASE: Note=In Alzheimer disease, the neuronal cytoskeleton in the CC brain is progressively disrupted and replaced by tangles of paired CC helical filaments (PHF) and straight filaments, mainly composed of CC hyperphosphorylated forms of TAU (PHF-TAU or AD P-TAU). O-GlcNAcylation CC is greatly reduced in Alzheimer disease brain cerebral cortex leading CC to an increase in TAU/MAPT phosphorylations. CC {ECO:0000269|PubMed:14517953, ECO:0000269|PubMed:26086902}. CC -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. In some cases, parkinsonian CC symptoms are prominent. Neuropathological changes include CC frontotemporal atrophy often associated with atrophy of the basal CC ganglia, substantia nigra, amygdala. In most cases, protein tau CC deposits are found in glial cells and/or neurons. CC {ECO:0000269|PubMed:10208578, ECO:0000269|PubMed:10214944, CC ECO:0000269|PubMed:10374757, ECO:0000269|PubMed:10489057, CC ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:10802785, CC ECO:0000269|PubMed:11071507, ECO:0000269|PubMed:11117541, CC ECO:0000269|PubMed:11278002, ECO:0000269|PubMed:11585254, CC ECO:0000269|PubMed:11889249, ECO:0000269|PubMed:11906000, CC ECO:0000269|PubMed:11921059, ECO:0000269|PubMed:12473774, CC ECO:0000269|PubMed:12509859, ECO:0000269|PubMed:14517953, CC ECO:0000269|PubMed:15883319, ECO:0000269|PubMed:16240366, CC ECO:0000269|PubMed:26086902, ECO:0000269|PubMed:32961270, CC ECO:0000269|PubMed:9629852, ECO:0000269|PubMed:9641683, CC ECO:0000269|PubMed:9736786, ECO:0000269|PubMed:9789048, CC ECO:0000269|PubMed:9973279}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of CC dementia pathologically defined by severe atrophy, neuronal loss and CC gliosis. It is characterized by the occurrence of tau-positive CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal CC inclusions known as Pick bodies that disproportionally affect the CC frontal and temporal cortical regions. Clinical features include CC aphasia, apraxia, confusion, anomia, memory loss and personality CC deterioration. {ECO:0000269|PubMed:10604746, CC ECO:0000269|PubMed:11089577, ECO:0000269|PubMed:11117542, CC ECO:0000269|PubMed:11601501, ECO:0000269|PubMed:11891833}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Note=Defects in MAPT are a cause of corticobasal degeneration CC (CBD). It is marked by extrapyramidal signs and apraxia and can be CC associated with memory loss. Neuropathologic features may overlap CC Alzheimer disease, progressive supranuclear palsy, and Parkinson CC disease. CC -!- DISEASE: Progressive supranuclear palsy 1 (PSNP1) [MIM:601104]: CC Characterized by akinetic-rigid syndrome, supranuclear gaze palsy, CC pyramidal tract dysfunction, pseudobulbar signs and cognitive CC capacities deterioration. Neurofibrillary tangles and gliosis but no CC amyloid plaques are found in diseased brains. Most cases appear to be CC sporadic, with a significant association with a common haplotype CC including the MAPT gene and the flanking regions. Familial cases show CC an autosomal dominant pattern of transmission with incomplete CC penetrance; genetic analysis of a few cases showed the occurrence of CC tau mutations, including a deletion of Asn-613. CC {ECO:0000269|PubMed:10534245, ECO:0000269|PubMed:11220749, CC ECO:0000269|PubMed:12325083, ECO:0000269|PubMed:14991828, CC ECO:0000269|PubMed:14991829, ECO:0000269|PubMed:16157753}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson-dementia syndrome (PARDE) [MIM:260540]: A syndrome CC characterized by parkinsonism, tremor, rigidity, dementia, CC ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration CC occurs in the hippocampus, basal ganglia and brainstem nuclei. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- WEB RESOURCE: Name=Alzforum; Note=MAPT mutations; CC URL="https://www.alzforum.org/mutations/mapt"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Vita minima - Issue 68 of CC March 2006; CC URL="https://www.proteinspotlight.org/back_issues/068"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tau protein entry; CC URL="https://en.wikipedia.org/wiki/Tau_protein"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J03778; AAA60615.1; -; mRNA. DR EMBL; X14474; CAA32636.1; -; mRNA. DR EMBL; AF047863; AAC04277.1; -; Genomic_DNA. DR EMBL; AF027491; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047856; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047857; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027492; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047858; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027493; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047859; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047860; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF047862; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027494; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027495; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027496; AAC04277.1; JOINED; Genomic_DNA. DR EMBL; AF027491; AAC04278.1; -; Genomic_DNA. DR EMBL; AF027492; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027493; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF047860; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF047862; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027495; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027496; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF047863; AAC04278.1; JOINED; Genomic_DNA. DR EMBL; AF027491; AAC04279.1; -; Genomic_DNA. DR EMBL; AF047856; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047857; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027492; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027493; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047860; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047862; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027494; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027495; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF027496; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047863; AAC04279.1; JOINED; Genomic_DNA. DR EMBL; AF047861; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AY730549; AAU45390.1; -; mRNA. DR EMBL; BT006772; AAP35418.1; -; mRNA. DR EMBL; AC004139; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC010792; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC217771; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC217779; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC000558; AAH00558.1; -; mRNA. DR EMBL; BC098281; AAH98281.1; -; mRNA. DR EMBL; BC099721; AAH99721.1; -; mRNA. DR EMBL; BC101936; AAI01937.1; -; mRNA. DR EMBL; BC114504; AAI14505.1; -; mRNA. DR EMBL; BC114948; AAI14949.1; -; mRNA. DR EMBL; AY526356; AAS17881.1; -; mRNA. DR EMBL; M25298; AAA57264.1; -; mRNA. DR EMBL; BN000503; CAG26750.1; -; mRNA. DR CCDS; CCDS11499.1; -. [P10636-8] DR CCDS; CCDS11500.1; -. [P10636-6] DR CCDS; CCDS11501.1; -. [P10636-1] DR CCDS; CCDS11502.1; -. [P10636-2] DR CCDS; CCDS45715.1; -. [P10636-9] DR CCDS; CCDS45716.1; -. [P10636-7] DR CCDS; CCDS56033.1; -. [P10636-5] DR CCDS; CCDS92347.1; -. [P10636-4] DR PIR; I52232; I52232. DR PIR; JS0370; QRHUT1. DR PIR; PN0001; QRHUT2. DR PIR; S26663; S26663. DR RefSeq; NP_001116538.2; NM_001123066.4. [P10636-9] DR RefSeq; NP_001116539.1; NM_001123067.4. [P10636-7] DR RefSeq; NP_001190180.1; NM_001203251.2. [P10636-4] DR RefSeq; NP_001190181.1; NM_001203252.2. [P10636-5] DR RefSeq; NP_001364197.1; NM_001377268.1. [P10636-2] DR RefSeq; NP_005901.2; NM_005910.5. [P10636-8] DR RefSeq; NP_058518.1; NM_016834.5. [P10636-6] DR RefSeq; NP_058519.3; NM_016835.5. [P10636-1] DR RefSeq; NP_058525.1; NM_016841.5. [P10636-2] DR PDB; 1I8H; NMR; -; A=542-554. DR PDB; 2MZ7; NMR; -; A=584-629. DR PDB; 2ON9; X-ray; 1.51 A; A/B=623-628. DR PDB; 3OVL; X-ray; 1.81 A; A=623-628. DR PDB; 4E0M; X-ray; 1.75 A; A/B/C/D=622-634. DR PDB; 4E0N; X-ray; 1.65 A; A/B/C/D=622-634. DR PDB; 4E0O; X-ray; 1.82 A; A/B/C/D=622-634. DR PDB; 4FL5; X-ray; 1.90 A; P/Q=527-536. DR PDB; 4GLR; X-ray; 1.90 A; A/B=541-557. DR PDB; 4NP8; X-ray; 1.51 A; A=623-628. DR PDB; 4TQE; X-ray; 1.60 A; A=532-547. DR PDB; 4Y32; X-ray; 1.70 A; C/D=528-534. DR PDB; 4Y5I; X-ray; 1.40 A; F/G=528-534. DR PDB; 5DMG; X-ray; 2.50 A; P/X/Z=733-747. DR PDB; 5E2V; X-ray; 1.64 A; P=511-528. DR PDB; 5E2W; X-ray; 1.50 A; P=511-528. DR PDB; 5HF3; X-ray; 1.80 A; B=528-534. DR PDB; 5K7N; EM; 1.10 A; Z=623-628. DR PDB; 5MO3; X-ray; 1.69 A; A=615-628. DR PDB; 5MP1; X-ray; 3.10 A; A/B/E/I=615-628. DR PDB; 5MP3; X-ray; 2.75 A; C/D=609-638. DR PDB; 5MP5; X-ray; 2.31 A; I/J/K=615-628. DR PDB; 5N5A; NMR; -; A=571-607. DR PDB; 5N5B; NMR; -; A=609-636. DR PDB; 5NVB; NMR; -; A=571-585. DR PDB; 5O3L; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 5O3O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 5O3T; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 5V5B; EM; 1.50 A; A=591-600. DR PDB; 5V5C; EM; 1.25 A; A=592-597. DR PDB; 5ZIA; X-ray; 2.60 A; C/F/J/N/Q/R=552-560. DR PDB; 5ZV3; X-ray; 2.09 A; A=52-71. DR PDB; 6BB4; X-ray; 2.10 A; P/Q/R=703-725. DR PDB; 6CVJ; EM; 3.20 A; D=514-717. DR PDB; 6CVN; EM; 3.90 A; D=514-717. DR PDB; 6DC8; X-ray; 1.80 A; P=696-725. DR PDB; 6DC9; X-ray; 3.00 A; P/Q=696-725. DR PDB; 6DCA; X-ray; 2.60 A; P/Q/R/S=696-725. DR PDB; 6FBW; X-ray; 1.45 A; B/D=528-533. DR PDB; 6FI5; X-ray; 1.70 A; B=529-533. DR PDB; 6GK7; X-ray; 2.95 A; A=625-635. DR PDB; 6GK8; X-ray; 2.85 A; I=52-71. DR PDB; 6GX5; EM; 3.20 A; A/B/C=602-695. DR PDB; 6H06; X-ray; 2.63 A; G/I/J/K=721-746. DR PDB; 6HRE; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 6HRF; EM; 3.30 A; A/B/C/D/E/F=1-758. DR PDB; 6LRA; X-ray; 1.90 A; C=592-597. DR PDB; 6N4P; X-ray; 1.85 A; A/C=5-10. DR PDB; 6NK4; EM; 1.99 A; A=591-599. DR PDB; 6NWP; EM; 2.30 A; A/B/C/D/E/F=1-758. DR PDB; 6NWQ; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 6ODG; X-ray; 1.00 A; A/B=622-627. DR PDB; 6PXR; X-ray; 1.56 A; A=15-22. DR PDB; 6QJH; EM; 3.30 A; A/B/C=589-647. DR PDB; 6QJM; EM; 3.30 A; A/B/C=591-638. DR PDB; 6QJP; EM; 3.50 A; A/B/C=591-638. DR PDB; 6QJQ; EM; 3.70 A; A/B/C/D/E/F=620-647. DR PDB; 6TJO; EM; 3.20 A; A/B/C=1-758. DR PDB; 6TJX; EM; 3.00 A; A/B/C/D/E/F=1-758. DR PDB; 6VH7; EM; 3.80 A; A/B/C/E/F/G=591-697. DR PDB; 6VHA; EM; 4.30 A; E/F/G=591-697. DR PDB; 6VHL; EM; 3.30 A; E/F=621-697. DR PDB; 6VI3; EM; 3.30 A; E/F=621-697. DR PDB; 6XLI; X-ray; 2.00 A; E/F/P=527-539. DR PDB; 7EYC; X-ray; 2.49 A; P/Q=594-601. DR PDB; 7KQK; X-ray; 2.60 A; C/P=541-550. DR PDB; 7MKF; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7MKG; EM; 3.07 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7MKH; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRQ; EM; 2.76 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRS; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRT; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRV; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7NRX; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P65; EM; 2.70 A; A/B/C/D/E=1-758. DR PDB; 7P66; EM; 3.00 A; A/B/C/D/E=1-758. DR PDB; 7P67; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P68; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P6A; EM; 1.90 A; A/B/C/D/E=1-758. DR PDB; 7P6B; EM; 2.20 A; A/B/C/D/E=1-758. DR PDB; 7P6C; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7P6D; EM; 3.30 A; A/B/C/D/E=1-758. DR PDB; 7P6E; EM; 3.40 A; A/B/C/D/E/F/I/J/Q/R=1-758. DR PDB; 7PQC; EM; 4.10 A; O=519-712. DR PDB; 7PQP; EM; 4.10 A; O=519-712. DR PDB; 7QJV; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758. DR PDB; 7QJW; EM; 2.81 A; A/B/C/D/E/F=1-758. DR PDB; 7QJX; EM; 2.99 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758. DR PDB; 7QJY; EM; 3.14 A; A/B/C/D/E/F=1-758. DR PDB; 7QJZ; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 7QK1; EM; 3.03 A; A/B/C/D/E/F=1-758. DR PDB; 7QK2; EM; 2.61 A; A/B/C/D/E/F=1-758. DR PDB; 7QK3; EM; 2.44 A; A/B/C=1-758. DR PDB; 7QK5; EM; 1.92 A; A/B/C/D/E/F/G/H/K=1-758. DR PDB; 7QK6; EM; 2.27 A; A/B/C=1-758. DR PDB; 7QKF; EM; 2.83 A; A/B/C/D/E/F=1-758. DR PDB; 7QKG; EM; 3.36 A; A/B/C=1-758. DR PDB; 7QKH; EM; 3.17 A; A/B/C/D/E/G=1-758. DR PDB; 7QKI; EM; 3.13 A; A/B/C/D/E/F=1-758. DR PDB; 7QKJ; EM; 3.26 A; A/B/C/D/E/F/G/H/I/J/K/L=1-758. DR PDB; 7QKK; EM; 2.80 A; A/B/C=1-758. DR PDB; 7QKL; EM; 2.07 A; A/B/C/D/E/F=1-758. DR PDB; 7QKM; EM; 2.66 A; A/B/C/D/E/F=1-758. DR PDB; 7QKU; EM; 2.57 A; A/B/C/D/E/F=1-758. DR PDB; 7QKV; EM; 3.23 A; A/B/C/D/E/F/G/H/I=1-758. DR PDB; 7QKW; EM; 2.32 A; A/B/C/D/E/F=1-758. DR PDB; 7QKX; EM; 3.16 A; A/B/C/D/E/G=1-758. DR PDB; 7QKY; EM; 1.86 A; A/B/C/D/E/F=1-758. DR PDB; 7QKZ; EM; 2.65 A; A/B/C/D/E/F/G/H/I=1-758. DR PDB; 7QL0; EM; 3.13 A; A/B/C/D/E/c=1-758. DR PDB; 7QL1; EM; 3.34 A; A/C/D=1-758. DR PDB; 7QL2; EM; 2.95 A; A/B/C=1-758. DR PDB; 7QL3; EM; 3.32 A; A/B/C/D/E/F=1-758. DR PDB; 7QL4; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 7R4T; EM; 2.75 A; A/B/C/D/E/F=1-758. DR PDB; 7R5H; EM; 2.59 A; A/B/C/D/E/F=1-758. DR PDB; 7SP1; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=1-758. DR PDB; 7U0Z; EM; 4.20 A; A/B/C=589-698. DR PDB; 7UPE; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7UPF; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7UPG; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 7YMN; EM; 3.46 A; A/B/C/D/E/F=614-708. DR PDB; 7YPG; EM; 2.50 A; A/B/C/D/E/F=614-708. DR PDB; 8AZU; EM; 3.10 A; C=1-758. DR PDB; 8BGS; EM; 3.16 A; A/B/C/D/E/F/r=1-758. DR PDB; 8BGV; EM; 3.27 A; A/B/C/D/E/F/n=1-758. DR PDB; 8BYN; EM; 2.60 A; A/B/C/D/E/F=1-758. DR PDB; 8CAQ; EM; 2.30 A; A/B/C/D/E=1-758. DR PDB; 8CAX; EM; 3.70 A; A/B/C/D/E/F=1-758. DR PDB; 8FNZ; EM; 3.88 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/a/b/c/d/e/f=580-597. DR PDB; 8FUG; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W=623-695. DR PDB; 8FYU; X-ray; 1.85 A; C/E=729-738. DR PDB; 8G54; NMR; -; A/B/C/D/E=515-716. DR PDB; 8G55; NMR; -; A/B/C/D/E/F/G/H/I/J=515-716. DR PDB; 8G58; NMR; -; A/B/C/D/E/F/G/H/I/J=614-708. DR PDB; 8GCK; X-ray; 1.37 A; C/E=733-738. DR PDB; 8KDX; X-ray; 1.01 A; B=524-538. DR PDB; 8OH2; EM; 2.60 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b/c/d=666-680. DR PDB; 8OHI; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=667-679. DR PDB; 8OHP; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X=667-679. DR PDB; 8OI0; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X=667-679. DR PDB; 8OP0; X-ray; 1.54 A; B=618-629. DR PDB; 8OPI; X-ray; 1.83 A; B=618-629. DR PDB; 8ORE; EM; 2.50 A; A/B/C=404-758. DR PDB; 8ORF; EM; 2.50 A; A/B/C=404-758. DR PDB; 8ORG; EM; 2.30 A; A/B/C=404-758. DR PDB; 8OT6; EM; 2.00 A; A/B/C/D/E=1-758. DR PDB; 8OT9; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 8OTC; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 8OTG; EM; 2.10 A; A/B/C/D/E=1-758. DR PDB; 8OTH; EM; 3.40 A; A/B/C/D/E=1-758. DR PDB; 8OTI; EM; 2.70 A; A/B/C/D/E/F=1-758. DR PDB; 8OTJ; EM; 3.30 A; A/B/C/D/E/F/G=1-758. DR PDB; 8P34; EM; 2.61 A; A=602-695. DR PDB; 8PII; X-ray; 2.35 A; B=618-631. DR PDB; 8PPO; EM; 2.00 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=1-758. DR PDB; 8Q27; EM; 2.02 A; A/B/C/D/E/F=427-758. DR PDB; 8Q2J; EM; 2.23 A; A/B/C/D/E/F=427-758. DR PDB; 8Q2K; EM; 2.88 A; A/B/C/D/E/F=427-758. DR PDB; 8Q2L; EM; 2.20 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7F; EM; 3.72 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7L; EM; 2.82 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7M; EM; 3.26 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q7P; EM; 3.28 A; A/B/C/D/E/F=427-758. DR PDB; 8Q7T; EM; 3.00 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q88; EM; 2.95 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8C; EM; 1.92 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8D; EM; 3.04 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8E; EM; 3.81 A; A/B/C/D/E/F/G/H/I/J/K/L=427-758. DR PDB; 8Q8F; EM; 2.93 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8L; EM; 3.04 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8M; EM; 2.95 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8R; EM; 2.10 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8S; EM; 2.68 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q8U; EM; 3.30 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8V; EM; 3.80 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8W; EM; 2.85 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8X; EM; 2.54 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8Y; EM; 2.88 A; A/B/C/D/E/F=427-758. DR PDB; 8Q8Z; EM; 3.16 A; A/B/C/D/E/F=427-758. DR PDB; 8Q92; EM; 3.05 A; A/B/C=588-681. DR PDB; 8Q97; EM; 2.99 A; A/B/C/D/E/F=427-758. DR PDB; 8Q98; EM; 1.75 A; A/B/C/D/E/F=427-758. DR PDB; 8Q99; EM; 2.70 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9A; EM; 3.04 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9B; EM; 3.10 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9C; EM; 3.40 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9D; EM; 3.16 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9E; EM; 2.97 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9F; EM; 1.91 A; A/B/C/D/E/c=427-758. DR PDB; 8Q9G; EM; 2.65 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9H; EM; 2.18 A; A/B/C/D/E/G=427-758. DR PDB; 8Q9I; EM; 2.56 A; A/C/E=427-758. DR PDB; 8Q9J; EM; 2.96 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9K; EM; 3.20 A; A/B/C/D/E/F=427-758. DR PDB; 8Q9L; EM; 2.76 A; A/B/C/D/E/F/G/H/I=427-758. DR PDB; 8Q9M; EM; 2.65 A; A/B/C/D/E/G=427-758. DR PDB; 8Q9O; EM; 3.10 A; A/B/C/D/E/G=427-758. DR PDB; 8QCP; EM; 3.21 A; A/B/C/D/E/F=427-758. DR PDB; 8QCR; EM; 2.75 A; A/C/E=427-758. DR PDB; 8QDV; X-ray; 2.50 A; C/F=527-539, C/F=635-648. DR PDB; 8QJJ; EM; 3.35 A; A/B/C/D/E/F=427-758. DR PDB; 8R3T; EM; 3.10 A; A/B/C/D/E/F=1-758. DR PDB; 8SEH; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 8SEI; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 8TTL; EM; 2.60 A; A/B/C/D/E/F=427-758. DR PDB; 8TTN; EM; 2.40 A; A/B/C/D/E=427-758. DR PDB; 8UQ7; EM; 2.31 A; A/B/C/D/E/F=622-696. DR PDB; 8V1N; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J/K/L=612-630. DR PDB; 8WCP; EM; 3.28 A; A/B/C=427-758. DR PDB; 8ZWL; EM; 3.40 A; A/B/C/D/E/F=1-758. DR PDB; 8ZWM; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 8ZX6; EM; 3.50 A; A/B/C/D/E/F=1-758. DR PDB; 9B3A; EM; 3.20 A; A/C/E/G/I/K/M/O/Q/S/U/W/Y/a/c=612-630. DR PDB; 9B3C; EM; 2.95 A; A/C/E/G/I/K/M/O/Q/S/U/W/Y/a/c=612-630. DR PDB; 9B4L; EM; 3.10 A; 0/1/A/B/C/D/M/N/O/P/Y/Z=1-758. DR PDB; 9B4M; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9B4N; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9B4O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9BBL; EM; 2.50 A; A/B/C/D/E/F/G/H/I=1-758. DR PDB; 9BBM; EM; 3.20 A; A/B/C/D/E/F=1-758. DR PDB; 9BXI; EM; 2.70 A; A/B/C/D/E/F=621-697. DR PDB; 9BXO; EM; 3.00 A; A/B/C/D/E/F=621-697. DR PDB; 9BXQ; EM; 3.10 A; C/D/E/F/G/H=621-697. DR PDB; 9BXR; EM; 3.20 A; C/D/E/F/G/H=621-697. DR PDB; 9CGX; EM; 2.97 A; A/B/C/D/E/F=427-758. DR PDB; 9CGZ; EM; 2.69 A; A/B/C/D/E/F=427-758. DR PDB; 9CZI; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=623-695. DR PDB; 9CZL; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=622-695. DR PDB; 9DME; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=612-630. DR PDB; 9EO7; EM; 2.80 A; A=1-758. DR PDB; 9EO9; EM; 3.30 A; A/B=1-758. DR PDB; 9EOE; EM; 2.30 A; A=1-758. DR PDB; 9EOG; EM; 3.00 A; A/B/C/D/E/F=1-758. DR PDB; 9EOH; EM; 2.80 A; A/B/C/D/E/F=1-758. DR PDB; 9ERM; EM; 2.30 A; A/B/C/D/E=1-758. DR PDB; 9ERN; EM; 2.50 A; A/B/C/D/E/F=1-758. DR PDB; 9ERO; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J=1-758. DR PDB; 9G13; X-ray; 1.80 A; B/D/F/H=686-698. DR PDB; 9GG0; EM; 2.81 A; A/B/C=588-694. DR PDB; 9GG1; EM; 2.26 A; A/B/C/D=590-696. DR