ID APOE_HUMAN Reviewed; 317 AA. AC P02649; B2RC15; C0JYY5; Q9P2S4; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 21-JUL-1986, sequence version 1. DT 28-JAN-2026, entry version 278. DE RecName: Full=Apolipoprotein E {ECO:0000305}; DE Short=Apo-E; DE Flags: Precursor; GN Name=APOE {ECO:0000312|HGNC:HGNC:613}; 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] (ALLELE APOE*3). RX PubMed=6325438; DOI=10.1016/s0021-9258(18)91039-2; RA Zannis V.I., McPherson J., Goldberger G., Karathanasis S.K., Breslow J.L.; RT "Synthesis, intracellular processing, and signal peptide of human RT apolipoprotein E."; RL J. Biol. Chem. 259:5495-5499(1984). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS THR-117 AND PRO-170. RX PubMed=6327682; DOI=10.1016/s0021-9258(20)82169-3; RA McLean J.W., Elshourbagy N.A., Chang D.J., Mahley R.W., Taylor J.M.; RT "Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a RT new variant."; RL J. Biol. Chem. 259:6498-6504(1984). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*4), AND VARIANT AD2 ARG-130. RX PubMed=2987927; DOI=10.1073/pnas.82.10.3445; RA Paik Y.-K., Chang D.J., Reardon C.A., Davies G.E., Mahley R.W., RA Taylor J.M.; RT "Nucleotide sequence and structure of the human apolipoprotein E gene."; RL Proc. Natl. Acad. Sci. U.S.A. 82:3445-3449(1985). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*2), AND VARIANT CYS-176. RX PubMed=3243553; DOI=10.1016/0888-7543(88)90130-9; RA Emi M., Wu L.L., Robertson M.A., Myers R.L., Hegele R.A., Williams R.R., RA White R., Lalouel J.-M.; RT "Genotyping and sequence analysis of apolipoprotein E isoforms."; RL Genomics 3:373-379(1988). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*3). RX PubMed=10520737; DOI=10.3109/10425179809086433; RA Freitas E.M., Zhang W.J., Lalonde J.P., Tay G.K., Gaudieri S., RA Ashworth L.K., Van Bockxmeer F.M., Dawkins R.L.; RT "Sequencing of 42kb of the APO E-C2 gene cluster reveals a new gene: RT PEREC1."; RL DNA Seq. 9:89-100(1998). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*3), AND VARIANTS PRO-46; RP ARG-130; CYS-163 AND CYS-176. RX PubMed=11042151; DOI=10.1101/gr.146900; RA Nickerson D.A., Taylor S.L., Fullerton S.M., Weiss K.M., Clark A.G., RA Stengard J.H., Salomaa V., Boerwinkle E., Sing C.F.; RT "Sequence diversity and large-scale typing of SNPs in the human RT apolipoprotein E gene."; RL Genome Res. 10:1532-1545(2000). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ALLELE APOE*3). 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 [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*3). RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ALLELE APOE*3). RC TISSUE=Eye; 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 16-78, AND VARIANT HIS-64. RC TISSUE=Blood; RA Imura T., Kimura H., Kawasaki M.; RT "A new apolipoprotein E variant (Gln46-->His)."; RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 99-317 (ALLELE APOE*3). RX PubMed=6897404; DOI=10.1016/s0021-9258(18)33328-3; RA Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W., Lofquist-Kahl F., RA Karathanasis S.K., Zannis V.I.; RT "Identification and DNA sequence of a human apolipoprotein E cDNA clone."; RL J. Biol. Chem. 257:14639-14641(1982). RN [12] RP ERRATUM OF PUBMED:6897404. RA Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W., Lofquist-Kahl F., RA Karathanasis S.K., Zannis V.I.; RL J. Biol. Chem. 258:11422-11422(1983). RN [13] RP PROTEIN SEQUENCE OF 19-317 (ALLELE APOE*2). RX PubMed=7068630; DOI=10.1016/s0021-9258(18)34702-1; RA Rall S.C. Jr., Weisgraber K.H., Mahley R.W.; RT "Human apolipoprotein E. The complete amino acid sequence."; RL J. Biol. Chem. 257:4171-4178(1982). RN [14] RP FUNCTION IN LIPOPROTEINS CONVERSION. RX PubMed=6860692; DOI=10.1016/0005-2760(83)90047-4; RA Marcel Y.L., Vezina C., Milne R.W.; RT "Cholesteryl ester and apolipoprotein E transfer between human high density RT lipoproteins and chylomicrons."; RL Biochim. Biophys. Acta 750:411-417(1983). RN [15] RP HEPARIN-BINDING SITES. RX PubMed=3947350; DOI=10.1016/s0006-291x(86)80489-2; RA Cardin A.D., Hirose N., Blankenship D.T., Jackson R.L., Harmony J.A.K., RA Sparrow D.A., Sparrow J.T.; RT "Binding of a high reactive heparin to human apolipoprotein E: RT identification of two heparin-binding domains."; RL Biochem. Biophys. Res. Commun. 