PDB; 9GG6; EM; 3.36 A; A/B/C=586-681. DR PDB; 9H5G; EM; 2.48 A; A/B/C/D/E/F=427-758. DR PDB; 9H5J; EM; 2.72 A; A/B/C/D/E/F=427-758. DR PDB; 9HBB; EM; 3.00 A; A/B/C/D/E/F=608-708. DR PDB; 9MR8; EM; 2.90 A; C=590-679. DR PDBsum; 1I8H; -. DR PDBsum; 2MZ7; -. DR PDBsum; 2ON9; -. DR PDBsum; 3OVL; -. DR PDBsum; 4E0M; -. DR PDBsum; 4E0N; -. DR PDBsum; 4E0O; -. DR PDBsum; 4FL5; -. DR PDBsum; 4GLR; -. DR PDBsum; 4NP8; -. DR PDBsum; 4TQE; -. DR PDBsum; 4Y32; -. DR PDBsum; 4Y5I; -. DR PDBsum; 5DMG; -. DR PDBsum; 5E2V; -. DR PDBsum; 5E2W; -. DR PDBsum; 5HF3; -. DR PDBsum; 5K7N; -. DR PDBsum; 5MO3; -. DR PDBsum; 5MP1; -. DR PDBsum; 5MP3; -. DR PDBsum; 5MP5; -. DR PDBsum; 5N5A; -. DR PDBsum; 5N5B; -. DR PDBsum; 5NVB; -. DR PDBsum; 5O3L; -. DR PDBsum; 5O3O; -. DR PDBsum; 5O3T; -. DR PDBsum; 5V5B; -. DR PDBsum; 5V5C; -. DR PDBsum; 5ZIA; -. DR PDBsum; 5ZV3; -. DR PDBsum; 6BB4; -. DR PDBsum; 6CVJ; -. DR PDBsum; 6CVN; -. DR PDBsum; 6DC8; -. DR PDBsum; 6DC9; -. DR PDBsum; 6DCA; -. DR PDBsum; 6FBW; -. DR PDBsum; 6FI5; -. DR PDBsum; 6GK7; -. DR PDBsum; 6GK8; -. DR PDBsum; 6GX5; -. DR PDBsum; 6H06; -. DR PDBsum; 6HRE; -. DR PDBsum; 6HRF; -. DR PDBsum; 6LRA; -. DR PDBsum; 6N4P; -. DR PDBsum; 6NK4; -. DR PDBsum; 6NWP; -. DR PDBsum; 6NWQ; -. DR PDBsum; 6ODG; -. DR PDBsum; 6PXR; -. DR PDBsum; 6QJH; -. DR PDBsum; 6QJM; -. DR PDBsum; 6QJP; -. DR PDBsum; 6QJQ; -. DR PDBsum; 6TJO; -. DR PDBsum; 6TJX; -. DR PDBsum; 6VH7; -. DR PDBsum; 6VHA; -. DR PDBsum; 6VHL; -. DR PDBsum; 6VI3; -. DR PDBsum; 6XLI; -. DR PDBsum; 7EYC; -. DR PDBsum; 7KQK; -. DR PDBsum; 7MKF; -. DR PDBsum; 7MKG; -. DR PDBsum; 7MKH; -. DR PDBsum; 7NRQ; -. DR PDBsum; 7NRS; -. DR PDBsum; 7NRT; -. DR PDBsum; 7NRV; -. DR PDBsum; 7NRX; -. DR PDBsum; 7P65; -. DR PDBsum; 7P66; -. DR PDBsum; 7P67; -. DR PDBsum; 7P68; -. DR PDBsum; 7P6A; -. DR PDBsum; 7P6B; -. DR PDBsum; 7P6C; -. DR PDBsum; 7P6D; -. DR PDBsum; 7P6E; -. DR PDBsum; 7PQC; -. DR PDBsum; 7PQP; -. DR PDBsum; 7QJV; -. DR PDBsum; 7QJW; -. DR PDBsum; 7QJX; -. DR PDBsum; 7QJY; -. DR PDBsum; 7QJZ; -. DR PDBsum; 7QK1; -. DR PDBsum; 7QK2; -. DR PDBsum; 7QK3; -. DR PDBsum; 7QK5; -. DR PDBsum; 7QK6; -. DR PDBsum; 7QKF; -. DR PDBsum; 7QKG; -. DR PDBsum; 7QKH; -. DR PDBsum; 7QKI; -. DR PDBsum; 7QKJ; -. DR PDBsum; 7QKK; -. DR PDBsum; 7QKL; -. DR PDBsum; 7QKM; -. DR PDBsum; 7QKU; -. DR PDBsum; 7QKV; -. DR PDBsum; 7QKW; -. DR PDBsum; 7QKX; -. DR PDBsum; 7QKY; -. DR PDBsum; 7QKZ; -. DR PDBsum; 7QL0; -. DR PDBsum; 7QL1; -. DR PDBsum; 7QL2; -. DR PDBsum; 7QL3; -. DR PDBsum; 7QL4; -. DR PDBsum; 7R4T; -. DR PDBsum; 7R5H; -. DR PDBsum; 7SP1; -. DR PDBsum; 7U0Z; -. DR PDBsum; 7UPE; -. DR PDBsum; 7UPF; -. DR PDBsum; 7UPG; -. DR PDBsum; 7YMN; -. DR PDBsum; 7YPG; -. DR PDBsum; 8AZU; -. DR PDBsum; 8BGS; -. DR PDBsum; 8BGV; -. DR PDBsum; 8BYN; -. DR PDBsum; 8CAQ; -. DR PDBsum; 8CAX; -. DR PDBsum; 8FNZ; -. DR PDBsum; 8FUG; -. DR PDBsum; 8FYU; -. DR PDBsum; 8G54; -. DR PDBsum; 8G55; -. DR PDBsum; 8G58; -. DR PDBsum; 8GCK; -. DR PDBsum; 8KDX; -. DR PDBsum; 8OH2; -. DR PDBsum; 8OHI; -. DR PDBsum; 8OHP; -. DR PDBsum; 8OI0; -. DR PDBsum; 8OP0; -. DR PDBsum; 8OPI; -. DR PDBsum; 8ORE; -. DR PDBsum; 8ORF; -. DR PDBsum; 8ORG; -. DR PDBsum; 8OT6; -. DR PDBsum; 8OT9; -. DR PDBsum; 8OTC; -. DR PDBsum; 8OTG; -. DR PDBsum; 8OTH; -. DR PDBsum; 8OTI; -. DR PDBsum; 8OTJ; -. DR PDBsum; 8P34; -. DR PDBsum; 8PII; -. DR PDBsum; 8PPO; -. DR PDBsum; 8Q27; -. DR PDBsum; 8Q2J; -. DR PDBsum; 8Q2K; -. DR PDBsum; 8Q2L; -. DR PDBsum; 8Q7F; -. DR PDBsum; 8Q7L; -. DR PDBsum; 8Q7M; -. DR PDBsum; 8Q7P; -. DR PDBsum; 8Q7T; -. DR PDBsum; 8Q88; -. DR PDBsum; 8Q8C; -. DR PDBsum; 8Q8D; -. DR PDBsum; 8Q8E; -. DR PDBsum; 8Q8F; -. DR PDBsum; 8Q8L; -. DR PDBsum; 8Q8M; -. DR PDBsum; 8Q8R; -. DR PDBsum; 8Q8S; -. DR PDBsum; 8Q8U; -. DR PDBsum; 8Q8V; -. DR PDBsum; 8Q8W; -. DR PDBsum; 8Q8X; -. DR PDBsum; 8Q8Y; -. DR PDBsum; 8Q8Z; -. DR PDBsum; 8Q92; -. DR PDBsum; 8Q97; -. DR PDBsum; 8Q98; -. DR PDBsum; 8Q99; -. DR PDBsum; 8Q9A; -. DR PDBsum; 8Q9B; -. DR PDBsum; 8Q9C; -. DR PDBsum; 8Q9D; -. DR PDBsum; 8Q9E; -. DR PDBsum; 8Q9F; -. DR PDBsum; 8Q9G; -. DR PDBsum; 8Q9H; -. DR PDBsum; 8Q9I; -. DR PDBsum; 8Q9J; -. DR PDBsum; 8Q9K; -. DR PDBsum; 8Q9L; -. DR PDBsum; 8Q9M; -. DR PDBsum; 8Q9O; -. DR PDBsum; 8QCP; -. DR PDBsum; 8QCR; -. DR PDBsum; 8QDV; -. DR PDBsum; 8QJJ; -. DR PDBsum; 8R3T; -. DR PDBsum; 8SEH; -. DR PDBsum; 8SEI; -. DR PDBsum; 8TTL; -. DR PDBsum; 8TTN; -. DR PDBsum; 8UQ7; -. DR PDBsum; 8V1N; -. DR PDBsum; 8WCP; -. DR PDBsum; 8ZWL; -. DR PDBsum; 8ZWM; -. DR PDBsum; 8ZX6; -. DR PDBsum; 9B3A; -. DR PDBsum; 9B3C; -. DR PDBsum; 9B4L; -. DR PDBsum; 9B4M; -. DR PDBsum; 9B4N; -. DR PDBsum; 9B4O; -. DR PDBsum; 9BBL; -. DR PDBsum; 9BBM; -. DR PDBsum; 9BXI; -. DR PDBsum; 9BXO; -. DR PDBsum; 9BXQ; -. DR PDBsum; 9BXR; -. DR PDBsum; 9CGX; -. DR PDBsum; 9CGZ; -. DR PDBsum; 9CZI; -. DR PDBsum; 9CZL; -. DR PDBsum; 9DME; -. DR PDBsum; 9EO7; -. DR PDBsum; 9EO9; -. DR PDBsum; 9EOE; -. DR PDBsum; 9EOG; -. DR PDBsum; 9EOH; -. DR PDBsum; 9ERM; -. DR PDBsum; 9ERN; -. DR PDBsum; 9ERO; -. DR PDBsum; 9G13; -. DR PDBsum; 9GG0; -. DR PDBsum; 9GG1; -. DR PDBsum; 9GG6; -. DR PDBsum; 9H5G; -. DR PDBsum; 9H5J; -. DR PDBsum; 9HBB; -. DR PDBsum; 9MR8; -. DR AlphaFoldDB; P10636; -. DR BMRB; P10636; -. DR EMDB; EMD-0077; -. DR EMDB; EMD-0259; -. DR EMDB; EMD-0260; -. DR EMDB; EMD-0527; -. DR EMDB; EMD-0528; -. DR EMDB; EMD-10512; -. DR EMDB; EMD-10514; -. DR EMDB; EMD-12549; -. DR EMDB; EMD-12550; -. DR EMDB; EMD-12551; -. DR EMDB; EMD-12552; -. DR EMDB; EMD-12553; -. DR EMDB; EMD-13218; -. DR EMDB; EMD-13219; -. DR EMDB; EMD-13220; -. DR EMDB; EMD-13221; -. DR EMDB; EMD-13223; -. DR EMDB; EMD-13224; -. DR EMDB; EMD-13225; -. DR EMDB; EMD-13226; -. DR EMDB; EMD-13227; -. DR EMDB; EMD-14023; -. DR EMDB; EMD-14024; -. DR EMDB; EMD-14025; -. DR EMDB; EMD-14026; -. DR EMDB; EMD-14027; -. DR EMDB; EMD-14028; -. DR EMDB; EMD-14029; -. DR EMDB; EMD-14030; -. DR EMDB; EMD-14038; -. DR EMDB; EMD-14039; -. DR EMDB; EMD-14040; -. DR EMDB; EMD-14041; -. DR EMDB; EMD-14042; -. DR EMDB; EMD-14043; -. DR EMDB; EMD-14044; -. DR EMDB; EMD-14045; -. DR EMDB; EMD-14046; -. DR EMDB; EMD-14047; -. DR EMDB; EMD-14053; -. DR EMDB; EMD-14054; -. DR EMDB; EMD-14055; -. DR EMDB; EMD-14056; -. DR EMDB; EMD-14057; -. DR EMDB; EMD-14058; -. DR EMDB; EMD-14059; -. DR EMDB; EMD-14060; -. DR EMDB; EMD-14061; -. DR EMDB; EMD-14062; -. DR EMDB; EMD-14063; -. DR EMDB; EMD-14316; -. DR EMDB; EMD-14320; -. DR EMDB; EMD-15772; -. DR EMDB; EMD-16035; -. DR EMDB; EMD-16039; -. DR EMDB; EMD-16329; -. DR EMDB; EMD-16532; -. DR EMDB; EMD-16535; -. DR EMDB; EMD-16876; -. DR EMDB; EMD-16881; -. DR EMDB; EMD-16883; -. DR EMDB; EMD-16886; -. DR EMDB; EMD-17121; -. DR EMDB; EMD-17122; -. DR EMDB; EMD-17123; -. DR EMDB; EMD-17171; -. DR EMDB; EMD-17173; -. DR EMDB; EMD-17174; -. DR EMDB; EMD-17178; -. DR EMDB; EMD-17179; -. DR EMDB; EMD-17180; -. DR EMDB; EMD-17181; -. DR EMDB; EMD-17383; -. DR EMDB; EMD-17806; -. DR EMDB; EMD-18070; -. DR EMDB; EMD-18109; -. DR EMDB; EMD-18111; -. DR EMDB; EMD-18112; -. DR EMDB; EMD-18215; -. DR EMDB; EMD-18219; -. DR EMDB; EMD-18224; -. DR EMDB; EMD-18228; -. DR EMDB; EMD-18233; -. DR EMDB; EMD-18249; -. DR EMDB; EMD-18250; -. DR EMDB; EMD-18251; -. DR EMDB; EMD-18252; -. DR EMDB; EMD-18253; -. DR EMDB; EMD-18254; -. DR EMDB; EMD-18255; -. DR EMDB; EMD-18258; -. DR EMDB; EMD-18259; -. DR EMDB; EMD-18261; -. DR EMDB; EMD-18262; -. DR EMDB; EMD-18263; -. DR EMDB; EMD-18264; -. DR EMDB; EMD-18265; -. DR EMDB; EMD-18266; -. DR EMDB; EMD-18268; -. DR EMDB; EMD-18270; -. DR EMDB; EMD-18271; -. DR EMDB; EMD-18272; -. DR EMDB; EMD-18273; -. DR EMDB; EMD-18275; -. DR EMDB; EMD-18276; -. DR EMDB; EMD-18277; -. DR EMDB; EMD-18278; -. DR EMDB; EMD-18279; -. DR EMDB; EMD-18280; -. DR EMDB; EMD-18281; -. DR EMDB; EMD-18282; -. DR EMDB; EMD-18283; -. DR EMDB; EMD-18284; -. DR EMDB; EMD-18285; -. DR EMDB; EMD-18286; -. DR EMDB; EMD-18287; -. DR EMDB; EMD-18331; -. DR EMDB; EMD-18333; -. DR EMDB; EMD-18448; -. DR EMDB; EMD-18874; -. DR EMDB; EMD-18990; -. DR EMDB; EMD-19846; -. DR EMDB; EMD-19849; -. DR EMDB; EMD-19852; -. DR EMDB; EMD-19854; -. DR EMDB; EMD-19855; -. DR EMDB; EMD-19926; -. DR EMDB; EMD-19927; -. DR EMDB; EMD-19928; -. DR EMDB; EMD-21200; -. DR EMDB; EMD-21201; -. DR EMDB; EMD-21207; -. DR EMDB; EMD-26268; -. DR EMDB; EMD-29458; -. DR EMDB; EMD-33934; -. DR EMDB; EMD-33999; -. DR EMDB; EMD-35403; -. DR EMDB; EMD-35404; -. DR EMDB; EMD-35405; -. DR EMDB; EMD-35406; -. DR EMDB; EMD-35407; -. DR EMDB; EMD-35408; -. DR EMDB; EMD-35409; -. DR EMDB; EMD-3741; -. DR EMDB; EMD-3742; -. DR EMDB; EMD-3743; -. DR EMDB; EMD-3744; -. DR EMDB; EMD-40411; -. DR EMDB; EMD-40413; -. DR EMDB; EMD-41610; -. DR EMDB; EMD-41611; -. DR EMDB; EMD-42463; -. DR EMDB; EMD-42886; -. DR EMDB; EMD-44133; -. DR EMDB; EMD-44134; -. DR EMDB; EMD-44184; -. DR EMDB; EMD-44185; -. DR EMDB; EMD-44186; -. DR EMDB; EMD-44187; -. DR EMDB; EMD-44421; -. DR EMDB; EMD-44422; -. DR EMDB; EMD-45005; -. DR EMDB; EMD-45007; -. DR EMDB; EMD-45008; -. DR EMDB; EMD-45009; -. DR EMDB; EMD-45588; -. DR EMDB; EMD-45589; -. DR EMDB; EMD-4563; -. DR EMDB; EMD-4565; -. DR EMDB; EMD-4566; -. DR EMDB; EMD-46417; -. DR EMDB; EMD-46420; -. DR EMDB; EMD-46689; -. DR EMDB; EMD-47002; -. DR EMDB; EMD-48555; -. DR EMDB; EMD-50148; -. DR EMDB; EMD-50152; -. DR EMDB; EMD-50153; -. DR EMDB; EMD-50155; -. DR EMDB; EMD-50156; -. DR EMDB; EMD-50157; -. DR EMDB; EMD-50159; -. DR EMDB; EMD-50160; -. DR EMDB; EMD-50161; -. DR EMDB; EMD-50162; -. DR EMDB; EMD-50441; -. DR EMDB; EMD-51319; -. DR EMDB; EMD-51320; -. DR EMDB; EMD-51325; -. DR EMDB; EMD-51884; -. DR EMDB; EMD-51886; -. DR EMDB; EMD-52014; -. DR EMDB; EMD-53527; -. DR EMDB; EMD-53530; -. DR EMDB; EMD-54485; -. DR EMDB; EMD-60531; -. DR EMDB; EMD-60532; -. DR EMDB; EMD-60533; -. DR EMDB; EMD-60539; -. DR EMDB; EMD-71636; -. DR EMDB; EMD-7520; -. DR EMDB; EMD-7522; -. DR EMDB; EMD-7523; -. DR EMDB; EMD-7769; -. DR EMDB; EMD-7771; -. DR EMDB; EMD-8634; -. DR EMDB; EMD-8635; -. DR SASBDB; P10636; -. DR SMR; P10636; -. DR BioGRID; 110308; 1104. DR CORUM; P10636; -. DR DIP; DIP-29753N; -. DR ELM; P10636; -. DR FunCoup; P10636; 523. DR IntAct; P10636; 2082. DR MINT; P10636; -. DR STRING; 9606.ENSP00000340820; -. DR BindingDB; P10636; -. DR ChEMBL; CHEMBL1293224; -. DR DrugBank; DB00637; Astemizole. DR DrugBank; DB15033; Flortaucipir. DR DrugBank; DB14914; Flortaucipir F-18. DR DrugBank; DB00448; Lansoprazole. DR DrugBank; DB05565; PBT-1033. DR DrugCentral; P10636; -. DR GlyConnect; 2885; 1 O-GlcNAc glycan (6 sites). DR GlyCosmos; P10636; 34 sites, 1 glycan. DR GlyGen; P10636; 12 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (6 sites). DR iPTMnet; P10636; -. DR MetOSite; P10636; -. DR PhosphoSitePlus; P10636; -. DR SwissPalm; P10636; -. DR BioMuta; MAPT; -. DR DMDM; 334302961; -. DR jPOST; P10636; -. DR MassIVE; P10636; -. DR PaxDb; 9606-ENSP00000340820; -. DR PeptideAtlas; P10636; -. DR ProteomicsDB; 52624; -. [P10636-1] DR ProteomicsDB; 52625; -. [P10636-2] DR ProteomicsDB; 52626; -. [P10636-3] DR ProteomicsDB; 52627; -. [P10636-4] DR ProteomicsDB; 52628; -. [P10636-5] DR ProteomicsDB; 52629; -. [P10636-6] DR ProteomicsDB; 52630; -. [P10636-7] DR ProteomicsDB; 52631; -. [P10636-8] DR ProteomicsDB; 52632; -. [P10636-9] DR Pumba; P10636; -. DR TopDownProteomics; P10636-3; -. [P10636-3] DR ABCD; P10636; 86 sequenced antibodies. DR Antibodypedia; 3124; 5679 antibodies from 54 providers. DR DNASU; 4137; -. DR Ensembl; ENST00000334239.12; ENSP00000334886.8; ENSG00000186868.19. [P10636-2] DR Ensembl; ENST00000351559.10; ENSP00000303214.7; ENSG00000186868.19. [P10636-8] DR Ensembl; ENST00000415613.6; ENSP00000410838.2; ENSG00000186868.19. [P10636-9] DR Ensembl; ENST00000420682.7; ENSP00000413056.2; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000431008.7; ENSP00000389250.3; ENSG00000186868.19. [P10636-5] DR Ensembl; ENST00000446361.7; ENSP00000408975.3; ENSG00000186868.19. [P10636-6] DR Ensembl; ENST00000535772.6; ENSP00000443028.2; ENSG00000186868.19. [P10636-4] DR Ensembl; ENST00000571987.5; ENSP00000458742.1; ENSG00000186868.19. [P10636-1] DR Ensembl; ENST00000574436.5; ENSP00000460965.1; ENSG00000186868.19. [P10636-8] DR Ensembl; ENST00000612872.4; ENSP00000478602.1; ENSG00000277956.4. [P10636-7] DR Ensembl; ENST00000613360.4; ENSP00000483784.1; ENSG00000276155.4. [P10636-7] DR Ensembl; ENST00000620070.4; ENSP00000484491.1; ENSG00000277956.4. [P10636-8] DR Ensembl; ENST00000620818.4; ENSP00000484321.1; ENSG00000277956.4. [P10636-5] DR Ensembl; ENST00000620981.4; ENSP00000481769.1; ENSG00000276155.4. [P10636-5] DR Ensembl; ENST00000621329.4; ENSP00000477703.1; ENSG00000276155.4. [P10636-8] DR Ensembl; ENST00000622106.2; ENSP00000482244.1; ENSG00000277956.4. [P10636-6] DR Ensembl; ENST00000622728.1; ENSP00000479142.1; ENSG00000276155.4. [P10636-6] DR Ensembl; ENST00000626571.2; ENSP00000486039.1; ENSG00000276155.4. [P10636-6] DR Ensembl; ENST00000628393.2; ENSP00000487570.1; ENSG00000276155.4. [P10636-2] DR Ensembl; ENST00000631447.1; ENSP00000488373.1; ENSG00000277956.4. [P10636-5] DR Ensembl; ENST00000632500.1; ENSP00000487837.1; ENSG00000277956.4. [P10636-7] DR Ensembl; ENST00000633047.1; ENSP00000488245.1; ENSG00000277956.4. [P10636-2] DR Ensembl; ENST00000634049.1; ENSP00000487819.1; ENSG00000277956.4. [P10636-8] DR Ensembl; ENST00000680542.1; ENSP00000505258.1; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000703922.1; ENSP00000515557.1; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000703923.1; ENSP00000515558.1; ENSG00000186868.19. [P10636-6] DR Ensembl; ENST00000703924.1; ENSP00000515559.1; ENSG00000186868.19. [P10636-7] DR Ensembl; ENST00000703978.1; ENSP00000515600.1; ENSG00000186868.19. [P10636-8] DR GeneID; 4137; -. DR KEGG; hsa:4137; -. DR UCSC; uc002ijr.5; human. [P10636-1] DR AGR; HGNC:6893; -. DR ClinPGx; PA238; -. DR CTD; 4137; -. DR DisGeNET; 4137; -. DR GeneCards; MAPT; -. DR GeneReviews; MAPT; -. DR HGNC; HGNC:6893; MAPT. DR HPA; ENSG00000186868; Tissue enhanced (brain, skeletal muscle). DR MalaCards; MAPT; -. DR MIM; 157140; gene+phenotype. DR MIM; 172700; phenotype. DR MIM; 260540; phenotype. DR MIM; 600274; phenotype. DR MIM; 601104; phenotype. DR OpenTargets; ENSG00000186868; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 240071; Classic progressive supranuclear palsy syndrome. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 240103; Progressive supranuclear palsy-corticobasal syndrome. DR Orphanet; 240085; Progressive supranuclear palsy-predominant parkinsonism syndrome. DR Orphanet; 240112; Progressive supranuclear palsy-progressive non-fluent aphasia syndrome. DR Orphanet; 240094; Progressive supranuclear palsy-pure akinesia with gait freezing syndrome. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000186868; -. DR eggNOG; KOG2418; Eukaryota. DR GeneTree; ENSGT00940000155494; -. DR HOGENOM; CLU_021741_2_0_1; -. DR InParanoid; P10636; -. DR OrthoDB; 9378527at2759; -. DR PAN-GO; P10636; 4 GO annotations based on evolutionary models. DR PathwayCommons; P10636; -. DR Reactome; R-HSA-264870; Caspase-mediated cleavage of cytoskeletal proteins. DR Reactome; R-HSA-9619483; Activation of AMPK downstream of NMDARs. [P10636-8] DR Reactome; R-HSA-9833482; PKR-mediated signaling. [P10636-8] DR SABIO-RK; P10636; -. DR SignaLink; P10636; -. DR SIGNOR; P10636; -. DR Agora; ENSG00000186868; -. DR BioGRID-ORCS; 4137; 23 hits in 1151 CRISPR screens. DR CD-CODE; 03D56D03; Tau inclusion. DR CD-CODE; 24B12ACB; Synthetic Condensate 000346. DR CD-CODE; 804901D1; Nuclear speckle. DR CD-CODE; 8188F968; Tau-Prion Multiphasic condensate. DR CD-CODE; 8C2F96ED; Centrosome. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; MAPT; human. DR EvolutionaryTrace; P10636; -. DR GeneWiki; Tau_protein; -. DR GenomeRNAi; 4137; -. DR Pharos; P10636; Tclin. DR PRO; PR:P10636; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P10636; protein. DR Bgee; ENSG00000186868; Expressed in cortical plate and 104 other cell types or tissues. DR ExpressionAtlas; P10636; baseline and differential. DR GO; GO:0030673; C:axolemma; IDA:CAFA. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0044297; C:cell body; IDA:ParkinsonsUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:CAFA. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0043197; C:dendritic spine; TAS:ARUK-UCL. DR GO; GO:0005576; C:extracellular region; NAS:ARUK-UCL. DR GO; GO:0097386; C:glial cell projection; ISS:ARUK-UCL. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0044304; C:main axon; ISS:ARUK-UCL. DR GO; GO:0045121; C:membrane raft; ISS:ARUK-UCL. DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW. DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:CAFA. DR GO; GO:0005739; C:mitochondrion; TAS:ARUK-UCL. DR GO; GO:0097418; C:neurofibrillary tangle; IDA:CAFA. DR GO; GO:0043005; C:neuron projection; IBA:GO_Central. DR GO; GO:0043025; C:neuronal cell body; IMP:ParkinsonsUK-UCL. DR GO; GO:0034399; C:nuclear periphery; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:ParkinsonsUK-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0036477; C:somatodendritic compartment; IMP:ParkinsonsUK-UCL. DR GO; GO:0045298; C:tubulin complex; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; TAS:ARUK-UCL. DR GO; GO:0034185; F:apolipoprotein binding; IPI:BHF-UCL. DR GO; GO:0003677; F:DNA binding; ISS:ParkinsonsUK-UCL. DR GO; GO:0003690; F:double-stranded DNA binding; TAS:ARUK-UCL. DR GO; GO:0034452; F:dynactin binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:ARUK-UCL. DR GO; GO:0099077; F:histone-dependent DNA binding; TAS:ARUK-UCL. DR GO; GO:0051879; F:Hsp90 protein binding; IPI:ARUK-UCL. DR GO; GO:0042802; F:identical protein binding; IDA:CAFA. DR GO; GO:0071813; F:lipoprotein particle binding; IPI:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0099609; F:microtubule lateral binding; IMP:CAFA. DR GO; GO:0003680; F:minor groove of adenine-thymine-rich DNA binding; TAS:ARUK-UCL. DR GO; GO:0035091; F:phosphatidylinositol binding; TAS:ARUK-UCL. DR GO; GO:1902936; F:phosphatidylinositol bisphosphate binding; TAS:ARUK-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:ARUK-UCL. DR GO; GO:0051721; F:protein phosphatase 2A binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:ARUK-UCL. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; TAS:ARUK-UCL. DR GO; GO:0003723; F:RNA binding; TAS:ARUK-UCL. DR GO; GO:0043565; F:sequence-specific DNA binding; TAS:ARUK-UCL. DR GO; GO:0017124; F:SH3 domain binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; TAS:ARUK-UCL. DR GO; GO:1990000; P:amyloid fibril formation; IDA:DisProt. DR GO; GO:0048143; P:astrocyte activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0061564; P:axon development; TAS:ARUK-UCL. DR GO; GO:0098930; P:axonal transport; TAS:ParkinsonsUK-UCL. DR GO; GO:0019896; P:axonal transport of mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0007267; P:cell-cell signaling; NAS:ARUK-UCL. DR GO; GO:1990416; P:cellular response to brain-derived neurotrophic factor stimulus; TAS:ARUK-UCL. DR GO; GO:0034605; P:cellular response to heat; TAS:ParkinsonsUK-UCL. DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; TAS:ARUK-UCL. DR GO; GO:0034614; P:cellular response to reactive oxygen species; TAS:ARUK-UCL. DR GO; GO:0021954; P:central nervous system neuron development; TAS:ARUK-UCL. DR GO; GO:0031122; P:cytoplasmic microtubule organization; TAS:ParkinsonsUK-UCL. DR GO; GO:0006974; P:DNA damage response; IMP:ParkinsonsUK-UCL. DR GO; GO:0048699; P:generation of neurons; NAS:UniProtKB. DR GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:ParkinsonsUK-UCL. DR GO; GO:0007611; P:learning or memory; IMP:ARUK-UCL. DR GO; GO:0007613; P:memory; IMP:ParkinsonsUK-UCL. DR GO; GO:0001774; P:microglial cell activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0000226; P:microtubule cytoskeleton organization; IDA:UniProtKB. DR GO; GO:0046785; P:microtubule polymerization; IDA:ARUK-UCL. DR GO; GO:1903748; P:negative regulation of establishment of protein localization to mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:0090258; P:negative regulation of mitochondrial fission; IMP:ARUK-UCL. DR GO; GO:0010917; P:negative regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:1902988; P:neurofibrillary tangle assembly; NAS:ParkinsonsUK-UCL. DR GO; GO:0031175; P:neuron projection development; IBA:GO_Central. DR GO; GO:0072386; P:plus-end-directed organelle transport along microtubule; TAS:ParkinsonsUK-UCL. DR GO; GO:0045773; P:positive regulation of axon extension; IDA:UniProtKB. DR GO; GO:0031116; P:positive regulation of microtubule polymerization; IDA:UniProtKB. DR GO; GO:1903829; P:positive regulation of protein localization; IMP:CAFA. DR GO; GO:1902474; P:positive regulation of protein localization to synapse; IMP:ParkinsonsUK-UCL. DR GO; GO:0032930; P:positive regulation of superoxide anion generation; IMP:ARUK-UCL. DR GO; GO:0051260; P:protein homooligomerization; IPI:ARUK-UCL. DR GO; GO:0051258; P:protein polymerization; IMP:UniProtKB. DR GO; GO:0010506; P:regulation of autophagy; IGI:MGI. DR GO; GO:0050848; P:regulation of calcium-mediated signaling; IDA:ARUK-UCL. DR GO; GO:1900034; P:regulation of cellular response to heat; IMP:ParkinsonsUK-UCL. DR GO; GO:0033044; P:regulation of chromosome organization; TAS:ARUK-UCL. DR GO; GO:1900452; P:regulation of long-term synaptic depression; TAS:ARUK-UCL. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IMP:CAFA. DR GO; GO:0031113; P:regulation of microtubule polymerization; TAS:ARUK-UCL. DR GO; GO:0031110; P:regulation of microtubule polymerization or depolymerization; IMP:CAFA. DR GO; GO:0060632; P:regulation of microtubule-based movement; IGI:ARUK-UCL. DR GO; GO:0090140; P:regulation of mitochondrial fission; IC:ParkinsonsUK-UCL. DR GO; GO:0048167; P:regulation of synaptic plasticity; TAS:ARUK-UCL. DR GO; GO:0010288; P:response to lead ion; ISS:ARUK-UCL. DR GO; GO:0016072; P:rRNA metabolic process; TAS:ARUK-UCL. DR GO; GO:0034063; P:stress granule assembly; TAS:ARUK-UCL. DR GO; GO:0097435; P:supramolecular fiber organization; IDA:CAFA. DR GO; GO:0007416; P:synapse assembly; IMP:ARUK-UCL. DR GO; GO:0050808; P:synapse organization; IMP:ParkinsonsUK-UCL. DR DisProt; DP01100; -. [P10636-8] DR DisProt; DP03552; -. [P10636-2] DR InterPro; IPR027324; MAP2/MAP4/Tau. DR InterPro; IPR001084; MAP_tubulin-bd_rpt. DR InterPro; IPR002955; Tau. DR PANTHER; PTHR11501; MICROTUBULE-ASSOCIATED PROTEIN; 1. DR PANTHER; PTHR11501:SF14; MICROTUBULE-ASSOCIATED PROTEIN TAU; 1. DR Pfam; PF00418; Tubulin-binding; 4. DR PRINTS; PR01261; TAUPROTEIN. DR PROSITE; PS00229; TAU_MAP_1; 4. DR PROSITE; PS51491; TAU_MAP_2; 4. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Alzheimer disease; KW Cell membrane; Cell projection; Cytoplasm; Cytoskeleton; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycation; KW Glycoprotein; Isopeptide bond; Membrane; Methylation; Microtubule; KW Neurodegeneration; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Repeat; Secreted; Ubl conjugation. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:1512244" FT CHAIN 2..758 FT /note="Microtubule-associated protein tau" FT /id="PRO_0000072739" FT REPEAT 561..591 FT /note="Tau/MAP 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REPEAT 592..622 FT /note="Tau/MAP 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REPEAT 623..653 FT /note="Tau/MAP 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REPEAT 654..685 FT /note="Tau/MAP 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00824, FT ECO:0000305|PubMed:7706316" FT REGION 1..573 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 561..685 FT /note="Microtubule-binding domain" FT /evidence="ECO:0000269|PubMed:7706316" FT REGION 715..734 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..26 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 61..71 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 179..189 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 207..216 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 217..228 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 314..323 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 324..340 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 344..356 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 381..393 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 442..453 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 455..466 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 491..503 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 504..531 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 718..733 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 24 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 44 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 67 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 381 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 391 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 392 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 394 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 465 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 497 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 507 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 541 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 557 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 571 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 574 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 584 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 591 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 607 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 611 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 615 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 628 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 634 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 638 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 648 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 657 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 660 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 687 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 692 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 700 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 702 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 712 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT SITE 755 FT /note="Not glycated" FT /evidence="ECO:0000269|PubMed:9326300" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|PubMed:1512244" FT MOD_RES 18 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:14999081" FT MOD_RES 29 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 46 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P19332" FT MOD_RES 61 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P19332" FT MOD_RES 69 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 71 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P19332" FT MOD_RES 111 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 214 FT /note="Phosphoserine; by SGK1" FT /evidence="ECO:0000269|PubMed:16982696" FT MOD_RES 470 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000269|PubMed:9614189" FT MOD_RES 472 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 480 FT /note="N6,N6-dimethyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 480 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 484 FT /note="Deamidated asparagine; in tau and PHF-tau; partial" FT /evidence="ECO:0000269|PubMed:1512244" FT MOD_RES 486 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 492 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 498 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000269|PubMed:15546861" FT MOD_RES 502 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 508 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 512 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 514 FT /note="Phosphotyrosine; by TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT MOD_RES 515 FT /note="Phosphoserine; by PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT MOD_RES 516 FT /note="Phosphoserine; by PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16923168, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:9614189" FT MOD_RES 519 FT /note="Phosphoserine; by CK1, PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16923168, FT ECO:0000269|PubMed:19451179, ECO:0000269|PubMed:21327254, FT ECO:0000269|PubMed:9614189, ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 522 FT /note="Phosphothreonine; by CK1 and PDPK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:19451179" FT MOD_RES 529 FT /note="Phosphothreonine; by BRSK1, BRSK2, DYRK2 and PDPK1" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21985311, ECO:0000269|PubMed:9614189" FT MOD_RES 531 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:9614189" FT MOD_RES 534 FT /note="Phosphothreonine; by PDPK1" FT /evidence="ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:19451179" FT MOD_RES 542 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 548 FT /note="Phosphothreonine; by GSK3-beta and PDPK1" FT /evidence="ECO:0000269|PubMed:14690523, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603, FT ECO:0007744|PubMed:23186163" FT MOD_RES 552 FT /note="Phosphoserine; by PDPK1" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:9614189, FT ECO:0007744|PubMed:23186163" FT MOD_RES 554 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:8999860" FT MOD_RES 576 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 576 FT /note="N6-methyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 579 FT /note="Phosphoserine; by MARK1, MARK2, MARK3, MARK4, BRSK1, FT BRSK2 and PHK" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0000269|PubMed:16443603, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21985311, ECO:0000269|PubMed:23666762, FT ECO:0000269|PubMed:7706316, ECO:0000269|PubMed:8999860, FT ECO:0000269|PubMed:9614189" FT MOD_RES 596 FT /note="Deamidated asparagine; in tau and PHF-tau; partial" FT /evidence="ECO:0000269|PubMed:1512244" FT MOD_RES 598 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 602 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:8999860" FT MOD_RES 607 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 610 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:7706316" FT MOD_RES 615 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 622 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:7706316, FT ECO:0000269|PubMed:8999860" FT MOD_RES 628 FT /note="N6,N6-dimethyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 628 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 634 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 638 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 641 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:7706316" FT MOD_RES 648 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 660 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 664 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 666 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 669 FT /note="Phosphoserine; by PHK" FT /evidence="ECO:0000269|PubMed:8999860" FT MOD_RES 673 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:7706316" FT MOD_RES 686 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 702 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 711 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 713 FT /note="Phosphoserine; by CK1 and PDPK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:1899488, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 717 FT /note="Phosphoserine; alternate" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 720 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P10637" FT MOD_RES 721 FT /note="Phosphoserine; by CK1 and PDPK1" FT /evidence="ECO:0000269|PubMed:14761950, FT ECO:0000269|PubMed:15546861, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:21327254, ECO:0000269|PubMed:9614189, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163" FT MOD_RES 726 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:15546861, FT ECO:0007744|PubMed:19690332" FT MOD_RES 733 FT /note="Phosphoserine; by CaMK2 and TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT MOD_RES 739 FT /note="Phosphoserine; by PDPK1 and TTBK1" FT /evidence="ECO:0000269|PubMed:16443603, FT ECO:0000269|PubMed:16923168, ECO:0000269|PubMed:19451179, FT ECO:0000269|PubMed:9614189" FT MOD_RES 744 FT /note="Phosphothreonine; by TTBK1" FT /evidence="ECO:0000269|PubMed:16923168" FT CARBOHYD 87 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 383 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 467 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 480 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 491 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 525 FT /note="O-linked (GlcNAc) serine" FT /evidence="ECO:0000269|PubMed:21327254" FT CARBOHYD 542 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 551 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 555 FT /note="O-linked (GlcNAc) serine" FT /evidence="ECO:0000269|PubMed:21327254" FT CARBOHYD 576 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 597 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 598 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 664 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 670 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 686 FT /note="N-linked (Glc) (glycation) lysine; in PHF-tau; in FT vitro" FT /evidence="ECO:0000269|PubMed:9326300" FT CARBOHYD 717 FT /note="O-linked (GlcNAc) serine; alternate" FT /evidence="ECO:0000269|PubMed:21327254" FT DISULFID 608..639 FT /evidence="ECO:0000250" FT CROSSLNK 44 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 571 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); in PHF-tau" FT /evidence="ECO:0000269|PubMed:16443603" FT CROSSLNK 576 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 584 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 598 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 615 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 628 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); in PHF-tau" FT /evidence="ECO:0000269|PubMed:16443603" FT CROSSLNK 634 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 638 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 648 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 660 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 664 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 670 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); in PHF-tau" FT /evidence="ECO:0000269|PubMed:16443603" FT CROSSLNK 686 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 692 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P10637" FT CROSSLNK 702 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:P10637" FT VAR_SEQ 1..44 FT /note="MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLK -> MLRA FT LQQRKR (in isoform Tau-A)" FT /evidence="ECO:0000303|PubMed:2516729" FT /id="VSP_003175" FT VAR_SEQ 45..73 FT /note="Missing (in isoform Tau-A, isoform Tau-D and isoform FT Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2498079, ECO:0000303|PubMed:2516729, FT ECO:0000303|PubMed:3131773, ECO:0000303|Ref.7" FT /id="VSP_003176" FT VAR_SEQ 74..102 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-D, isoform Tau-E and isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079, FT ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773, FT ECO:0000303|Ref.6, ECO:0000303|Ref.7" FT /id="VSP_003177" FT VAR_SEQ 103..104 FT /note="Missing (in isoform Tau-A)" FT /evidence="ECO:0000303|PubMed:2516729" FT /id="VSP_003178" FT VAR_SEQ 125..375 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-C, isoform Tau-D, isoform Tau-E, isoform Tau-F and FT isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079, FT ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773, FT ECO:0000303|Ref.6, ECO:0000303|Ref.7" FT /id="VSP_003179" FT VAR_SEQ 395..460 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-C, isoform Tau-D, isoform Tau-E, isoform Tau-F and FT isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2498079, FT ECO:0000303|PubMed:2516729, ECO:0000303|PubMed:3131773, FT ECO:0000303|Ref.6, ECO:0000303|Ref.7" FT /id="VSP_003180" FT VAR_SEQ 502 FT /note="S -> SATKQVQRRPPPAGPRSER (in isoform Tau-G)" FT /evidence="ECO:0000305" FT /id="VSP_026780" FT VAR_SEQ 592..622 FT /note="Missing (in isoform Tau-A, isoform Tau-B, isoform FT Tau-C and isoform Fetal-tau)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2484340, ECO:0000303|PubMed:2516729, FT ECO:0000303|PubMed:3131773, ECO:0000303|Ref.7" FT /id="VSP_003181" FT VARIANT 5 FT /note="R -> H (in FTD1; reduces the ability of tau to FT promote microtubule assembly and promotes fibril formation FT in vitro; dbSNP:rs63750959)" FT /evidence="ECO:0000269|PubMed:11921059" FT /id="VAR_019660" FT VARIANT 5 FT /note="R -> L (in PSNP1; delays assembly initiation and FT lowers the mass of microtubules formed; but the assembly FT rate is increased compared to normal tau; FT dbSNP:rs63750959)" FT /evidence="ECO:0000269|PubMed:12325083" FT /id="VAR_019661" FT VARIANT 17 FT /note="T -> M (in dbSNP:rs144611688)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064622" FT VARIANT 30 FT /note="T -> A (in dbSNP:rs748728879)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064623" FT VARIANT 285 FT /note="D -> N (risk factor for PSNP1; dbSNP:rs62063786)" FT /evidence="ECO:0000269|PubMed:10534245, FT ECO:0000269|PubMed:9629852" FT /id="VAR_010340" FT VARIANT 289 FT /note="V -> A (risk factor for PSNP1; dbSNP:rs62063787)" FT /evidence="ECO:0000269|PubMed:10534245, FT ECO:0000269|PubMed:9629852" FT /id="VAR_010341" FT VARIANT 370 FT /note="R -> W (in dbSNP:rs17651549)" FT /id="VAR_056121" FT VARIANT 441 FT /note="Y -> H (in dbSNP:rs2258689)" FT /evidence="ECO:0000269|PubMed:1420178, FT ECO:0000269|PubMed:15365985, ECO:0000269|PubMed:9629852" FT /id="VAR_010342" FT VARIANT 447 FT /note="S -> P (in dbSNP:rs10445337)" FT /evidence="ECO:0000269|PubMed:9629852" FT /id="VAR_010343" FT VARIANT 574 FT /note="K -> T (in PIDB; reduces the ability to promote FT microtubule assembly by 70%; dbSNP:rs63750129)" FT /evidence="ECO:0000269|PubMed:11089577, FT ECO:0000269|PubMed:11117542" FT /id="VAR_010344" FT VARIANT 583 FT /note="L -> V (in FTD1; less able to promote microtubule FT assembly than wild-type tau; dbSNP:rs63750349)" FT /evidence="ECO:0000269|PubMed:12509859" FT /id="VAR_019662" FT VARIANT 589 FT /note="G -> V (in FTD1; dbSNP:rs63750376)" FT /evidence="ECO:0000269|PubMed:9641683, FT ECO:0000269|PubMed:9973279" FT /id="VAR_010345" FT VARIANT 590 FT /note="G -> R (in FTD1; increased aggregation propensity FT and altered binding affinity towards microtubules and F- FT actin; dbSNP:rs1247408229)" FT /evidence="ECO:0000269|PubMed:32961270" FT /id="VAR_084361" FT VARIANT 596 FT /note="N -> K (in FTD1; with parkinsonism; FT dbSNP:rs63750756)" FT /evidence="ECO:0000269|PubMed:10412802, FT ECO:0000269|PubMed:10489057, ECO:0000269|PubMed:10802785, FT ECO:0000269|PubMed:12473774, ECO:0000269|PubMed:9789048" FT /id="VAR_010346" FT VARIANT 597 FT /note="Missing (in FTD1; dbSNP:rs63750688)" FT /evidence="ECO:0000269|PubMed:9973279" FT /id="VAR_010347" FT VARIANT 613 FT /note="N -> H (in FTD1; reduced the ability of tau to FT promote microtubule assembly without having a significant FT effect on tau filament formation; effects at both the RNA FT and the protein level; dbSNP:rs63750416)" FT /evidence="ECO:0000269|PubMed:11585254, FT ECO:0000269|PubMed:11906000" FT /id="VAR_019663" FT VARIANT 613 FT /note="Missing (in PSNP1/atypical PSNP1; heterozygosity may FT be a risk factor for both a PSNP1-like syndrome and FT Parkinson disease; reduced the ability of tau to promote FT microtubule assembly without having a significant effect on FT tau filament formation; effects at both the RNA and the FT protein level)" FT /evidence="ECO:0000269|PubMed:11220749, FT ECO:0000269|PubMed:11906000, ECO:0000269|PubMed:14991828, FT ECO:0000269|PubMed:14991829" FT /id="VAR_019664" FT VARIANT 617 FT /note="V -> I (in dbSNP:rs116733906)" FT /evidence="ECO:0000269|PubMed:20020531" FT /id="VAR_064624" FT VARIANT 618 FT /note="P -> L (in FTD1; most common mutation; reduction in FT the ability to promote microtubule assembly; accelerates FT aggregation of tau into filaments; dbSNP:rs63751273)" FT /evidence="ECO:0000269|PubMed:10214944, FT ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9736786, FT ECO:0000269|PubMed:9789048, ECO:0000269|PubMed:9973279" FT /id="VAR_010348" FT VARIANT 618 FT /note="P -> S (in FTD1 and CBD; reduction in the ability to FT promote microtubule assembly; dbSNP:rs63751438)" FT /evidence="ECO:0000269|PubMed:10374757, FT ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:11071507, FT ECO:0000269|PubMed:16240366" FT /id="VAR_010349" FT VARIANT 620 FT /note="G -> V (in PSNP1; dbSNP:rs63751391)" FT /evidence="ECO:0000269|PubMed:16157753" FT /id="VAR_037439" FT VARIANT 622 FT /note="S -> N (in FTD1; minimal parkinsonism; very early FT age of onset; dbSNP:rs63751165)" FT /evidence="ECO:0000269|PubMed:10208578" FT /id="VAR_010350" FT VARIANT 634 FT /note="K -> M (in FTD1; dbSNP:rs63750092)" FT /evidence="ECO:0000269|PubMed:15883319" FT /id="VAR_037440" FT VARIANT 637 FT /note="S -> F (in PIDB; markedly reduced ability of tau to FT promote microtubule assembly; dbSNP:rs63750635)" FT /evidence="ECO:0000269|PubMed:11891833" FT /id="VAR_019665" FT VARIANT 654 FT /note="V -> M (in FTD1; ultrastructural and biochemical FT characteristics indistinguishable from Alzheimer disease; FT accelerates aggregation of tau into filaments; FT dbSNP:rs63750570)" FT /evidence="ECO:0000269|PubMed:10214944, FT ECO:0000269|PubMed:9629852" FT /id="VAR_010351" FT VARIANT 659 FT /note="E -> V (in FTD1; dbSNP:rs63750711)" FT /evidence="ECO:0000269|PubMed:11117541" FT /id="VAR_019666" FT VARIANT 669 FT /note="S -> L (in fatal respiratory hypoventilation; FT unusual apparent autosomal recessive inheritance; reduced FT binding to microtubules as well as increased fibrillization FT and aggregation; dbSNP:rs63750425)" FT /evidence="ECO:0000269|PubMed:14595660" FT /id="VAR_019667" FT VARIANT 686 FT /note="K -> I (in PIDB; 90% reduction in the rate of FT microtubule assembly; dbSNP:rs63751264)" FT /evidence="ECO:0000269|PubMed:11601501" FT /id="VAR_019668" FT VARIANT 706 FT /note="G -> R (in PIDB; in vitro the mutation reduces the FT ability of tau to promote microtubule assembly by 25 to FT 30%; dbSNP:rs63750512)" FT /evidence="ECO:0000269|PubMed:10604746, FT ECO:0000269|PubMed:11117542" FT /id="VAR_010352" FT VARIANT 723 FT /note="R -> W (in FTD1/Alzheimer disease; accelerates FT aggregation of tau into filaments; reduces tau FT phosphorylation in cells compared to both the wild-type and FT other mutant forms; dbSNP:rs63750424)" FT /evidence="ECO:0000269|PubMed:10214944, FT ECO:0000269|PubMed:11278002, ECO:0000269|PubMed:11889249, FT ECO:0000269|PubMed:14517953, ECO:0000269|PubMed:26086902, FT ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9973279" FT /id="VAR_010353" FT MUTAGEN 515 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 516 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 519 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 531 FT /note="S->A: No decrease in microtubule-binding and FT nucleation activity after in vitro phosphorylation of FT mutant protein." FT MUTAGEN 548 FT /note="T->A: 50% Decrease in microtubule-binding after in FT vitro phosphorylation of mutant protein." FT MUTAGEN 548 FT /note="T->E: No association with plasma membrane." FT MUTAGEN 552 FT /note="S->A: 70% decrease in microtubule-binding after in FT vitro phosphorylation of mutant protein." FT MUTAGEN 552 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 579 FT /note="S->A: 8% decrease in microtubule-binding after in FT vitro phosphorylation of mutant protein." FT MUTAGEN 713 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 721 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 726 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 730 FT /note="S->E: No association with plasma membrane." FT MUTAGEN 739 FT /note="S->E: No association with plasma membrane." FT CONFLICT 48 FT /note="L -> P (in Ref. 6; AAU45390)" FT /evidence="ECO:0000305" FT CONFLICT 414 FT /note="H -> L (in Ref. 5; AAC04277)" FT /evidence="ECO:0000305" FT CONFLICT 557 FT /note="K -> M (in Ref. 12; AAS17881)" FT /evidence="ECO:0000305" FT CONFLICT 591 FT /note="K -> S (in Ref. 12; AAS17881)" FT /evidence="ECO:0000305" FT CONFLICT 617 FT /note="V -> Q (in Ref. 17; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 622 FT /note="S -> K (in Ref. 17; AA sequence)" FT /evidence="ECO:0000305" FT STRAND 7..9 FT /evidence="ECO:0007829|PDB:6N4P" FT HELIX 60..62 FT /evidence="ECO:0007829|PDB:5ZV3" FT TURN 63..65 FT /evidence="ECO:0007829|PDB:5ZV3" FT TURN 579..582 FT /evidence="ECO:0007829|PDB:6CVJ" FT STRAND 587..590 FT /evidence="ECO:0007829|PDB:5N5A" FT STRAND 592..610 FT /evidence="ECO:0007829|PDB:7P6A" FT STRAND 613..615 FT /evidence="ECO:0007829|PDB:7QK6" FT STRAND 618..620 FT /evidence="ECO:0007829|PDB:5MP5" FT STRAND 624..626 FT /evidence="ECO:0007829|PDB:8OP0" FT STRAND 629..631 FT /evidence="ECO:0007829|PDB:7QKZ" FT STRAND 634..643 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 645..648 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 654..660 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 662..665 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 667..671 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 673..679 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 682..684 FT /evidence="ECO:0007829|PDB:7P6A" FT STRAND 685..695 FT /evidence="ECO:0007829|PDB:8Q98" FT STRAND 698..703 FT /evidence="ECO:0007829|PDB:7R5H" FT STRAND 709..712 FT /evidence="ECO:0007829|PDB:7QKY" FT STRAND 716..720 FT /evidence="ECO:0007829|PDB:7SP1" FT STRAND 723..732 FT /evidence="ECO:0007829|PDB:7QKY" FT STRAND 734..736 FT /evidence="ECO:0007829|PDB:8FYU" FT STRAND 741..751 FT /evidence="ECO:0007829|PDB:7QKY" FT STRAND 753..755 FT /evidence="ECO:0007829|PDB:7QKY" SQ SEQUENCE 758 AA; 78928 MW; D46C66CDBCD196E8 CRC64; MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQAA AQPHTEIPEG TTAEEAGIGD TPSLEDEAAG HVTQEPESGK VVQEGFLREP GPPGLSHQLM SGMPGAPLLP EGPREATRQP SGTGPEDTEG GRHAPELLKH QLLGDLHQEG PPLKGAGGKE RPGSKEEVDE DRDVDESSPQ DSPPSKASPA QDGRPPQTAA REATSIPGFP AEGAIPLPVD FLSKVSTEIP ASEPDGPSVG RAKGQDAPLE FTFHVEITPN VQKEQAHSEE HLGRAAFPGA PGEGPEARGP SLGEDTKEAD LPEPSEKQPA AAPRGKPVSR VPQLKARMVS KSKDGTGSDD KKAKTSTRSS AKTLKNRPCL SPKHPTPGSS DPLIQPSSPA VCPEPPSSPK YVSSVTSRTG SSGAKEMKLK GADGKTKIAT PRGAAPPGQK GQANATRIPA KTPPAPKTPP SSGEPPKSGD RSGYSSPGSP GTPGSRSRTP SLPTPPTREP KKVAVVRTPP KSPSSAKSRL QTAPVPMPDL KNVKSKIGST ENLKHQPGGG KVQIINKKLD LSNVQSKCGS KDNIKHVPGG GSVQIVYKPV DLSKVTSKCG SLGNIHHKPG GGQVEVKSEK LDFKDRVQSK IGSLDNITHV PGGGNKKIET HKLTFRENAK AKTDHGAEIV YKSPVVSGDT SPRHLSNVSS TGSIDMVDSP QLATLADEVS ASLAKQGL // ID TERA_HUMAN Reviewed; 806 AA. AC P55072; B2R5T8; Q0V924; Q2TAI5; Q969G7; Q9UCD5; V9HW80; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 4. DT 28-JAN-2026, entry version 248. DE RecName: Full=Transitional endoplasmic reticulum ATPase; DE Short=TER ATPase; DE EC=3.6.4.6 {ECO:0000269|PubMed:26471729}; DE AltName: Full=15S Mg(2+)-ATPase p97 subunit; DE AltName: Full=Valosin-containing protein; DE Short=VCP; GN Name=VCP; GN Synonyms=HEL-220 {ECO:0000312|EMBL:ACI46036.1}, GN HEL-S-70 {ECO:0000312|EMBL:ACI46044.1}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Lamerdin J.E., McCready P.M., Skowronski E., Adamson A.W., RA Burkhart-Schultz K., Gordon L., Kyle A., Ramirez M., Stilwagen S., Phan H., RA Velasco N., Garnes J., Danganan L., Poundstone P., Christensen M., RA Georgescu A., Avila J., Liu S., Attix C., Andreise T., Trankheim M., RA Amico-Keller G., Coefield J., Duarte S., Lucas S., Bruce R., Thomas P., RA Quan G., Kronmiller B., Arellano A., Montgomery M., Ow D., Nolan M., RA Trong S., Kobayashi A., Olsen A.O., Carrano A.V.; RT "Sequence analysis of a human P1 clone containing the XRCC9 DNA repair RT gene."; RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Li J., Wang H., Liu J., Liu F.; RL Submitted (SEP-2008) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pituitary; RX PubMed=10931946; DOI=10.1073/pnas.160270997; RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J., RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., RA Chen M.-D., Chen J.-L.; RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis RT and full-length cDNA cloning."; RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 2-25. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., RA Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass spectrometric RT identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [9] RP PROTEIN SEQUENCE OF 2-18; 148-155; 278-287; 296-312; 366-377; 466-487; RP 587-599; 639-651 AND 669-677, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION RP AT ALA-2, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Platelet; RA Bienvenut W.V., Claeys D.; RL Submitted (NOV-2005) to UniProtKB. RN [10] RP PROTEIN SEQUENCE OF 27-41 AND 233-238, AND INTERACTION WITH CLATHRIN. RC TISSUE=Glial tumor; RX PubMed=8413590; DOI=10.1038/365459a0; RA Pleasure I.T., Black M.M., Keen J.H.; RT "Valosin-containing protein, VCP, is a ubiquitous clathrin-binding RT protein."; RL Nature 365:459-462(1993). RN [11] RP PROTEIN SEQUENCE OF 46-53; 66-81; 96-109; 148-155; 240-251; 323-336; RP 454-502; 530-560; 600-614; 639-651; 678-693; 714-732 AND 754-766, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [12] RP PROTEIN SEQUENCE OF 314-322, IDENTIFICATION BY MASS SPECTROMETRY, RP METHYLATION AT LYS-315, MUTAGENESIS OF LYS-315, CHARACTERIZATION OF RP VARIANTS IBMPFD1 HIS-155 AND GLN-191, AND CHARACTERIZATION OF VARIANT RP FTDALS6 GLY-159. RX PubMed=23349634; DOI=10.1371/journal.pgen.1003210; RA Cloutier P., Lavallee-Adam M., Faubert D., Blanchette M., Coulombe B.; RT "A newly uncovered group of distantly related lysine methyltransferases RT preferentially interact with molecular chaperones to regulate their RT activity."; RL PLoS Genet. 9:E1003210-E1003210(2013). RN [13] RP NUCLEOTIDE SEQUENCE [MRNA] OF 388-483. RC TISSUE=Fetal brain; RA Dmitrenko V.V., Garifulin O.M., Kavsan V.M.; RT "Characterization of different mRNA types expressed in human brain."; RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases. RN [14] RP INTERACTION WITH NGLY1. RX PubMed=15362974; DOI=10.1042/bj20041498; RA McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P.; RT "A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is RT a substrate for SAPKs."; RL Biochem. J. 384:391-400(2004). RN [15] RP FUNCTION, INTERACTION WITH RNF19A, IDENTIFICATION BY MASS SPECTROMETRY, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-524. RX PubMed=15456787; DOI=10.1074/jbc.m406683200; RA Ishigaki S., Hishikawa N., Niwa J., Iemura S., Natsume T., Hori S., RA Kakizuka A., Tanaka K., Sobue G.; RT "Physical and functional interaction between dorfin and valosin-containing RT protein that are colocalized in ubiquitylated inclusions in RT neurodegenerative disorders."; RL J. Biol. Chem. 279:51376-51385(2004). RN [16] RP INTERACTION WITH SELENOS, AND SUBCELLULAR LOCATION. RX PubMed=15215856; DOI=10.1038/nature02656; RA Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A.; RT "A membrane protein complex mediates retro-translocation from the ER lumen RT into the cytosol."; RL Nature 429:841-847(2004). RN [17] RP ISGYLATION. RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132; RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J., RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.; RT "Proteomic identification of proteins conjugated to ISG15 in mouse and RT human cells."; RL Biochem. Biophys. Res. Commun. 336:496-506(2005). RN [18] RP INTERACTION WITH SYVN1 AND DERL1. RX PubMed=16289116; DOI=10.1016/j.jmb.2005.10.020; RA Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S., Wiertz E., RA Koning F., Kloetzel P.-M., Seeger M.; RT "The ubiquitin-domain protein HERP forms a complex with components of the RT endoplasmic reticulum associated degradation pathway."; RL J. Mol. Biol. 354:1021-1027(2005). RN [19] RP INTERACTION WITH AMFR, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP LYS-251 AND LYS-524. RX PubMed=16168377; DOI=10.1016/j.molcel.2005.08.009; RA Song B.L., Sever N., DeBose-Boyd R.A.; RT "Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and RT couples sterol-regulated ubiquitination to degradation of HMG CoA RT reductase."; RL Mol. Cell 19:829-840(2005). RN [20] RP FUNCTION, AND INTERACTION WITH DERL1; AMFR; SYVN1 AND SELENOS. RX PubMed=16186510; DOI=10.1073/pnas.0505006102; RA Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E., Rapoport T.A.; RT "Recruitment of the p97 ATPase and ubiquitin ligases to the site of RT retrotranslocation at the endoplasmic reticulum membrane."; RL Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005). RN [21] RP INTERACTION WITH DERL1 AND DERL2. RX PubMed=16186509; DOI=10.1073/pnas.0505014102; RA Lilley B.N., Ploegh H.L.; RT "Multiprotein complexes that link dislocation, ubiquitination, and RT extraction of misfolded proteins from the endoplasmic reticulum membrane."; RL Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005). RN [22] RP INTERACTION WITH CASR AND RNF19A. RX PubMed=16513638; DOI=10.1074/jbc.m513552200; RA Huang Y., Niwa J., Sobue G., Breitwieser G.E.; RT "Calcium-sensing receptor ubiquitination and degradation mediated by the E3 RT ubiquitin ligase dorfin."; RL J. Biol. Chem. 281:11610-11617(2006). RN [23] RP INTERACTION WITH DERL1; DERL2 AND DERL3. RX PubMed=16449189; DOI=10.1083/jcb.200507057; RA Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K.; RT "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein RT response and are required for ER-associated degradation."; RL J. Cell Biol. 172:383-393(2006). RN [24] RP INTERACTION WITH UBXN4. RX PubMed=16968747; DOI=10.1242/jcs.03163; RA Liang J., Yin C., Doong H., Fang S., Peterhoff C., Nixon R.A., RA Monteiro M.J.; RT "Characterization of erasin (UBXD2): a new ER protein that promotes ER- RT associated protein degradation."; RL J. Cell Sci. 119:4011-4024(2006). RN [25] RP INTERACTION WITH SVIP AND DERL1. RX PubMed=17872946; DOI=10.1074/jbc.m704446200; RA Ballar P., Zhong Y., Nagahama M., Tagaya M., Shen Y., Fang S.; RT "Identification of SVIP as an endogenous inhibitor of endoplasmic RT reticulum-associated degradation."; RL J. Biol. Chem. 282:33908-33914(2007). RN [26] RP INTERACTION WITH TRIM13. RX PubMed=17314412; DOI=10.1091/mbc.e06-03-0248; RA Lerner M., Corcoran M., Cepeda D., Nielsen M.L., Zubarev R., Ponten F., RA Uhlen M., Hober S., Grander D., Sangfelt O.; RT "The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin RT ligase involved in ERAD."; RL Mol. Biol. Cell 18:1670-1682(2007). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [28] RP INTERACTION WITH RNF103. RX PubMed=18675248; DOI=10.1016/j.bbrc.2008.07.126; RA Maruyama Y., Yamada M., Takahashi K., Yamada M.; RT "Ubiquitin ligase Kf-1 is involved in the endoplasmic reticulum-associated RT degradation pathway."; RL Biochem. Biophys. Res. Commun. 374:737-741(2008). RN [29] RP INTERACTION WITH UBXN6. RX PubMed=18656546; DOI=10.1016/j.biocel.2008.06.008; RA Madsen L., Andersen K.M., Prag S., Moos T., Semple C.A., Seeger M., RA Hartmann-Petersen R.; RT "Ubxd1 is a novel co-factor of the human p97 ATPase."; RL Int. J. Biochem. Cell Biol. 40:2927-2942(2008). RN [30] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; THR-436 AND SER-787, 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 [31] RP INTERACTION WITH TRIM21. RX PubMed=18022694; DOI=10.1016/j.molimm.2007.10.023; RA Takahata M., Bohgaki M., Tsukiyama T., Kondo T., Asaka M., Hatakeyama S.; RT "Ro52 functionally interacts with IgG1 and regulates its quality control RT via the ERAD system."; RL Mol. Immunol. 45:2045-2054(2008). RN [32] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [33] RP INTERACTION WITH UBXN6. RX PubMed=19174149; DOI=10.1016/j.bbrc.2009.01.076; RA Kern M., Fernandez-Saiz V., Schaefer Z., Buchberger A.; RT "UBXD1 binds p97 through two independent binding sites."; RL Biochem. Biophys. Res. Commun. 380:303-307(2009). RN [34] RP INTERACTION WITH UBXN6. RX PubMed=19275885; DOI=10.1016/j.bbrc.2009.03.012; RA Nagahama M., Ohnishi M., Kawate Y., Matsui T., Miyake H., Yuasa K., RA Tani K., Tagaya M., Tsuji A.; RT "UBXD1 is a VCP-interacting protein that is involved in ER-associated RT degradation."; RL Biochem. Biophys. Res. Commun. 382:303-308(2009). RN [35] RP INTERACTION WITH UBXN4, AND IDENTIFICATION IN A COMPLEX WITH UBQLN1 AND RP UBXN4. RX PubMed=19822669; DOI=10.1083/jcb.200903024; RA Lim P.J., Danner R., Liang J., Doong H., Harman C., Srinivasan D., RA Rothenberg C., Wang H., Ye Y., Fang S., Monteiro M.J.; RT "Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD."; RL J. Cell Biol. 187:201-217(2009). RN [36] RP INTERACTION WITH YOD1. RX PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016; RA Ernst R., Mueller B., Ploegh H.L., Schlieker C.; RT "The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to RT facilitate protein dislocation from the ER."; RL Mol. Cell 36:28-38(2009). RN [37] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-3 AND SER-37, CLEAVAGE OF INITIATOR METHIONINE [LARGE RP SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP 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 [38] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-770 AND SER-775, 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 [39] RP INTERACTION WITH WASHC5. RX PubMed=20833645; DOI=10.1093/brain/awq222; RA Clemen C.S., Tangavelou K., Strucksberg K.H., Just S., Gaertner L., RA Regus-Leidig H., Stumpf M., Reimann J., Coras R., Morgan R.O., RA Fernandez M.P., Hofmann A., Muller S., Schoser B., Hanisch F.G., RA Rottbauer W., Blumcke I., von Horsten S., Eichinger L., Schroder R.; RT "Strumpellin is a novel valosin-containing protein binding partner linking RT hereditary spastic paraplegia to protein aggregation diseases."; RL Brain 133:2920-2941(2010). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [41] RP 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 [42] RP FUNCTION IN OMM PROTEIN TURNOVER. RX PubMed=21118995; DOI=10.1091/mbc.e10-09-0748; RA Xu S., Peng G., Wang Y., Fang S., Karbowski M.; RT "The AAA-ATPase p97 is essential for outer mitochondrial membrane protein RT turnover."; RL Mol. Biol. Cell 22:291-300(2011). RN [43] RP INTERACTION WITH BAG6. RX PubMed=21636303; DOI=10.1016/j.molcel.2011.05.010; RA Wang Q., Liu Y., Soetandyo N., Baek K., Hegde R., Ye Y.; RT "A ubiquitin ligase-associated chaperone holdase maintains polypeptides in RT soluble states for proteasome degradation."; RL Mol. Cell 42:758-770(2011). RN [44] RP FUNCTION, INTERACTION WITH CAV1 AND UBXN6, CHARACTERIZATION OF VARIANTS RP IBMPFD1 GLY-95; HIS-155 AND GLU-232, AND MUTAGENESIS OF GLU-578. RX PubMed=21822278; DOI=10.1038/ncb2301; RA Ritz D., Vuk M., Kirchner P., Bug M., Schuetz S., Hayer A., Bremer S., RA Lusk C., Baloh R.H., Lee H., Glatter T., Gstaiger M., Aebersold R., RA Weihl C.C., Meyer H.; RT "Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and RT UBXD1 and impaired by VCP disease mutations."; RL Nat. Cell Biol. 13:1116-1123(2011). RN [45] RP FUNCTION. RX PubMed=22020440; DOI=10.1038/ncb2367; RA Meerang M., Ritz D., Paliwal S., Garajova Z., Bosshard M., Mailand N., RA Janscak P., Hubscher U., Meyer H., Ramadan K.; RT "The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA RT double-strand breaks."; RL Nat. Cell Biol. 13:1376-1382(2011). RN [46] RP FUNCTION, INTERACTION WITH L3MBTL1, AND SUBCELLULAR LOCATION. RX PubMed=22120668; DOI=10.1038/nsmb.2188; RA Acs K., Luijsterburg M.S., Ackermann L., Salomons F.A., Hoppe T., RA Dantuma N.P.; RT "The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from RT DNA double-strand breaks."; RL Nat. Struct. Mol. Biol. 18:1345-1350(2011). RN [47] RP INTERACTION WITH UBXN8. RX PubMed=21949850; DOI=10.1371/journal.pone.0025061; RA Madsen L., Kriegenburg F., Vala A., Best D., Prag S., Hofmann K., RA Seeger M., Adams I.R., Hartmann-Petersen R.; RT "The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum RT membrane for degradation of misfolded proteins."; RL PLoS ONE 6:E25061-E25061(2011). RN [48] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-3, CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE RP ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [49] RP INTERACTION WITH UBXN7. RX PubMed=22537386; DOI=10.1186/1741-7007-10-36; RA Bandau S., Knebel A., Gage Z.O., Wood N.T., Alexandru G.; RT "UBXN7 docks on neddylated cullin complexes using its UIM motif and causes RT HIF1alpha accumulation."; RL BMC Biol. 10:36-36(2012). RN [50] RP INTERACTION WITH RHBDD1, MUTAGENESIS OF LYS-251; LYS-524 AND GLU-578, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22795130; DOI=10.1016/j.molcel.2012.06.008; RA Fleig L., Bergbold N., Sahasrabudhe P., Geiger B., Kaltak L., Lemberg M.K.; RT "Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of RT membrane proteins."; RL Mol. Cell 47:558-569(2012). RN [51] RP INTERACTION WITH SPRTN. RX PubMed=22902628; DOI=10.1074/jbc.m112.400135; RA Ghosal G., Leung J.W., Nair B.C., Fong K.W., Chen J.; RT "Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a RT regulator of translesion synthesis."; RL J. Biol. Chem. 287:34225-34233(2012). RN [52] RP FUNCTION IN ERAD PATHWAY. RX PubMed=22607976; DOI=10.1016/j.molcel.2012.04.015; RA Sato T., Sako Y., Sho M., Momohara M., Suico M.A., Shuto T., Nishitoh H., RA Okiyoneda T., Kokame K., Kaneko M., Taura M., Miyata M., Chosa K., Koga T., RA Morino-Koga S., Wada I., Kai H.; RT "STT3B-dependent posttranslational N-glycosylation as a surveillance system RT for secretory protein."; RL Mol. Cell 47:99-110(2012). RN [53] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [54] RP METHYLATION AT LYS-315, AND MUTAGENESIS OF LYS-312; ARG-313; GLU-314; RP LYS-315; THR-316; HIS-317 AND GLY-318. RX PubMed=22948820; DOI=10.1038/ncomms2041; RA Kernstock S., Davydova E., Jakobsson M., Moen A., Pettersen S., RA Maelandsmo G.M., Egge-Jacobsen W., Falnes P.O.; RT "Lysine methylation of VCP by a member of a novel human protein RT methyltransferase family."; RL Nat. Commun. 3:1038-1038(2012). RN [55] RP FUNCTION, AND INTERACTION WITH SPRTN. RX PubMed=23042607; DOI=10.1038/nsmb.2394; RA Davis E.J., Lachaud C., Appleton P., Macartney T.J., Nathke I., Rouse J.; RT "DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA RT damage."; RL Nat. Struct. Mol. Biol. 19:1093-1100(2012). RN [56] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SPRTN. RX PubMed=23042605; DOI=10.1038/nsmb.2395; RA Mosbech A., Gibbs-Seymour I., Kagias K., Thorslund T., Beli P., Povlsen L., RA Nielsen S.V., Smedegaard S., Sedgwick G., Lukas C., Hartmann-Petersen R., RA Lukas J., Choudhary C., Pocock R., Bekker-Jensen S., Mailand N.; RT "DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes RT ubiquitin-dependent responses to replication blocks."; RL Nat. Struct. Mol. Biol. 19:1084-1092(2012). RN [57] RP FUNCTION. RX PubMed=23335559; DOI=10.1074/jbc.m112.429076; RA Kirchner P., Bug M., Meyer H.; RT "Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal RT sorting by the VCP/p97 AAA-ATPase."; RL J. Biol. Chem. 288:7363-7372(2013). RN [58] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; SER-7; SER-13; SER-462 AND RP SER-702, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [59] RP INTERACTION WITH ZFAND2B. RX PubMed=24160817; DOI=10.1042/bj20130710; RA Glinka T., Alter J., Braunstein I., Tzach L., Wei Sheng C., Geifman S., RA Edelmann M.J., Kessler B.M., Stanhill A.; RT "Signal-peptide-mediated translocation is regulated by a p97-AIRAPL RT complex."; RL Biochem. J. 457:253-261(2014). RN [60] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [61] RP INTERACTION WITH RNF31. RX PubMed=24726327; DOI=10.1016/j.molcel.2014.03.016; RA Schaeffer V., Akutsu M., Olma M.H., Gomes L.C., Kawasaki M., Dikic I.; RT "Binding of OTULIN to the PUB domain of HOIP controls NF-kappaB RT signaling."; RL Mol. Cell 54:349-361(2014). RN [62] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH STUB1; UBXN2A AND CHRNA3, AND RP INTERACTION WITH UBXN2A. RX PubMed=26265139; DOI=10.1016/j.bcp.2015.08.084; RA Teng Y., Rezvani K., De Biasi M.; RT "UBXN2A regulates nicotinic receptor degradation by modulating the E3 RT ligase activity of CHIP."; RL Biochem. Pharmacol. 97:518-530(2015). RN [63] RP FUNCTION. RX PubMed=26565908; DOI=10.1016/j.celrep.2015.09.047; RA Kadowaki H., Nagai A., Maruyama T., Takami Y., Satrimafitrah P., Kato H., RA Honda A., Hatta T., Natsume T., Sato T., Kai H., Ichijo H., Nishitoh H.; RT "Pre-emptive quality control protects the ER from protein overload via the RT proximity of ERAD components and SRP."; RL Cell Rep. 13:944-956(2015). RN [64] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH RIGI AND RNF125, AND RP MUTAGENESIS OF 52-PHE--ASP-55; TYR-110; GLU-305 AND GLU-578. RX PubMed=26471729; DOI=10.15252/embj.201591888; RA Hao Q., Jiao S., Shi Z., Li C., Meng X., Zhang Z., Wang Y., Song X., RA Wang W., Zhang R., Zhao Y., Wong C.C., Zhou Z.; RT "A non-canonical role of the p97 complex in RIG-I antiviral signaling."; RL EMBO J. 34:2903-2920(2015). RN [65] RP INTERACTION WITH ZFAND2B. RX PubMed=26337389; DOI=10.1091/mbc.e15-02-0085; RA Braunstein I., Zach L., Allan S., Kalies K.U., Stanhill A.; RT "Proteasomal degradation of preemptive quality control (pQC) substrates is RT mediated by an AIRAPL-p97 complex."; RL Mol. Biol. Cell 26:3719-3727(2015). RN [66] RP INTERACTION WITH UBXN10. RX PubMed=26389662; DOI=10.1038/ncb3238; RA Raman M., Sergeev M., Garnaas M., Lydeard J.R., Huttlin E.L., Goessling W., RA Shah J.V., Harper J.W.; RT "Systematic proteomics of the VCP-UBXD adaptor network identifies a role RT for UBXN10 in regulating ciliogenesis."; RL Nat. Cell Biol. 17:1356-1369(2015). RN [67] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [68] RP INTERACTION WITH FAF1, AND SUBCELLULAR LOCATION. RX PubMed=26842564; DOI=10.1038/ncomms10612; RA Franz A., Pirson P.A., Pilger D., Halder S., Achuthankutty D., Kashkar H., RA Ramadan K., Hoppe T.; RT "Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard RT DNA replication fork progression."; RL Nat. Commun. 7:10612-10612(2016). RN [69] RP FUNCTION. RX PubMed=26692333; DOI=10.1038/nm.4013; RA Osorio F.G., Soria-Valles C., Santiago-Fernandez O., Bernal T., RA Mittelbrunn M., Colado E., Rodriguez F., Bonzon-Kulichenko E., Vazquez J., RA Porta-de-la-Riva M., Ceron J., Fueyo A., Li J., Green A.R., Freije J.M., RA Lopez-Otin C.; RT "Loss of the proteostasis factor AIRAPL causes myeloid transformation by RT deregulating IGF-1 signaling."; RL Nat. Med. 22:91-96(2016). RN [70] RP INTERACTION WITH ANKZF1. RX PubMed=28302725; DOI=10.1074/jbc.m116.772038; RA van Haaften-Visser D.Y., Harakalova M., Mocholi E., van Montfrans J.M., RA Elkadri A., Rieter E., Fiedler K., van Hasselt P.M., Triffaux E.M.M., RA van Haelst M.M., Nijman I.J., Kloosterman W.P., Nieuwenhuis E.E.S., RA Muise A.M., Cuppen E., Houwen R.H.J., Coffer P.J.; RT "Ankyrin repeat and zinc-finger domain-containing 1 mutations are RT associated with infantile-onset inflammatory bowel disease."; RL J. Biol. Chem. 292:7904-7920(2017). RN [71] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-8 AND LYS-18, AND IDENTIFICATION RP BY MASS 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 [72] RP INTERACTION WITH ATXN3. RX PubMed=30455355; DOI=10.1074/jbc.ra118.005801; RA Weishaeupl D., Schneider J., Peixoto Pinheiro B., Ruess C., Dold S.M., RA von Zweydorf F., Gloeckner C.J., Schmidt J., Riess O., Schmidt T.; RT "Physiological and pathophysiological characteristics of ataxin-3 RT isoforms."; RL J. Biol. Chem. 294:644-661(2019). RN [73] RP INTERACTION WITH LMBR1L. RX PubMed=31073040; DOI=10.1126/science.aau0812; RA Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J., RA Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M., RA Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y., RA Beutler B.; RT "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling."; RL Science 364:0-0(2019). RN [74] RP FUNCTION, AND INTERACTION WITH TEX264. RX PubMed=32152270; DOI=10.1038/s41467-020-15000-w; RA Fielden J., Wiseman K., Torrecilla I., Li S., Hume S., Chiang S.C., RA Ruggiano A., Narayan Singh A., Freire R., Hassanieh S., Domingo E., RA Vendrell I., Fischer R., Kessler B.M., Maughan T.S., El-Khamisy S.F., RA Ramadan K.; RT "TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1- RT DNA adducts."; RL Nat. Commun. 11:1274-1274(2020). RN [75] RP FUNCTION. RX PubMed=34739333; DOI=10.1126/science.abf6548; RA Gwon Y., Maxwell B.A., Kolaitis R.M., Zhang P., Kim H.J., Taylor J.P.; RT "Ubiquitination of G3BP1 mediates stress granule disassembly in a context- RT specific manner."; RL Science 372:eabf6548-eabf6548(2021). RN [76] RP FUNCTION. RX PubMed=35013556; DOI=10.1038/s41556-021-00807-6; RA Krastev D.B., Li S., Sun Y., Wicks A.J., Hoslett G., Weekes D., RA Badder L.M., Knight E.G., Marlow R., Pardo M.C., Yu L., Talele T.T., RA Bartek J., Choudhary J.S., Pommier Y., Pettitt S.J., Tutt A.N.J., RA Ramadan K., Lord C.J.; RT "The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from RT chromatin."; RL Nat. Cell Biol. 24:62-73(2022). RN [77] RP FUNCTION, UFMYLATION AT LYS-109, INTERACTION WITH NPLOC4, AND MUTAGENESIS RP OF LYS-109 AND TYR-110. RX PubMed=38762759; DOI=10.1080/15548627.2024.2356488; RA Wang Z., Xiong S., Wu Z., Wang X., Gong Y., Zhu W.G., Xu X.; RT "VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of RT autophagy."; RL Autophagy 20:2041-2054(2024). RN [78] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-481 IN COMPLEX WITH ATP ANALOG, RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155, MUTAGENESIS OF RP ARG-53 AND ARG-86, AND SUBUNIT. RX PubMed=20512113; DOI=10.1038/emboj.2010.104; RA Tang W.K., Li D., Li C.C., Esser L., Dai R., Guo L., Xia D.; RT "A novel ATP-dependent conformation in p97 N-D1 fragment revealed by RT crystal structures of disease-related mutants."; RL EMBO J. 29:2217-2229(2010). RN [79] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 797-806 IN COMPLEX WITH PLAA. RX PubMed=19887378; DOI=10.1074/jbc.m109.044685; RA Qiu L., Pashkova N., Walker J.R., Winistorfer S., Allali-Hassani A., RA Akutsu M., Piper R., Dhe-Paganon S.; RT "Structure and function of the PLAA/Ufd3-p97/Cdc48 complex."; RL J. Biol. Chem. 285:365-372(2010). RN [80] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-187 IN COMPLEX WITH AMFR. RX PubMed=21914798; DOI=10.1074/jbc.m111.274506; RA Hanzelmann P., Schindelin H.; RT "The structural and functional basis of the p97/valosin-containing protein RT (VCP)-interacting motif (VIM): mutually exclusive binding of cofactors to RT the N-terminal domain of p97."; RL J. Biol. Chem. 286:38679-38690(2011). RN [81] {ECO:0007744|PDB:5GLF} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 21-199 IN COMPLEX WITH DERL1, RP INTERACTION WITH DERL1, AND MUTAGENESIS OF 113-ARG--HIS-115; PHE-131; RP LEU-140; ASP-179 AND HIS-183. RX PubMed=27714797; DOI=10.1002/1873-3468.12447; RA Lim J.J., Lee Y., Yoon S.Y., Ly T.T., Kang J.Y., Youn H.S., An J.Y., RA Lee J.G., Park K.R., Kim T.G., Yang J.K., Jun Y., Eom S.H.; RT "Structural insights into the interaction of human p97 N-terminal domain RT and SHP motif in Derlin-1 rhomboid pseudoprotease."; RL FEBS Lett. 590:4402-4413(2016). RN [82] RP VARIANTS IBMPFD1 GLY-95; CYS-155; HIS-155; PRO-155; GLN-191 AND GLU-232. RX PubMed=15034582; DOI=10.1038/ng1332; RA Watts G.D.J., Wymer J., Kovach M.J., Mehta S.G., Mumm S., Darvish D., RA Pestronk A., Whyte M.P., Kimonis V.E.; RT "Inclusion body myopathy associated with Paget disease of bone and RT frontotemporal dementia is caused by mutant valosin-containing protein."; RL Nat. Genet. 36:377-381(2004). RN [83] RP VARIANT IBMPFD1 CYS-155. RX PubMed=15732117; DOI=10.1002/ana.20407; RA Schroeder R., Watts G.D.J., Mehta S.G., Evert B.O., Broich P., RA Fliessbach K., Pauls K., Hans V.H., Kimonis V., Thal D.R.; RT "Mutant valosin-containing protein causes a novel type of frontotemporal RT dementia."; RL Ann. Neurol. 57:457-461(2005). RN [84] RP VARIANT IBMPFD1 HIS-159. RX PubMed=16247064; DOI=10.1212/01.wnl.0000180407.15369.92; RA Haubenberger D., Bittner R.E., Rauch-Shorny S., Zimprich F., Mannhalter C., RA Wagner L., Mineva I., Vass K., Auff E., Zimprich A.; RT "Inclusion body myopathy and Paget disease is linked to a novel mutation in RT the VCP gene."; RL Neurology 65:1304-1305(2005). RN [85] RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155. RX PubMed=16321991; DOI=10.1093/hmg/ddi426; RA Weihl C.C., Dalal S., Pestronk A., Hanson P.I.; RT "Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic RT reticulum-associated degradation."; RL Hum. Mol. Genet. 15:189-199(2006). RN [86] RP VARIANTS IBMPFD1 TRP-198 AND HIS-387. RX PubMed=17935506; DOI=10.1111/j.1399-0004.2007.00887.x; RA Watts G.D., Thomasova D., Ramdeen S.K., Fulchiero E.C., Mehta S.G., RA Drachman D.A., Weihl C.C., Jamrozik Z., Kwiecinski H., Kaminska A., RA Kimonis V.E.; RT "Novel VCP mutations in inclusion body myopathy associated with Paget RT disease of bone and frontotemporal dementia."; RL Clin. Genet. 72:420-426(2007). RN [87] RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; SER-155 AND GLU-232, RP MUTAGENESIS OF GLU-305 AND GLU-578, AND FUNCTION. RX PubMed=20104022; DOI=10.4161/auto.6.2.11014; RA Tresse E., Salomons F.A., Vesa J., Bott L.C., Kimonis V., Yao T.P., RA Dantuma N.P., Taylor J.P.; RT "VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes RT and this function is impaired by mutations that cause IBMPFD."; RL Autophagy 6:217-227(2010). RN [88] RP FUNCTION, INTERACTION WITH ZFAND1, MUTAGENESIS OF GLU-578, AND RP CHARACTERIZATION OF VARIANT IBMPFD1 HIS-155. RX PubMed=29804830; DOI=10.1016/j.molcel.2018.04.021; RA Turakhiya A., Meyer S.R., Marincola G., Boehm S., Vanselow J.T., RA Schlosser A., Hofmann K., Buchberger A.; RT "ZFAND1 recruits p97 and the 26S proteasome to promote the clearance of RT arsenite-induced stress granules."; RL Mol. Cell 70:906-919(2018). RN [89] RP INTERACTION WITH FBXL4. RX PubMed=36896912; DOI=10.15252/embj.2022113033; RA Cao Y., Zheng J., Wan H., Sun Y., Fu S., Liu S., He B., Cai G., Cao Y., RA Huang H., Li Q., Ma Y., Chen S., Wang F., Jiang H.; RT "A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and RT NIX to restrain mitophagy and prevent mitochondrial disease."; RL EMBO J. 42:e113033-e113033(2023). RN [90] RP VARIANTS IBMPFD1 LEU-155 AND TRP-198. RX PubMed=20335036; DOI=10.1016/j.nmd.2010.03.002; RA Kumar K.R., Needham M., Mina K., Davis M., Brewer J., Staples C., Ng K., RA Sue C.M., Mastaglia F.L.; RT "Two Australian families with inclusion-body myopathy, Paget's disease of RT bone and frontotemporal dementia: novel clinical and genetic findings."; RL Neuromuscul. Disord. 20:330-334(2010). RN [91] RP VARIANTS FTDALS6 HIS-155; GLY-159; GLN-191 AND ASN-592. RX PubMed=21145000; DOI=10.1016/j.neuron.2010.11.036; RA Johnson J.O., Mandrioli J., Benatar M., Abramzon Y., Van Deerlin V.M., RA Trojanowski J.Q., Gibbs J.R., Brunetti M., Gronka S., Wuu J., Ding J., RA McCluskey L., Martinez-Lage M., Falcone D., Hernandez D.G., Arepalli S., RA Chong S., Schymick J.C., Rothstein J., Landi F., Wang Y.D., Calvo A., RA Mora G., Sabatelli M., Monsurro M.R., Battistini S., Salvi F., Spataro R., RA Sola P., Borghero G., Galassi G., Scholz S.W., Taylor J.P., Restagno G., RA Chio A., Traynor B.J.; RT "Exome sequencing reveals VCP mutations as a cause of familial ALS."; RL Neuron 68:857-864(2010). RN [92] RP VARIANT CMT2Y LYS-185, CHARACTERIZATION OF VARIANT CMT2Y LYS-185, AND RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155 AND GLU-232. RX PubMed=25125609; DOI=10.1093/brain/awu224; RA Gonzalez M.A., Feely S.M., Speziani F., Strickland A.V., Danzi M., RA Bacon C., Lee Y., Chou T.F., Blanton S.H., Weihl C.C., Zuchner S., RA Shy M.E.; RT "A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease."; RL Brain 137:2897-2902(2014). RN [93] RP VARIANT CMT2Y GLU-97, CHARACTERIZATION OF VARIANT CMT2Y GLU-97, AND RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; TRP-198 AND GLU-232. RX PubMed=25878907; DOI=10.1155/2015/239167; RA Jerath N.U., Crockett C.D., Moore S.A., Shy M.E., Weihl C.C., Chou T.F., RA Grider T., Gonzalez M.A., Zuchner S., Swenson A.; RT "Rare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation."; RL Case Rep. Genet. 2015:239167-239167(2015). RN [94] RP VARIANT IBMPFD1 PHE-126. RX PubMed=27209344; DOI=10.1016/j.nmd.2016.05.001; RA Matsubara S., Shimizu T., Komori T., Mori-Yoshimura M., Minami N., RA Hayashi Y.K.; RT "Nuclear inclusions mimicking poly(A)-binding protein nuclear 1 inclusions RT in a case of inclusion body myopathy associated with Paget disease of bone RT and frontotemporal dementia with a novel mutation in the valosin-containing RT protein gene."; RL Neuromuscul. Disord. 26:436-440(2016). RN [95] RP FUNCTION, INTERACTION WITH PLAA; UBXN6 AND YOD1, SUBCELLULAR LOCATION, RP CHARACTERIZATION OF VARIANTS IBMPFD1 HIS-155; TRP-198 AND GLU-232, AND RP MUTAGENESIS OF GLU-578. RX PubMed=27753622; DOI=10.15252/embj.201695148; RA Papadopoulos C., Kirchner P., Bug M., Grum D., Koerver L., Schulze N., RA Poehler R., Dressler A., Fengler S., Arhzaouy K., Lux V., Ehrmann M., RA Weihl C.C., Meyer H.; RT "VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of RT ruptured lysosomes by autophagy."; RL EMBO J. 36:135-150(2017). RN [96] RP VARIANTS IBMPFD1 THR-160; PHE-254 AND THR-369. RX PubMed=36980948; DOI=10.3390/genes14030676; RA Columbres R.C.A., Chin Y., Pratti S., Quinn C., Gonzalez-Cuyar L.F., RA Weiss M., Quintero-Rivera F., Kimonis V.; RT "Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1."; RL Genes (Basel) 14:0-0(2023). CC -!- FUNCTION: Necessary for the fragmentation of Golgi stacks during CC mitosis and for their reassembly after mitosis. Involved in the CC formation of the transitional endoplasmic reticulum (tER). The transfer CC of membranes from the endoplasmic reticulum to the Golgi apparatus CC occurs via 50-70 nm transition vesicles which derive from part-rough, CC part-smooth transitional elements of the endoplasmic reticulum (tER). CC Vesicle budding from the tER is an ATP-dependent process. The ternary CC complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins CC and is necessary for the export of misfolded proteins from the ER to CC the cytoplasm, where they are degraded by the proteasome. The NPLOC4- CC UFD1-VCP complex regulates spindle disassembly at the end of mitosis CC and is necessary for the formation of a closed nuclear envelope. CC Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of CC the VCP/p97-AMFR/gp78 complex that participates in the final step of CC the sterol-mediated ubiquitination and endoplasmic reticulum-associated CC degradation (ERAD) of HMGCR. Mediates the endoplasmic reticulum- CC associated degradation of CHRNA3 in cortical neurons as part of the CC STUB1-VCP-UBXN2A complex (PubMed:26265139). Involved in endoplasmic CC reticulum stress-induced pre-emptive quality control, a mechanism that CC selectively attenuates the translocation of newly synthesized proteins CC into the endoplasmic reticulum and reroutes them to the cytosol for CC proteasomal degradation (PubMed:26565908). Involved in clearance CC process by mediating G3BP1 extraction from stress granules CC (PubMed:29804830, PubMed:34739333). Also involved in DNA damage CC response: recruited to double-strand breaks (DSBs) sites in a RNF8- and CC RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA CC damage sites (PubMed:22020440, PubMed:22120668). Recruited to stalled CC replication forks by SPRTN: may act by mediating extraction of DNA CC polymerase eta (POLH) to prevent excessive translesion DNA synthesis CC and limit the incidence of mutations induced by DNA damage CC (PubMed:23042605, PubMed:23042607). Together with SPRTN CC metalloprotease, involved in the repair of covalent DNA-protein cross- CC links (DPCs) during DNA synthesis (PubMed:32152270). Involved in CC interstrand cross-link repair in response to replication stress by CC mediating unloading of the ubiquitinated CMG helicase complex (By CC similarity). Mediates extraction of PARP1 trapped to chromatin: CC recognizes and binds ubiquitinated PARP1 and promotes its removal CC (PubMed:35013556). Required for cytoplasmic retrotranslocation of CC stressed/damaged mitochondrial outer-membrane proteins and their CC subsequent proteasomal degradation (PubMed:16186510, PubMed:21118995). CC Essential for the maturation of ubiquitin-containing autophagosomes and CC the clearance of ubiquitinated protein by autophagy (PubMed:20104022, CC PubMed:27753622, PubMed:38762759). Acts as a negative regulator of type CC I interferon production by interacting with RIGI: interaction takes CC place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CC CARD domains, leading to recruit RNF125 and promote ubiquitination and CC degradation of RIGI (PubMed:26471729). May play a role in the CC ubiquitin-dependent sorting of membrane proteins to lysosomes where CC they undergo degradation (PubMed:21822278). May more particularly play CC a role in caveolins sorting in cells (PubMed:21822278, CC PubMed:23335559). By controlling the steady-state expression of the CC IGF1R receptor, indirectly regulates the insulin-like growth factor CC receptor signaling pathway (PubMed:26692333). CC {ECO:0000250|UniProtKB:P23787, ECO:0000269|PubMed:15456787, CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:16186510, CC ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:21118995, CC ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:22020440, CC ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22607976, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, CC ECO:0000269|PubMed:23335559, ECO:0000269|PubMed:26265139, CC ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:26565908, CC ECO:0000269|PubMed:26692333, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:32152270, CC ECO:0000269|PubMed:34739333, ECO:0000269|PubMed:35013556, CC ECO:0000269|PubMed:38762759}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.6; CC Evidence={ECO:0000269|PubMed:26471729}; CC -!- SUBUNIT: Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, CC that displays 6-fold radial symmetry. Part of a ternary complex CC containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds CC to one end of a VCP homohexamer. The complex binds to membranes CC enriched in phosphatidylethanolamine-containing lipids and promotes CC Golgi membrane fusion. Binds to a heterodimer of NPLOC4 and UFD1, CC binding to this heterodimer inhibits Golgi-membrane fusion CC (PubMed:26471729, PubMed:38762759). Interaction with VCIP135 leads to CC dissociation of the complex via ATP hydrolysis by VCP. Part of a CC ternary complex containing NPLOC4, UFD1 and VCP. Interacts with NSFL1C- CC like protein p37; the complex has membrane fusion activity and is CC required for Golgi and endoplasmic reticulum biogenesis. Interacts with CC SELENOS and SYVN1, as well as with DERL1 (via SHP-box motif), DERL2 and CC DERL3; which probably transfer misfolded proteins from the ER to VCP CC (PubMed:15215856, PubMed:16186509, PubMed:16186510, PubMed:16289116, CC PubMed:16449189, PubMed:27714797). Interacts with SVIP and forms a CC complex with SVIP and DERL1 (PubMed:17872946). Component of a complex CC required to couple retrotranslocation, ubiquitination and CC deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Part of CC a complex composed of STUB1/CHIP, VCP/p97, CHRNA3, and UBXN2A that CC modulates the ubiquitination and endoplasmic reticulum-associated CC degradation (ERAD) of CHRNA3 (PubMed:26265139). Within the complex CC UBXN2A acts as a scaffold protein required for the interaction of CC CHRNA3 with VCP/p97, this interaction also inhibits CHRNA3 CC ubiquitination by STUB1/CHIP and subsequently ERAD (PubMed:26265139). CC Interacts with UBXN2A (via UBX domain); the interaction is required for CC the interaction of CHRNA3 in the STUB1-VCP-UBXN2A complex CC (PubMed:26265139). Directly interacts with UBXN4 and RNF19A. Interacts CC with CASR. Interacts with UBE4B and YOD1. Interacts with clathrin. CC Interacts with RNF103. Interacts with TRIM13 and TRIM21. Component of a CC VCP/p97-AMFR/gp78 complex that participates in the final step of the CC endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Interacts CC directly with AMFR/gp78 (via its VIM). Interacts with RHBDD1 (via C- CC terminal domain). Interacts with SPRTN; leading to recruitment to CC stalled replication forks (PubMed:23042605, PubMed:23042607). Interacts CC with WASHC5. Interacts with UBOX5. Interacts (via N-terminus) with CC UBXN7, UBXN8, and probably several other UBX domain-containing proteins CC (via UBX domains); the interactions are mutually exclusive with VIM- CC dependent interactions such as those with AMFR and SELENOS. Forms a CC complex with UBQLN1 and UBXN4. Interacts (via the PIM motif) with RNF31 CC (via the PUB domain) (PubMed:24726327). Interacts with RIGI and RNF125; CC interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked CC ubiquitin on its CARD domains, leading to recruit RNF125 and promote CC ubiquitination and degradation of RIGI (PubMed:26471729). Interacts CC with BAG6 (PubMed:21636303). Interacts with UBXN10 (PubMed:26389662). CC Interacts with UBXN6; the interaction with UBXN6 is direct and CC competitive with UFD1 (PubMed:19174149, PubMed:19275885). Forms a CC ternary complex with CAV1 and UBXN6 (PubMed:18656546, PubMed:19174149, CC PubMed:21822278). Interacts with PLAA, UBXN6 and YOD1; may form a CC complex involved in macroautophagy (PubMed:27753622). Interacts with CC ANKZF1 (PubMed:28302725). Interacts with ubiquitin-binding protein FAF1 CC (PubMed:26842564). Interacts with ZFAND2B (via VIM motif); the CC interaction is direct (PubMed:24160817, PubMed:26337389). Interacts CC with ZFAND1 (via its ubiquitin-like region); this interaction occurs in CC an arsenite-dependent manner (PubMed:29804830). Interacts with CCDC47 CC (By similarity). Interacts with UBAC2 (By similarity). Interacts with CC LMBR1L (PubMed:31073040). Interacts with ATXN3 (PubMed:30455355). CC Interacts with TEX264; bridging VCP to covalent DNA-protein cross-links CC (DPCs) (PubMed:32152270). Interacts with FBXL4 (PubMed:36896912). CC {ECO:0000250|UniProtKB:P46462, ECO:0000250|UniProtKB:Q01853, CC ECO:0000269|PubMed:15215856, ECO:0000269|PubMed:15362974, CC ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16168377, CC ECO:0000269|PubMed:16186509, ECO:0000269|PubMed:16186510, CC ECO:0000269|PubMed:16289116, ECO:0000269|PubMed:16449189, CC ECO:0000269|PubMed:16513638, ECO:0000269|PubMed:16968747, CC ECO:0000269|PubMed:17314412, ECO:0000269|PubMed:17872946, CC ECO:0000269|PubMed:18022694, ECO:0000269|PubMed:18656546, CC ECO:0000269|PubMed:18675248, ECO:0000269|PubMed:19174149, CC ECO:0000269|PubMed:19275885, ECO:0000269|PubMed:19818707, CC ECO:0000269|PubMed:19822669, ECO:0000269|PubMed:19887378, CC ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:20833645, CC ECO:0000269|PubMed:21636303, ECO:0000269|PubMed:21822278, CC ECO:0000269|PubMed:21914798, ECO:0000269|PubMed:21949850, CC ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22537386, CC ECO:0000269|PubMed:22795130, ECO:0000269|PubMed:22902628, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607, CC ECO:0000269|PubMed:24160817, ECO:0000269|PubMed:24726327, CC ECO:0000269|PubMed:26265139, ECO:0000269|PubMed:26337389, CC ECO:0000269|PubMed:26389662, ECO:0000269|PubMed:26471729, CC ECO:0000269|PubMed:26842564, ECO:0000269|PubMed:27714797, CC ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:28302725, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:30455355, CC ECO:0000269|PubMed:32152270, ECO:0000269|PubMed:36896912, CC ECO:0000269|PubMed:38762759, ECO:0000269|PubMed:8413590, CC ECO:0000305|PubMed:31073040}. CC -!- INTERACTION: CC P55072; Q9UKV5: AMFR; NbExp=12; IntAct=EBI-355164, EBI-1046367; CC P55072; Q9BZE9: ASPSCR1; NbExp=36; IntAct=EBI-355164, EBI-1993677; CC P55072; A9UGY9: ATG5; NbExp=3; IntAct=EBI-355164, EBI-10175276; CC P55072; P54253: ATXN1; NbExp=3; IntAct=EBI-355164, EBI-930964; CC P55072; P54252: ATXN3; NbExp=4; IntAct=EBI-355164, EBI-946046; CC P55072; P54252-1: ATXN3; NbExp=18; IntAct=EBI-355164, EBI-946068; CC P55072; Q96LK0: CEP19; NbExp=6; IntAct=EBI-355164, EBI-741885; CC P55072; O96017: CHEK2; NbExp=2; IntAct=EBI-355164, EBI-1180783; CC P55072; O75175: CNOT3; NbExp=3; IntAct=EBI-355164, EBI-743073; CC P55072; Q13619: CUL4A; NbExp=2; IntAct=EBI-355164, EBI-456106; CC P55072; O60941: DTNB; NbExp=4; IntAct=EBI-355164, EBI-740402; CC P55072; O60941-5: DTNB; NbExp=3; IntAct=EBI-355164, EBI-11984733; CC P55072; P26378-2: ELAVL4; NbExp=3; IntAct=EBI-355164, EBI-21603100; CC P55072; Q96J88-3: EPSTI1; NbExp=3; IntAct=EBI-355164, EBI-25885343; CC P55072; Q9UNN5: FAF1; NbExp=3; IntAct=EBI-355164, EBI-718246; CC P55072; Q9UNN5-1: FAF1; NbExp=4; IntAct=EBI-355164, EBI-15930546; CC P55072; Q96CS3: FAF2; NbExp=16; IntAct=EBI-355164, EBI-1055805; CC P55072; O94868: FCHSD2; NbExp=2; IntAct=EBI-355164, EBI-1215612; CC P55072; P09471: GNAO1; NbExp=5; IntAct=EBI-355164, EBI-715087; CC P55072; P62993: GRB2; NbExp=5; IntAct=EBI-355164, EBI-401755; CC P55072; P04792: HSPB1; NbExp=3; IntAct=EBI-355164, EBI-352682; CC P55072; P42858: HTT; NbExp=10; IntAct=EBI-355164, EBI-466029; CC P55072; Q8TBB1: LNX1; NbExp=7; IntAct=EBI-355164, EBI-739832; CC P55072; Q8WZA0: LZIC; NbExp=3; IntAct=EBI-355164, EBI-5774346; CC P55072; Q9H7H0-2: METTL17; NbExp=3; IntAct=EBI-355164, EBI-11098807; CC P55072; Q9HC29: NOD2; NbExp=5; IntAct=EBI-355164, EBI-7445625; CC P55072; Q8TAT6: NPLOC4; NbExp=17; IntAct=EBI-355164, EBI-1994109; CC P55072; Q9UNZ2: NSFL1C; NbExp=28; IntAct=EBI-355164, EBI-721577; CC P55072; Q96HA8: NTAQ1; NbExp=6; IntAct=EBI-355164, EBI-741158; CC P55072; Q9Y263: PLAA; NbExp=9; IntAct=EBI-355164, EBI-1994037; CC P55072; Q07869: PPARA; NbExp=3; IntAct=EBI-355164, EBI-78615; CC P55072; P62136: PPP1CA; NbExp=3; IntAct=EBI-355164, EBI-357253; CC P55072; P07602-1: PSAP; NbExp=3; IntAct=EBI-355164, EBI-10635648; CC P55072; P25786: PSMA1; NbExp=8; IntAct=EBI-355164, EBI-359352; CC P55072; P62191: PSMC1; NbExp=5; IntAct=EBI-355164, EBI-357598; CC P55072; P26045: PTPN3; NbExp=2; IntAct=EBI-355164, EBI-1047946; CC P55072; Q9Y4L5: RNF115; NbExp=3; IntAct=EBI-355164, EBI-2129242; CC P55072; Q96EQ8: RNF125; NbExp=3; IntAct=EBI-355164, EBI-2339208; CC P55072; O76064: RNF8; NbExp=3; IntAct=EBI-355164, EBI-373337; CC P55072; P32969: RPL9P9; NbExp=7; IntAct=EBI-355164, EBI-358122; CC P55072; Q9H0K1: SIK2; NbExp=4; IntAct=EBI-355164, EBI-1181664; CC P55072; Q8NBI5: SLC43A3; NbExp=3; IntAct=EBI-355164, EBI-2855542; CC P55072; Q16560-2: SNRNP35; NbExp=3; IntAct=EBI-355164, EBI-12938570; CC P55072; P46977: STT3A; NbExp=3; IntAct=EBI-355164, EBI-719212; CC P55072; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-355164, EBI-359276; CC P55072; P51668: UBE2D1; NbExp=3; IntAct=EBI-355164, EBI-743540; CC P55072; B1AQ61: UBE4B; NbExp=4; IntAct=EBI-355164, EBI-7931266; CC P55072; O94941: UBOX5; NbExp=6; IntAct=EBI-355164, EBI-751901; CC P55072; Q04323: UBXN1; NbExp=9; IntAct=EBI-355164, EBI-1058647; CC P55072; Q96LJ8: UBXN10; NbExp=7; IntAct=EBI-355164, EBI-1993941; CC P55072; Q5T124-6: UBXN11; NbExp=7; IntAct=EBI-355164, EBI-11524408; CC P55072; P68543: UBXN2A; NbExp=20; IntAct=EBI-355164, EBI-1993668; CC P55072; Q14CS0: UBXN2B; NbExp=16; IntAct=EBI-355164, EBI-1993619; CC P55072; Q92575: UBXN4; NbExp=12; IntAct=EBI-355164, EBI-723441; CC P55072; Q9BZV1: UBXN6; NbExp=26; IntAct=EBI-355164, EBI-1993899; CC P55072; Q9BZV1-2: UBXN6; NbExp=3; IntAct=EBI-355164, EBI-21851820; CC P55072; O94888: UBXN7; NbExp=19; IntAct=EBI-355164, EBI-1993627; CC P55072; O00124: UBXN8; NbExp=9; IntAct=EBI-355164, EBI-1993850; CC P55072; Q92890: UFD1; NbExp=10; IntAct=EBI-355164, EBI-1994090; CC P55072; P63027: VAMP2; NbExp=5; IntAct=EBI-355164, EBI-520113; CC P55072; Q969W3: VCF1; NbExp=10; IntAct=EBI-355164, EBI-10281506; CC P55072; P55072: VCP; NbExp=8; IntAct=EBI-355164, EBI-355164; CC P55072; Q6GPH4: XAF1; NbExp=3; IntAct=EBI-355164, EBI-2815120; CC P55072; Q5VVQ6: YOD1; NbExp=3; IntAct=EBI-355164, EBI-2510804; CC P55072; P63104: YWHAZ; NbExp=4; IntAct=EBI-355164, EBI-347088; CC P55072; P24278: ZBTB25; NbExp=3; IntAct=EBI-355164, EBI-739899; CC P55072; Q9WTX6: Cul1; Xeno; NbExp=2; IntAct=EBI-355164, EBI-1551052; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:15456787}. CC Endoplasmic reticulum {ECO:0000269|PubMed:15215856}. Nucleus CC {ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:26842564}. Cytoplasm, CC Stress granule {ECO:0000269|PubMed:29804830}. Note=Present in the CC neuronal hyaline inclusion bodies specifically found in motor neurons CC from amyotrophic lateral sclerosis patients (PubMed:15456787). Present CC in the Lewy bodies specifically found in neurons from Parkinson disease CC patients (PubMed:15456787). Recruited to the cytoplasmic surface of the CC endoplasmic reticulum via interaction with AMFR/gp78 (PubMed:16168377). CC Following DNA double-strand breaks, recruited to the sites of damage CC (PubMed:22120668). Recruited to stalled replication forks via CC interaction with SPRTN (PubMed:23042605). Recruited to damaged CC lysosomes decorated with K48-linked ubiquitin chains (PubMed:27753622). CC Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules CC (SGs) in response to arsenite-induced stress treatment CC (PubMed:29804830). {ECO:0000269|PubMed:15456787, CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22120668, CC ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830}. CC -!- DOMAIN: The PIM (PUB-interaction motif) motif mediates interaction with CC the PUB domain of RNF31. {ECO:0000269|PubMed:24726327}. CC -!- PTM: Phosphorylated by tyrosine kinases in response to T-cell antigen CC receptor activation. Phosphorylated in mitotic cells. CC {ECO:0000250|UniProtKB:P46462}. CC -!- PTM: ISGylated. {ECO:0000269|PubMed:16139798}. CC -!- PTM: Methylation at Lys-315 catalyzed by VCPKMT is increased in the CC presence of ASPSCR1. Lys-315 methylation may decrease ATPase activity. CC {ECO:0000269|PubMed:22948820, ECO:0000269|PubMed:23349634}. CC -!- PTM: UFMylated al Lys-109; UFMylation enhances the interactions between CC BECN1 and other components of the PtdIns3K complex and thereby promotes CC cellular autophagy initiation. {ECO:0000269|PubMed:38762759}. CC -!- DISEASE: Inclusion body myopathy with early-onset Paget disease with or CC without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]: An autosomal CC dominant disease characterized by disabling muscle weakness clinically CC resembling to limb girdle muscular dystrophy, osteolytic bone lesions CC consistent with Paget disease, and premature frontotemporal dementia. CC Clinical features show incomplete penetrance. CC {ECO:0000269|PubMed:15034582, ECO:0000269|PubMed:15732117, CC ECO:0000269|PubMed:16247064, ECO:0000269|PubMed:16321991, CC ECO:0000269|PubMed:17935506, ECO:0000269|PubMed:20104022, CC ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:20512113, CC ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, CC ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, CC ECO:0000269|PubMed:27209344, ECO:0000269|PubMed:27753622, CC ECO:0000269|PubMed:29804830, ECO:0000269|PubMed:36980948}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 CC (FTDALS6) [MIM:613954]: 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 (FTD) is characterized by frontal and temporal CC lobe atrophy associated with neuronal loss, gliosis, and dementia. CC Patients exhibit progressive changes in social, behavioral, and/or CC language function. Amyotrophic lateral sclerosis (ALS) is characterized CC by the death of motor neurons in the brain, brainstem, and spinal cord, CC resulting in fatal paralysis. FTDALS6 is an autosomal dominant form CC characterized by onset of ALS or FTD in adulthood. Some patients with CC the disorder may have features of both diseases. CC {ECO:0000269|PubMed:21145000, ECO:0000269|PubMed:23349634}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Charcot-Marie-Tooth disease, axonal, type 2Y (CMT2Y) CC [MIM:616687]: An autosomal dominant, axonal form of Charcot-Marie-Tooth CC disease, a disorder of the peripheral nervous system, characterized by CC progressive weakness and atrophy, initially of the peroneal muscles and CC later of the distal muscles of the arms. Charcot-Marie-Tooth disease is CC classified in two main groups on the basis of electrophysiologic CC properties and histopathology: primary peripheral demyelinating CC neuropathies (designated CMT1 when they are dominantly inherited) and CC primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 CC group are characterized by signs of axonal degeneration in the absence CC of obvious myelin alterations, normal or slightly reduced nerve CC conduction velocities, and progressive distal muscle weakness and CC atrophy. {ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the AAA ATPase family. {ECO:0000305}. CC -!- CAUTION: It is unclear how it participates in the recruitment of CC TP53BP1 at DNA damage sites. According to a first report, participates CC in the recruitment of TP53BP1 by promoting ubiquitination and removal CC of L3MBTL1 from DNA damage sites (PubMed:22120668). According to a CC second report, it acts by removing 'Lys-48'-linked ubiquitination from CC sites of DNA damage (PubMed:22020440). {ECO:0000305|PubMed:22020440, CC ECO:0000305|PubMed:22120668}. 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; AC004472; AAC07984.1; -; Genomic_DNA. DR EMBL; FJ224344; ACI46036.1; -; mRNA. DR EMBL; FJ224352; ACI46044.1; -; mRNA. DR EMBL; AF100752; AAD43016.1; -; mRNA. DR EMBL; AK312310; BAG35235.1; -; mRNA. DR EMBL; AL353795; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471071; EAW58404.1; -; Genomic_DNA. DR EMBL; BC110913; AAI10914.1; -; mRNA. DR EMBL; BC121794; AAI21795.1; -; mRNA. DR EMBL; Z70768; CAA94809.1; -; mRNA. DR CCDS; CCDS6573.1; -. DR PIR; T02243; T02243. DR RefSeq; NP_009057.1; NM_007126.5. DR PDB; 3EBB; X-ray; 1.90 A; E/F/G/H=797-806. DR PDB; 3HU1; X-ray; 2.81 A; A/B/C/D/E/F=1-481. DR PDB; 3HU2; X-ray; 2.85 A; A/B/C/D/E/F=1-481. DR PDB; 3HU3; X-ray; 2.20 A; A/B=1-481. DR PDB; 3QC8; X-ray; 2.20 A; A=21-196. DR PDB; 3QQ7; X-ray; 2.65 A; A=2-187. DR PDB; 3QQ8; X-ray; 2.00 A; A=2-187. DR PDB; 3QWZ; X-ray; 2.00 A; A=1-208. DR PDB; 3TIW; X-ray; 1.80 A; A/B=1-187. DR PDB; 4KDI; X-ray; 1.86 A; A/B=21-196. DR PDB; 4KDL; X-ray; 1.81 A; A=21-196. DR PDB; 4KLN; X-ray; 2.62 A; A/B/C/D/E/F=1-481. DR PDB; 4KO8; X-ray; 1.98 A; A/B=1-481. DR PDB; 4KOD; X-ray; 2.96 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481. DR PDB; 4P0A; X-ray; 2.30 A; B/D=797-806. DR PDB; 5B6C; X-ray; 1.55 A; A=21-191. DR PDB; 5C18; X-ray; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 5C19; X-ray; 4.20 A; A/B/C/D/E/F=2-806. DR PDB; 5C1A; X-ray; 3.80 A; A/B/C/D/E/F/G/H/I/J/K/L=2-806. DR PDB; 5C1B; X-ray; 3.08 A; A/B/C/D/E/F=2-806. DR PDB; 5DYG; X-ray; 2.20 A; A=1-460. DR PDB; 5DYI; X-ray; 3.71 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481. DR PDB; 5EPP; X-ray; 1.88 A; A=21-199. DR PDB; 5FTJ; EM; 2.30 A; A/B/C/D/E/F=1-806. DR PDB; 5FTK; EM; 2.40 A; A/B/C/D/E/F=1-806. DR PDB; 5FTL; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 5FTM; EM; 3.20 A; A/B/C/D/E/F=1-806. DR PDB; 5FTN; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 5GLF; X-ray; 2.25 A; A/C/E/G=21-199. DR PDB; 5IFS; X-ray; 2.46 A; B/D=1-481. DR PDB; 5IFW; X-ray; 3.40 A; B=2-806. DR PDB; 5KIW; X-ray; 3.41 A; A/B=1-460. DR PDB; 5KIY; X-ray; 2.79 A; A=1-460. DR PDB; 5X4L; X-ray; 2.40 A; A/B=23-196. DR PDB; 6G2V; X-ray; 1.90 A; A=462-764. DR PDB; 6G2W; X-ray; 2.68 A; A=462-764. DR PDB; 6G2X; X-ray; 2.08 A; A=462-764. DR PDB; 6G2Y; X-ray; 2.15 A; A=462-764. DR PDB; 6G2Z; X-ray; 1.92 A; A=462-764. DR PDB; 6G30; X-ray; 2.42 A; A=462-764. DR PDB; 6HD0; X-ray; 3.73 A; A/B/C/T/U/V=1-481. DR PDB; 6MCK; X-ray; 3.77 A; A/B/C/D/E/F/G/H/I/J/K/L=210-806. DR PDB; 7BP8; EM; 3.90 A; A/B/C/D/E/F=1-806. DR PDB; 7BP9; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 7BPA; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 7BPB; EM; 4.30 A; A/B/C/D/E/F=1-806. DR PDB; 7JY5; EM; 2.89 A; A/B/C/D/E/F=1-806. DR PDB; 7K56; EM; 3.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7K57; EM; 3.70 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7K59; EM; 4.20 A; A/B/C/D/E/F=1-806. DR PDB; 7L5W; EM; 3.34 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7L5X; EM; 6.10 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7LMY; EM; 2.40 A; A/B/C/D/E/F=1-806. DR PDB; 7LMZ; EM; 3.06 A; A/B/C/D/E/F=1-806. DR PDB; 7LN0; EM; 2.98 A; A/B/C/D/E/F=1-806. DR PDB; 7LN1; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 7LN2; EM; 3.63 A; A/B/C/D/E/F=1-806. DR PDB; 7LN3; EM; 3.45 A; A/B/C/D/E/F=1-806. DR PDB; 7LN4; EM; 3.00 A; A/B/C/D/E/F=1-806. DR PDB; 7LN5; EM; 3.09 A; A/B/C/D/E/F=1-806. DR PDB; 7LN6; EM; 3.58 A; A/B/C/D/E/F=1-806. DR PDB; 7MDM; EM; 4.86 A; A/B/C/D/E/F=1-806. DR PDB; 7MDO; EM; 4.12 A; A/B/C/D/E/F=1-806. DR PDB; 7MHS; EM; 3.60 A; A/B/C/D/E=1-806. DR PDB; 7OAT; X-ray; 3.00 A; B=2-480. DR PDB; 7PUX; X-ray; 1.73 A; A=1-460. DR PDB; 7R7S; EM; 4.23 A; A/B/C/D/E/F=1-806. DR PDB; 7R7T; EM; 4.50 A; A/B/C/D/E/F=1-806. DR PDB; 7R7U; EM; 4.30 A; A/B/C/D/E/F=1-806. DR PDB; 7RL6; EM; 3.70 A; A/B/C/D/E/F=2-806. DR PDB; 7RL7; EM; 3.00 A; A/B/C/D/E/F=2-806. DR PDB; 7RL9; EM; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 7RLA; EM; 3.10 A; A/B/C/D/E/F=2-806. DR PDB; 7RLB; EM; 3.30 A; A/B/C/D/E/F=2-806. DR PDB; 7RLC; EM; 3.20 A; A/B/C/D/E/F=2-806. DR PDB; 7RLD; EM; 3.40 A; A/B/C/D/E/F=2-806. DR PDB; 7RLF; EM; 3.10 A; A/B/C/D/E/F=1-806. DR PDB; 7RLG; EM; 3.70 A; A/B/C/D/E/F=2-806. DR PDB; 7RLH; EM; 3.00 A; A/B/C/D/E/F=1-806. DR PDB; 7RLI; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L=2-806. DR PDB; 7RLJ; EM; 3.80 A; A/B/C/D/E/F/G/H/I/J/K/L=21-775. DR PDB; 7VCS; EM; 3.32 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7VCT; EM; 3.21 A; A/B/C/D/E/F=1-806. DR PDB; 7VCU; EM; 3.15 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 7VCV; EM; 3.21 A; A/B/C/D/E/F=1-806. DR PDB; 7VCX; EM; 3.24 A; A/B/C/D/E/F=1-806. DR PDB; 7Y4W; EM; 3.67 A; A/B/C/D/E/F=21-806. DR PDB; 7Y53; EM; 3.61 A; A/B/C/D/E/F=21-806. DR PDB; 7Y59; EM; 4.51 A; A/B/C/D/E/F=21-806. DR PDB; 8B5R; EM; 6.10 A; A/B/C/D/E/F=2-806. DR PDB; 8FCL; EM; 3.51 A; A/B/C/D/E/F=1-806. DR PDB; 8FCM; EM; 3.27 A; A/B/C/D/E/F=1-806. DR PDB; 8FCN; EM; 2.95 A; A/B/C/D/E/F=1-806. DR PDB; 8FCO; EM; 3.31 A; A/B/C/D/E/F=1-806. DR PDB; 8FCP; EM; 3.52 A; A/B/C/D/E/F=1-806. DR PDB; 8FCQ; EM; 3.93 A; A/B/C/D/E/F=1-806. DR PDB; 8FCR; EM; 4.12 A; A/B/C/D/E/F=1-806. DR PDB; 8FCT; EM; 3.42 A; A/B/C/D/E/F=1-806. DR PDB; 8HL7; X-ray; 2.80 A; B=23-458. DR PDB; 8HRZ; X-ray; 2.70 A; A/B/C/D/E/F/G/H/I/J/K/L=21-458. DR PDB; 8KG2; X-ray; 3.10 A; A/B/C/D/E/F/G/H/I/J/K/L=21-458. DR PDB; 8OOI; EM; 2.61 A; A/B/C/D/E/F=1-806. DR PDB; 8PQX; EM; 3.30 A; A/B/C/D/E/F=1-806. DR PDB; 8R0E; EM; 2.70 A; A/B/C/D/E/F=1-806. DR PDB; 8RS9; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 8RSB; EM; 3.40 A; A/B/C/D/E/F=1-806. DR PDB; 8RSC; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8UV2; EM; 3.23 A; A/B/C/D/E/F=1-806. DR PDB; 8UVO; EM; 3.22 A; A/B/C/D/E/F=1-806. DR PDB; 8UVP; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8UVQ; EM; 3.42 A; A/B/C/D/E/F=1-806. DR PDB; 8VKU; EM; 3.50 A; A/B/C/D/E/F=1-806. DR PDB; 8VLS; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 8VOV; EM; 3.60 A; A/B/C/D/E/F=1-806. DR PDB; 8YKA; EM; 3.45 A; A/B/C/D/E/F=12-775. DR PDB; 9BOQ; EM; 3.33 A; A/B/C/D/E/F/G/H/I/J/K/L=1-806. DR PDB; 9DIL; EM; 3.30 A; A/B=1-806. DR PDB; 9MQ6; EM; 3.30 A; A/B=1-806. DR PDBsum; 3EBB; -. DR PDBsum; 3HU1; -. DR PDBsum; 3HU2; -. DR PDBsum; 3HU3; -. DR PDBsum; 3QC8; -. DR PDBsum; 3QQ7; -. DR PDBsum; 3QQ8; -. DR PDBsum; 3QWZ; -. DR PDBsum; 3TIW; -. DR PDBsum; 4KDI; -. DR PDBsum; 4KDL; -. DR PDBsum; 4KLN; -. DR PDBsum; 4KO8; -. DR PDBsum; 4KOD; -. DR PDBsum; 4P0A; -. DR PDBsum; 5B6C; -. DR PDBsum; 5C18; -. DR PDBsum; 5C19; -. DR PDBsum; 5C1A; -. DR PDBsum; 5C1B; -. DR PDBsum; 5DYG; -. DR PDBsum; 5DYI; -. DR PDBsum; 5EPP; -. DR PDBsum; 5FTJ; -. DR PDBsum; 5FTK; -. DR PDBsum; 5FTL; -. DR PDBsum; 5FTM; -. DR PDBsum; 5FTN; -. DR PDBsum; 5GLF; -. DR PDBsum; 5IFS; -. DR PDBsum; 5IFW; -. DR PDBsum; 5KIW; -. DR PDBsum; 5KIY; -. DR PDBsum; 5X4L; -. DR PDBsum; 6G2V; -. DR PDBsum; 6G2W; -. DR PDBsum; 6G2X; -. DR PDBsum; 6G2Y; -. DR PDBsum; 6G2Z; -. DR PDBsum; 6G30; -. DR PDBsum; 6HD0; -. DR PDBsum; 6MCK; -. DR PDBsum; 7BP8; -. DR PDBsum; 7BP9; -. DR PDBsum; 7BPA; -. DR PDBsum; 7BPB; -. DR PDBsum; 7JY5; -. DR PDBsum; 7K56; -. DR PDBsum; 7K57; -. DR PDBsum; 7K59; -. DR PDBsum; 7L5W; -. DR PDBsum; 7L5X; -. DR PDBsum; 7LMY; -. DR PDBsum; 7LMZ; -. DR PDBsum; 7LN0; -. DR PDBsum; 7LN1; -. DR PDBsum; 7LN2; -. DR PDBsum; 7LN3; -. DR PDBsum; 7LN4; -. DR PDBsum; 7LN5; -. DR PDBsum; 7LN6; -. DR PDBsum; 7MDM; -. DR PDBsum; 7MDO; -. DR PDBsum; 7MHS; -. DR PDBsum; 7OAT; -. DR PDBsum; 7PUX; -. DR PDBsum; 7R7S; -. DR PDBsum; 7R7T; -. DR PDBsum; 7R7U; -. DR PDBsum; 7RL6; -. DR PDBsum; 7RL7; -. DR PDBsum; 7RL9; -. DR PDBsum; 7RLA; -. DR PDBsum; 7RLB; -. DR PDBsum; 7RLC; -. DR PDBsum; 7RLD; -. DR PDBsum; 7RLF; -. DR PDBsum; 7RLG; -. DR PDBsum; 7RLH; -. DR PDBsum; 7RLI; -. DR PDBsum; 7RLJ; -. DR PDBsum; 7VCS; -. DR PDBsum; 7VCT; -. DR PDBsum; 7VCU; -. DR PDBsum; 7VCV; -. DR PDBsum; 7VCX; -. DR PDBsum; 7Y4W; -. DR PDBsum; 7Y53; -. DR PDBsum; 7Y59; -. DR PDBsum; 8B5R; -. DR PDBsum; 8FCL; -. DR PDBsum; 8FCM; -. DR PDBsum; 8FCN; -. DR PDBsum; 8FCO; -. DR PDBsum; 8FCP; -. DR PDBsum; 8FCQ; -. DR PDBsum; 8FCR; -. DR PDBsum; 8FCT; -. DR PDBsum; 8HL7; -. DR PDBsum; 8HRZ; -. DR PDBsum; 8KG2; -. DR PDBsum; 8OOI; -. DR PDBsum; 8PQX; -. DR PDBsum; 8R0E; -. DR PDBsum; 8RS9; -. DR PDBsum; 8RSB; -. DR PDBsum; 8RSC; -. DR PDBsum; 8UV2; -. DR PDBsum; 8UVO; -. DR PDBsum; 8UVP; -. DR PDBsum; 8UVQ; -. DR PDBsum; 8VKU; -. DR PDBsum; 8VLS; -. DR PDBsum; 8VOV; -. DR PDBsum; 8YKA; -. DR PDBsum; 9BOQ; -. DR PDBsum; 9DIL; -. DR PDBsum; 9MQ6; -. DR AlphaFoldDB; P55072; -. DR EMDB; EMD-15774; -. DR EMDB; EMD-15861; -. DR EMDB; EMD-16781; -. DR EMDB; EMD-17016; -. DR EMDB; EMD-17024; -. DR EMDB; EMD-17128; -. DR EMDB; EMD-17827; -. DR EMDB; EMD-17837; -. DR EMDB; EMD-18517; -. DR EMDB; EMD-18790; -. DR EMDB; EMD-19473; -. DR EMDB; EMD-19475; -. DR EMDB; EMD-19476; -. DR EMDB; EMD-22521; -. DR EMDB; EMD-22675; -. DR EMDB; EMD-22676; -. DR EMDB; EMD-22678; -. DR EMDB; EMD-23191; -. DR EMDB; EMD-23192; -. DR EMDB; EMD-23442; -. DR EMDB; EMD-23443; -. DR EMDB; EMD-23444; -. DR EMDB; EMD-23445; -. DR EMDB; EMD-23446; -. DR EMDB; EMD-23447; -. DR EMDB; EMD-23448; -. DR EMDB; EMD-23449; -. DR EMDB; EMD-23450; -. DR EMDB; EMD-23451; -. DR EMDB; EMD-23452; -. DR EMDB; EMD-23453; -. DR EMDB; EMD-23454; -. DR EMDB; EMD-23455; -. DR EMDB; EMD-23456; -. DR EMDB; EMD-23457; -. DR EMDB; EMD-23458; -. DR EMDB; EMD-23775; -. DR EMDB; EMD-23776; -. DR EMDB; EMD-23835; -. DR EMDB; EMD-24302; -. DR EMDB; EMD-24304; -. DR EMDB; EMD-24305; -. DR EMDB; EMD-24306; -. DR EMDB; EMD-24518; -. DR EMDB; EMD-24519; -. DR EMDB; EMD-24522; -. DR EMDB; EMD-24523; -. DR EMDB; EMD-24524; -. DR EMDB; EMD-24525; -. DR EMDB; EMD-24526; -. DR EMDB; EMD-24528; -. DR EMDB; EMD-24529; -. DR EMDB; EMD-24530; -. DR EMDB; EMD-24531; -. DR EMDB; EMD-24532; -. DR EMDB; EMD-28982; -. DR EMDB; EMD-28983; -. DR EMDB; EMD-28984; -. DR EMDB; EMD-28985; -. DR EMDB; EMD-28986; -. DR EMDB; EMD-28987; -. DR EMDB; EMD-28988; -. DR EMDB; EMD-28989; -. DR EMDB; EMD-28990; -. DR EMDB; EMD-28991; -. DR EMDB; EMD-28992; -. DR EMDB; EMD-30147; -. DR EMDB; EMD-30148; -. DR EMDB; EMD-30149; -. DR EMDB; EMD-30150; -. DR EMDB; EMD-31894; -. DR EMDB; EMD-31895; -. DR EMDB; EMD-31896; -. DR EMDB; EMD-31897; -. DR EMDB; EMD-31899; -. DR EMDB; EMD-32827; -. DR EMDB; EMD-3295; -. DR EMDB; EMD-3296; -. DR EMDB; EMD-3297; -. DR EMDB; EMD-3298; -. DR EMDB; EMD-3299; -. DR EMDB; EMD-3323; -. DR EMDB; EMD-3324; -. DR EMDB; EMD-3325; -. DR EMDB; EMD-3326; -. DR EMDB; EMD-3327; -. DR EMDB; EMD-3328; -. DR EMDB; EMD-33608; -. DR EMDB; EMD-33611; -. DR EMDB; EMD-33613; -. DR EMDB; EMD-38770; -. DR EMDB; EMD-38771; -. DR EMDB; EMD-38772; -. DR EMDB; EMD-39360; -. DR EMDB; EMD-42603; -. DR EMDB; EMD-42625; -. DR EMDB; EMD-42626; -. DR EMDB; EMD-42627; -. DR EMDB; EMD-43329; -. DR EMDB; EMD-43343; -. DR EMDB; EMD-43392; -. DR EMDB; EMD-44748; -. DR EMDB; EMD-46912; -. DR EMDB; EMD-48514; -. DR SMR; P55072; -. DR BioGRID; 113258; 1454. DR ComplexPortal; CPX-137; VCP-NPL4-UFD1 AAA ATPase complex. DR ComplexPortal; CPX-262; VCP-NSFL1C AAA ATPase complex. DR ComplexPortal; CPX-8095; VCP-FAF1 AAA ATPase complex. DR ComplexPortal; CPX-8096; VCP-NPL4-UFD1-FAF1 AAA ATPase complex. DR ComplexPortal; CPX-8101; VCP-NPL4-UFD1-UBXN7 AAA ATPase complex. DR ComplexPortal; CPX-8104; VCP-NPL4-UFD1-FAF2 AAA ATPase complex. DR ComplexPortal; CPX-8105; VCP-NPL4-UFD1-UBXN1 AAA ATPase complex. DR ComplexPortal; CPX-8121; VCP-UBXN2B AAA ATPase complex. DR ComplexPortal; CPX-8124; VCP-UBXN2A AAA ATPase complex. DR ComplexPortal; CPX-8128; VCP-YOD1 AAA ATPase complex. DR ComplexPortal; CPX-8129; VCP-PLAA AAA ATPase complex. DR ComplexPortal; CPX-8132; VCP-VCPIP1 AAA ATPase complex. DR ComplexPortal; CPX-8133; VCP-UBXN6 AAA ATPase complex. DR ComplexPortal; CPX-8134; VCP-AMFR AAA ATPase complex. DR ComplexPortal; CPX-8570; VCP-DERL1 AAA ATPase complex. DR ComplexPortal; CPX-8782; VCP-DERL2 AAA ATPase complex. DR ComplexPortal; CPX-8783; VCP-DERL3 AAA ATPase complex. DR CORUM; P55072; -. DR DIP; DIP-33543N; -. DR FunCoup; P55072; 2295. DR IntAct; P55072; 915. DR MINT; P55072; -. DR STRING; 9606.ENSP00000351777; -. DR BindingDB; P55072; -. DR ChEMBL; CHEMBL1075145; -. DR DrugBank; DB16874; CB-5083. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester. DR DrugCentral; P55072; -. DR MoonDB; P55072; Predicted. DR TCDB; 3.A.16.1.1; the endoplasmic reticular retrotranslocon (er-rt) family. DR CarbonylDB; P55072; -. DR GlyGen; P55072; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; P55072; -. DR MetOSite; P55072; -. DR PhosphoSitePlus; P55072; -. DR SwissPalm; P55072; -. DR BioMuta; VCP; -. DR DMDM; 6094447; -. DR OGP; P55072; -. DR REPRODUCTION-2DPAGE; IPI00022774; -. DR REPRODUCTION-2DPAGE; P55072; -. DR CPTAC; CPTAC-295; -. DR CPTAC; CPTAC-296; -. DR jPOST; P55072; -. DR MassIVE; P55072; -. DR PaxDb; 9606-ENSP00000351777; -. DR PeptideAtlas; P55072; -. DR PRIDE; P55072; -. DR ProteomicsDB; 56776; -. DR Pumba; P55072; -. DR TopDownProteomics; P55072; -. DR ABCD; P55072; 1 sequenced antibody. DR Antibodypedia; 2215; 680 antibodies from 44 providers. DR DNASU; 7415; -. DR Ensembl; ENST00000358901.11; ENSP00000351777.6; ENSG00000165280.19. DR GeneID; 7415; -. DR KEGG; hsa:7415; -. DR MANE-Select; ENST00000358901.11; ENSP00000351777.6; NM_007126.5; NP_009057.1. DR AGR; HGNC:12666; -. DR ClinPGx; PA37289; -. DR CTD; 7415; -. DR DisGeNET; 7415; -. DR GeneCards; VCP; -. DR GeneReviews; VCP; -. DR HGNC; HGNC:12666; VCP. DR HPA; ENSG00000165280; Low tissue specificity. DR MalaCards; VCP; -. DR MIM; 167320; phenotype. DR MIM; 601023; gene. DR MIM; 613954; phenotype. DR MIM; 616687; phenotype. DR OpenTargets; ENSG00000165280; -. DR Orphanet; 329478; Adult-onset distal myopathy due to VCP mutation. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 435387; Autosomal dominant Charcot-Marie-Tooth disease type 2Y. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 275872; Frontotemporal dementia with motor neuron disease. DR Orphanet; 52430; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 329475; Spastic paraplegia-Paget disease of bone syndrome. DR VEuPathDB; HostDB:ENSG00000165280; -. DR eggNOG; KOG0730; Eukaryota. DR GeneTree; ENSGT00900000141071; -. DR HOGENOM; CLU_000688_12_3_1; -. DR InParanoid; P55072; -. DR OMA; VWPAYPE; -. DR OrthoDB; 27435at2759; -. DR PAN-GO; P55072; 10 GO annotations based on evolutionary models. DR PhylomeDB; P55072; -. DR BRENDA; 3.6.4.6; 2681. DR PathwayCommons; P55072; -. DR Reactome; R-HSA-110320; Translesion Synthesis by POLH. DR Reactome; R-HSA-3371511; HSF1 activation. DR Reactome; R-HSA-382556; ABC-family proteins mediated transport. DR Reactome; R-HSA-532668; N-glycan trimming in the ER and Calnexin/Calreticulin cycle. DR Reactome; R-HSA-5358346; Hedgehog ligand biogenesis. DR Reactome; R-HSA-5362768; Hh mutants are degraded by ERAD. DR Reactome; R-HSA-5678895; Defective CFTR causes cystic fibrosis. DR Reactome; R-HSA-5689877; Josephin domain DUBs. DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-8866654; E3 ubiquitin ligases ubiquitinate target proteins. DR Reactome; R-HSA-8876725; Protein methylation. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9013407; RHOH GTPase cycle. DR Reactome; R-HSA-9646399; Aggrephagy. DR Reactome; R-HSA-9678110; Attachment and Entry. DR Reactome; R-HSA-9694614; Attachment and Entry. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR SignaLink; P55072; -. DR SIGNOR; P55072; -. DR Agora; ENSG00000165280; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 7415; 852 hits in 1138 CRISPR screens. DR CD-CODE; 550E224B; Proteasome condensate. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; B5B9A610; PML body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; VCP; human. DR EvolutionaryTrace; P55072; -. DR GeneWiki; Valosin-containing_protein; -. DR GenomeRNAi; 7415; -. DR Pharos; P55072; Tchem. DR PRO; PR:P55072; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; P55072; protein. DR Bgee; ENSG00000165280; Expressed in stromal cell of endometrium and 210 other cell types or tissues. DR ExpressionAtlas; P55072; baseline and differential. DR GO; GO:1904949; C:ATPase complex; IEA:Ensembl. DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0097542; C:ciliary tip; IDA:HPA. DR GO; GO:0035869; C:ciliary transition zone; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0000153; C:cytoplasmic ubiquitin ligase complex; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0036513; C:Derlin-1 retrotranslocation complex; IDA:UniProtKB. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB. DR GO; GO:0005811; C:lipid droplet; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0000502; C:proteasome complex; IDA:BHF-UCL. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0034774; C:secretory granule lumen; TAS:Reactome. DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB. DR GO; GO:0034098; C:VCP-NPL4-UFD1 AAA ATPase complex; IPI:ComplexPortal. DR GO; GO:1990730; C:VCP-NSFL1C complex; IPI:ComplexPortal. DR GO; GO:0043531; F:ADP binding; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:UniProt. DR GO; GO:1904288; F:BAT3 complex binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0035800; F:deubiquitinase activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0036435; F:K48-linked polyubiquitin modification-dependent protein binding; IDA:UniProt. DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW. DR GO; GO:0042288; F:MHC class I protein binding; IEA:Ensembl. DR GO; GO:0031593; F:polyubiquitin modification-dependent protein binding; IDA:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0019903; F:protein phosphatase binding; IPI:BHF-UCL. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0044389; F:ubiquitin-like protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0140036; F:ubiquitin-modified protein reader activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0070842; P:aggresome assembly; IEA:Ensembl. DR GO; GO:0046034; P:ATP metabolic process; IEA:Ensembl. DR GO; GO:0097352; P:autophagosome maturation; IMP:UniProtKB. DR GO; GO:0006914; P:autophagy; IMP:UniProtKB. DR GO; GO:1903843; P:cellular response to arsenite ion; IMP:UniProtKB. DR GO; GO:0034605; P:cellular response to heat; IMP:UniProtKB. DR GO; GO:0071218; P:cellular response to misfolded protein; IMP:ParkinsonsUK-UCL. DR GO; GO:0140455; P:cytoplasm protein quality control; IDA:UniProt. DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; NAS:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB. DR GO; GO:0061857; P:endoplasmic reticulum stress-induced pre-emptive quality control; IMP:UniProtKB. DR GO; GO:0006888; P:endoplasmic reticulum to Golgi vesicle-mediated transport; IEA:Ensembl. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; TAS:UniProtKB. DR GO; GO:0032510; P:endosome to lysosome transport via multivesicular body sorting pathway; IMP:UniProtKB. DR GO; GO:0036503; P:ERAD pathway; IDA:UniProtKB. DR GO; GO:0045184; P:establishment of protein localization; TAS:UniProtKB. DR GO; GO:0072389; P:flavin adenine dinucleotide catabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0036297; P:interstrand cross-link repair; ISS:UniProtKB. DR GO; GO:0016236; P:macroautophagy; IMP:UniProtKB. DR GO; GO:0051228; P:mitotic spindle disassembly; IBA:GO_Central. DR GO; GO:0019674; P:NAD+ metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0035331; P:negative regulation of hippo signaling; IGI:FlyBase. DR GO; GO:0120186; P:negative regulation of protein localization to chromatin; IDA:UniProt. DR GO; GO:0045879; P:negative regulation of smoothened signaling pathway; IMP:FlyBase. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IDA:FlyBase. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IMP:ParkinsonsUK-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:UniProt. DR GO; GO:1903862; P:positive regulation of oxidative phosphorylation; IMP:ParkinsonsUK-UCL. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:BHF-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:BHF-UCL. DR GO; GO:1903006; P:positive regulation of protein K63-linked deubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProt. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0106300; P:protein-DNA covalent cross-linking repair; IDA:UniProtKB. DR GO; GO:1903715; P:regulation of aerobic respiration; IMP:ParkinsonsUK-UCL. DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:1905634; P:regulation of protein localization to chromatin; IDA:UniProtKB. DR GO; GO:0050807; P:regulation of synapse organization; IEA:Ensembl. DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IDA:UniProtKB. DR GO; GO:0035617; P:stress granule disassembly; IDA:UniProtKB. DR GO; GO:0019985; P:translesion synthesis; IMP:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; NAS:ComplexPortal. DR GO; GO:0019079; P:viral genome replication; IMP:CACAO. DR CDD; cd19519; RecA-like_CDC48_r1-like; 1. DR CDD; cd19528; RecA-like_CDC48_r2-like; 1. DR DisProt; DP03238; -. DR FunFam; 1.10.8.60:FF:000004; Cell division control 48; 1. DR FunFam; 3.10.330.10:FF:000001; Cell division control 48; 1. DR FunFam; 2.40.40.20:FF:000003; Transitional endoplasmic reticulum ATPase; 1. DR FunFam; 3.40.50.300:FF:000012; Transitional endoplasmic reticulum ATPase; 1. DR FunFam; 3.40.50.300:FF:000048; Transitional endoplasmic reticulum ATPase; 1. DR Gene3D; 1.10.8.60; -; 1. DR Gene3D; 2.40.40.20; -; 1. DR Gene3D; 3.10.330.10; -; 1. DR Gene3D; 6.10.20.150; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR IDEAL; IID00201; -. DR InterPro; IPR003593; AAA+_ATPase. DR InterPro; IPR005938; AAA_ATPase_CDC48. DR InterPro; IPR050168; AAA_ATPase_domain. DR InterPro; IPR041569; AAA_lid_3. DR InterPro; IPR009010; Asp_de-COase-like_dom_sf. DR InterPro; IPR003959; ATPase_AAA_core. DR InterPro; IPR003960; ATPase_AAA_CS. DR InterPro; IPR004201; Cdc48_dom2. DR InterPro; IPR029067; CDC48_domain_2-like_sf. DR InterPro; IPR003338; CDC4_N-term_subdom. DR InterPro; IPR027417; P-loop_NTPase. DR NCBIfam; TIGR01243; CDC48; 1. DR PANTHER; PTHR23077; AAA-FAMILY ATPASE; 1. DR PANTHER; PTHR23077:SF69; TRANSITIONAL ENDOPLASMIC RETICULUM ATPASE; 1. DR Pfam; PF00004; AAA; 2. DR Pfam; PF17862; AAA_lid_3; 2. DR Pfam; PF02933; CDC48_2; 1. DR Pfam; PF02359; CDC48_N; 1. DR SMART; SM00382; AAA; 2. DR SMART; SM01072; CDC48_2; 1. DR SMART; SM01073; CDC48_N; 1. DR SUPFAM; SSF50692; ADC-like; 1. DR SUPFAM; SSF54585; Cdc48 domain 2-like; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2. DR PROSITE; PS00674; AAA; 2. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis; ATP-binding; KW Autophagy; Charcot-Marie-Tooth disease; Cytoplasm; KW Direct protein sequencing; Disease variant; DNA damage; DNA repair; KW Endoplasmic reticulum; Hydrolase; Isopeptide bond; Lipid-binding; KW Methylation; Neurodegeneration; Neuropathy; Nucleotide-binding; Nucleus; KW Phosphoprotein; Proteomics identification; Reference proteome; Transport; KW Ubl conjugation; Ubl conjugation pathway. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:12665801, ECO:0000269|Ref.9, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:22223895, FT ECO:0007744|PubMed:25944712" FT CHAIN 2..806 FT /note="Transitional endoplasmic reticulum ATPase" FT /id="PRO_0000084572" FT REGION 708..727 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 768..806 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 797..806 FT /note="Interaction with UBXN6" FT /evidence="ECO:0000269|PubMed:18656546" FT MOTIF 802..806 FT /note="PIM motif" FT /evidence="ECO:0000269|PubMed:24726327" FT COMPBIAS 777..793 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 247..253 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 348 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 384 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:20512113" FT BINDING 521..526 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|Ref.9, ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:25944712" FT MOD_RES 3 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 13 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 37 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 315 FT /note="N6,N6,N6-trimethyllysine; by VCPKMT" FT /evidence="ECO:0000269|PubMed:22948820, FT ECO:0000269|PubMed:23349634" FT MOD_RES 436 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 462 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 502 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 505 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 668 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 668 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 702 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 754 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT MOD_RES 770 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 775 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 787 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 805 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q01853" FT CROSSLNK 8 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 18 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 109 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in UFM1)" FT /evidence="ECO:0000269|PubMed:38762759" FT VARIANT 95 FT /note="R -> G (in IBMPFD1; cultured cells expressing the FT mutant protein show a marked general increase in the level FT of ubiquitin-conjugated proteins and impaired protein FT degradation through the endoplasmic reticulum-associated FT degradation (ERAD) pathway; shows strongly reduced affinity FT for ADP and increased affinity for ATP; abolishes FT enhancement of K-315 methylation by ASPSCR1; decreased FT interaction with CAV1 and UBXN6; dbSNP:rs121909332)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:20512113, FT ECO:0000269|PubMed:21822278" FT /id="VAR_033016" FT VARIANT 97 FT /note="G -> E (in CMT2Y; increased ATPase activity; FT dbSNP:rs864309502)" FT /evidence="ECO:0000269|PubMed:25878907" FT /id="VAR_076464" FT VARIANT 126 FT /note="I -> F (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:27209344" FT /id="VAR_076465" FT VARIANT 155 FT /note="R -> C (in IBMPFD1; also in one patient without FT evidence of Paget disease of the bone; dbSNP:rs121909330)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:15732117" FT /id="VAR_033017" FT VARIANT 155 FT /note="R -> H (in FTDALS6 and IBMPFD1; properly assembles FT into a hexameric structure; cultured cells expressing the FT mutant protein show a marked general increase in the level FT of ubiquitin-conjugated proteins and impaired protein FT degradation through the endoplasmic reticulum-associated FT degradation (ERAD) pathway; shows strongly reduced affinity FT for ADP and increased affinity for ATP; shows normal ATPase FT activity according to PubMed:16321991 while according to FT PubMed:25878907 and PubMed:25125609 shows increased ATPase FT activity; no defect in ubiquitin-dependent protein FT degradation by the proteasome; impaired autophagic FT function; defective maturation of ubiquitin-containing FT autophagosomes; decreased interaction with CAV1 and UBXN6; FT decreased endosome to lysosome transport via multivesicular FT body sorting pathway of CAV1; decreases the arsenite- FT induced stress granules (SGs) clearance process; FT dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:21145000, FT ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, FT ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622, ECO:0000269|PubMed:29804830" FT /id="VAR_033018" FT VARIANT 155 FT /note="R -> L (in IBMPFD1; dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:20335036" FT /id="VAR_078910" FT VARIANT 155 FT /note="R -> P (in IBMPFD1; dbSNP:rs121909329)" FT /evidence="ECO:0000269|PubMed:15034582" FT /id="VAR_033019" FT VARIANT 155 FT /note="R -> S (in IBMPFD1; impaired autophagic function; FT dbSNP:rs121909330)" FT /evidence="ECO:0000269|PubMed:20104022" FT /id="VAR_076466" FT VARIANT 159 FT /note="R -> G (in FTDALS6; dbSNP:rs387906789)" FT /evidence="ECO:0000269|PubMed:21145000, FT ECO:0000269|PubMed:23349634" FT /id="VAR_065910" FT VARIANT 159 FT /note="R -> H (in IBMPFD1; without frontotemporal dementia; FT abolishes enhancement of K-315 methylation by ASPSCR1; FT dbSNP:rs121909335)" FT /evidence="ECO:0000269|PubMed:16247064" FT /id="VAR_033020" FT VARIANT 160 FT /note="A -> T (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088265" FT VARIANT 185 FT /note="E -> K (in CMT2Y; normal ATPase activity; impaired FT autophagic function; dbSNP:rs864309501)" FT /evidence="ECO:0000269|PubMed:25125609" FT /id="VAR_076467" FT VARIANT 191 FT /note="R -> Q (in FTDALS6 and IBMPFD1; abolishes FT enhancement of K-315 methylation by ASPSCR1; FT dbSNP:rs121909334)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:21145000, ECO:0000269|PubMed:23349634" FT /id="VAR_033021" FT VARIANT 198 FT /note="L -> W (in IBMPFD1; increased ATPase activity; FT impaired autophagic function; dbSNP:rs748447593)" FT /evidence="ECO:0000269|PubMed:17935506, FT ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622" FT /id="VAR_076468" FT VARIANT 232 FT /note="A -> E (in IBMPFD1; increased ATPase activity; no FT defect in ubiquitin-dependent protein degradation by the FT proteasome; impaired autophagic function; defect in FT maturation of ubiquitin-containing autophagosomes; FT decreased interaction with CAV1 and UBXN6; FT dbSNP:rs121909331)" FT /evidence="ECO:0000269|PubMed:15034582, FT ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:21822278, FT ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, FT ECO:0000269|PubMed:27753622" FT /id="VAR_033022" FT VARIANT 254 FT /note="I -> F (in IBMPFD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088266" FT VARIANT 369 FT /note="I -> T (in IBMPFD1; uncertain significance; FT dbSNP:rs1828723406)" FT /evidence="ECO:0000269|PubMed:36980948" FT /id="VAR_088267" FT VARIANT 387 FT /note="N -> H (in IBMPFD1; uncertain significance; FT dbSNP:rs1554668420)" FT /evidence="ECO:0000269|PubMed:17935506" FT /id="VAR_078911" FT VARIANT 592 FT /note="D -> N (in FTDALS6; dbSNP:rs387906790)" FT /evidence="ECO:0000269|PubMed:21145000" FT /id="VAR_065911" FT MUTAGEN 52..55 FT /note="FRGD->ARGA: Abolishes interaction with NPLOC4; when FT associated with A-110." FT /evidence="ECO:0000269|PubMed:26471729" FT MUTAGEN 53 FT /note="R->A: Minor effect on affinity for ATP and ADP." FT /evidence="ECO:0000269|PubMed:20512113" FT MUTAGEN 86 FT /note="R->A: Strongly increased affinity for ATP. Strongly FT reduced affinity for ADP." FT /evidence="ECO:0000269|PubMed:20512113" FT MUTAGEN 109 FT /note="K->R: Impaired UFMylation." FT /evidence="ECO:0000269|PubMed:38762759" FT MUTAGEN 110 FT /note="Y->A: Abolishes interaction with NPLOC4; when FT associated with 52-A--A-55. Impaired UFMylation." FT /evidence="ECO:0000269|PubMed:26471729, FT ECO:0000269|PubMed:38762759" FT MUTAGEN 113..115 FT /note="RIH->TIT: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 131 FT /note="F->R: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 140 FT /note="L->D: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 179 FT /note="D->R: No effect on binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 183 FT /note="H->W: Severely reduced binding to DERL1." FT /evidence="ECO:0000269|PubMed:27714797" FT MUTAGEN 251 FT /note="K->Q: Impairs ERAD degradation of HMGCR and does not FT inhibit interaction with RHBDD1; when associated with Q- FT 524." FT /evidence="ECO:0000269|PubMed:16168377, FT ECO:0000269|PubMed:22795130" FT MUTAGEN 305 FT /note="E->Q: Defect in ubiquitin-dependent protein FT degradation by the proteasome; when associated with Q-578." FT /evidence="ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:26471729" FT MUTAGEN 312 FT /note="K->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 313 FT /note="R->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 314 FT /note="E->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 314 FT /note="Missing: Strongly impairs methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 315 FT /note="K->L,Q,R: Abolishes methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820, FT ECO:0000269|PubMed:23349634" FT MUTAGEN 316 FT /note="T->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 317 FT /note="H->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 318 FT /note="G->A: Does not affect methylation by VCPKMT." FT /evidence="ECO:0000269|PubMed:22948820" FT MUTAGEN 524 FT /note="K->A: Impairs catalytic activity of RNF19A toward FT SOD1 mutant. Does not inhibit interaction with RHBDD1; when FT associated with A-251." FT /evidence="ECO:0000269|PubMed:15456787, FT ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22795130" FT MUTAGEN 524 FT /note="K->Q: Impairs ERAD degradation of HMGCR; when FT associated with Q-251." FT /evidence="ECO:0000269|PubMed:15456787, FT ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:22795130" FT MUTAGEN 578 FT /note="E->Q: Does not inhibit interaction with RHBDD1. FT Increased interaction with CAV1 and UBXN6. Impaired FT autophagic function. Defect in ubiquitin-dependent protein FT degradation by the proteasome; when associated with Q-305. FT Increases interaction with ZFAND1 in an arsenite-dependent FT manner." FT /evidence="ECO:0000269|PubMed:20104022, FT ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:22795130, FT ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:29804830" FT CONFLICT 169 FT /note="D -> H (in Ref. 7; AAI21795)" FT /evidence="ECO:0000305" FT CONFLICT 312 FT /note="K -> I (in Ref. 4; BAG35235)" FT /evidence="ECO:0000305" FT HELIX 15..17 FT /evidence="ECO:0007829|PDB:7LMY" FT TURN 21..23 FT /evidence="ECO:0007829|PDB:7BPA" FT STRAND 25..29 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 32..37 FT /evidence="ECO:0007829|PDB:8R0E" FT STRAND 38..41 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 43..48 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 53..55 FT /evidence="ECO:0007829|PDB:5FTN" FT STRAND 56..60 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 62..64 FT /evidence="ECO:0007829|PDB:3QQ8" FT STRAND 66..73 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 75..77 FT /evidence="ECO:0007829|PDB:8OOI" FT STRAND 81..83 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 86..92 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 94..97 FT /evidence="ECO:0007829|PDB:8R0E" FT STRAND 99..104 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 112..119 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 120..123 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 126..128 FT /evidence="ECO:0007829|PDB:5IFS" FT HELIX 130..133 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 135..139 FT /evidence="ECO:0007829|PDB:5B6C" FT TURN 140..142 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 144..147 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 151..154 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 157..159 FT /evidence="ECO:0007829|PDB:4KDI" FT STRAND 161..176 FT /evidence="ECO:0007829|PDB:5B6C" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:5B6C" FT HELIX 191..193 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 198..200 FT /evidence="ECO:0007829|PDB:5FTJ" FT HELIX 203..205 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 210..225 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 229..232 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 240..244 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 246..250 FT /evidence="ECO:0007829|PDB:4KLN" FT HELIX 251..262 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 265..270 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 278..280 FT /evidence="ECO:0007829|PDB:8OOI" FT HELIX 281..295 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 298..304 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 306..308 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 313..315 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 319..334 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 335..337 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 338..340 FT /evidence="ECO:0007829|PDB:8HRZ" FT STRAND 341..348 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 350..352 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 355..358 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 360..362 FT /evidence="ECO:0007829|PDB:8OOI" FT STRAND 365..368 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 374..384 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 385..387 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 388..390 FT /evidence="ECO:0007829|PDB:5DYG" FT HELIX 392..394 FT /evidence="ECO:0007829|PDB:8PQX" FT HELIX 396..402 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 403..405 FT /evidence="ECO:0007829|PDB:5FTJ" FT HELIX 408..427 FT /evidence="ECO:0007829|PDB:7PUX" FT TURN 428..430 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 432..436 FT /evidence="ECO:0007829|PDB:3HU1" FT HELIX 439..444 FT /evidence="ECO:0007829|PDB:7PUX" FT HELIX 449..456 FT /evidence="ECO:0007829|PDB:7PUX" FT STRAND 458..461 FT /evidence="ECO:0007829|PDB:4KO8" FT TURN 462..468 FT /evidence="ECO:0007829|PDB:4KO8" FT HELIX 476..478 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 483..498 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 500..505 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 513..519 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 520..523 FT /evidence="ECO:0007829|PDB:8UV2" FT HELIX 524..534 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 538..543 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 544..547 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 550..553 FT /evidence="ECO:0007829|PDB:7LN0" FT HELIX 557..568 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 571..577 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 579..581 FT /evidence="ECO:0007829|PDB:6G2V" FT TURN 584..586 FT /evidence="ECO:0007829|PDB:5FTN" FT STRAND 588..590 FT /evidence="ECO:0007829|PDB:5FTJ" FT STRAND 592..594 FT /evidence="ECO:0007829|PDB:8OOI" FT HELIX 597..609 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 613..615 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 617..624 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 626..628 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 631..634 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 635..639 FT /evidence="ECO:0007829|PDB:5FTK" FT STRAND 641..644 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 650..661 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 662..664 FT /evidence="ECO:0007829|PDB:7LN0" FT HELIX 672..677 FT /evidence="ECO:0007829|PDB:6G2V" FT TURN 678..681 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 684..711 FT /evidence="ECO:0007829|PDB:6G2V" FT STRAND 718..721 FT /evidence="ECO:0007829|PDB:7VCU" FT STRAND 722..724 FT /evidence="ECO:0007829|PDB:5IFW" FT STRAND 729..731 FT /evidence="ECO:0007829|PDB:7LMY" FT HELIX 733..739 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 740..742 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 749..761 FT /evidence="ECO:0007829|PDB:6G2V" FT HELIX 763..765 FT /evidence="ECO:0007829|PDB:7JY5" FT STRAND 767..770 FT /evidence="ECO:0007829|PDB:7RLI" SQ SEQUENCE 806 AA; 89322 MW; 501B721D3A77BA8A CRC64; MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVRN NLRVRLGDVI SIQPCPDVKY GKRIHVLPID DTVEGITGNL FEVYLKPYFL EAYRPIRKGD IFLVRGGMRA VEFKVVETDP SPYCIVAPDT VIHCEGEPIK REDEEESLNE VGYDDIGGCR KQLAQIKEMV ELPLRHPALF KAIGVKPPRG ILLYGPPGTG KTLIARAVAN ETGAFFFLIN GPEIMSKLAG ESESNLRKAF EEAEKNAPAI IFIDELDAIA PKREKTHGEV ERRIVSQLLT LMDGLKQRAH VIVMAATNRP NSIDPALRRF GRFDREVDIG IPDATGRLEI LQIHTKNMKL ADDVDLEQVA NETHGHVGAD LAALCSEAAL QAIRKKMDLI DLEDETIDAE VMNSLAVTMD DFRWALSQSN PSALRETVVE VPQVTWEDIG GLEDVKRELQ ELVQYPVEHP DKFLKFGMTP SKGVLFYGPP GCGKTLLAKA IANECQANFI SIKGPELLTM WFGESEANVR EIFDKARQAA PCVLFFDELD SIAKARGGNI GDGGGAADRV INQILTEMDG MSTKKNVFII GATNRPDIID PAILRPGRLD QLIYIPLPDE KSRVAILKAN LRKSPVAKDV DLEFLAKMTN GFSGADLTEI CQRACKLAIR ESIESEIRRE RERQTNPSAM EVEEDDPVPE IRRDHFEEAM RFARRSVSDN DIRKYEMFAQ TLQQSRGFGS FRFPSGNQGG AGPSQGSGGG TGGSVYTEDN DDDLYG //