134:783-789(1986). RN [16] RP TISSUE SPECIFICITY. RX PubMed=3115992; DOI=10.1016/s0021-9258(18)47945-8; RA Pitas R.E., Boyles J.K., Lee S.H., Hui D., Weisgraber K.H.; RT "Lipoproteins and their receptors in the central nervous system. RT Characterization of the lipoproteins in cerebrospinal fluid and RT identification of apolipoprotein B,E(LDL) receptors in the brain."; RL J. Biol. Chem. 262:14352-14360(1987). RN [17] RP INTERACTION WITH SORL1. RX PubMed=30448281; DOI=10.1016/j.cca.2018.11.024; RA Yano K., Hirayama S., Misawa N., Furuta A., Ueno T., Motoi Y., Seino U., RA Ebinuma H., Ikeuchi T., Schneider W.J., Bujo H., Miida T.; RT "Soluble LR11 competes with amyloid beta in binding to cerebrospinal fluid- RT high-density lipoprotein."; RL Clin. Chim. Acta 489:29-34(2019). RN [18] RP CHARACTERIZATION OF VARIANTS SER-154 AND PRO-170, AND MUTAGENESIS OF RP SER-157; HIS-158; LYS-161; LEU-162; LEU-167 AND ARG-168. RX PubMed=2831187; DOI=10.1016/s0021-9258(18)68957-4; RA Lalazar A., Weisgraber K.H., Rall S.C. Jr., Giladi H., Innerarity T.L., RA Levanon A.Z., Boyles J.K., Amit B., Gorecki M., Mahley R.W.; RT "Site-specific mutagenesis of human apolipoprotein E. Receptor binding RT activity of variants with single amino acid substitutions."; RL J. Biol. Chem. 263:3542-3545(1988). RN [19] RP SUBCELLULAR LOCATION, GLYCOSYLATION AT THR-212, AND MUTAGENESIS OF THR-212. RX PubMed=2498325; DOI=10.1016/s0021-9258(18)81907-x; RA Wernette-Hammond M.E., Lauer S.J., Corsini A., Walker D., Taylor J.M., RA Rall S.C. Jr.; RT "Glycosylation of human apolipoprotein E. The carbohydrate attachment site RT is threonine 194."; RL J. Biol. Chem. 264:9094-9101(1989). RN [20] RP FUNCTION IN VLDL CLEARANCE. RX PubMed=2762297; DOI=10.1073/pnas.86.15.5810; RA Kowal R.C., Herz J., Goldstein J.L., Esser V., Brown M.S.; RT "Low density lipoprotein receptor-related protein mediates uptake of RT cholesteryl esters derived from apoprotein E-enriched lipoproteins."; RL Proc. Natl. Acad. Sci. U.S.A. 86:5810-5814(1989). RN [21] RP REGION, AND CHARACTERIZATION OF VARIANT ARG-130 AND ARG-176. RX PubMed=2280190; RA Weisgraber K.H.; RT "Apolipoprotein E distribution among human plasma lipoproteins: role of the RT cysteine-arginine interchange at residue 112."; RL J. Lipid Res. 31:1503-1511(1990). RN [22] RP FUNCTION IN CHYLOMICRONS CLEARANCE, AND SUBCELLULAR LOCATION. RX PubMed=1911868; DOI=10.1016/0005-2760(91)90138-8; RA Arnon R., Sehayek E., Vogel T., Eisenberg S.; RT "Effects of exogenous apo E-3 and of cholesterol-enriched meals on the RT cellular metabolism of human chylomicrons and their remnants."; RL Biochim. Biophys. Acta 1085:336-342(1991). RN [23] RP FUNCTION IN VLDL AND IDL CLEARANCE. RX PubMed=1917954; DOI=10.1016/s0021-9258(18)55263-7; RA Sehayek E., Eisenberg S.; RT "Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent RT cellular metabolism of human triglyceride-rich lipoproteins through the low RT density lipoprotein receptor pathway."; RL J. Biol. Chem. 266:18259-18267(1991). RN [24] RP SUBUNIT, SUBCELLULAR LOCATION, AND REGION. RX PubMed=8340399; DOI=10.1016/s0021-9258(18)82318-3; RA Westerlund J.A., Weisgraber K.H.; RT "Discrete carboxyl-terminal segments of apolipoprotein E mediate RT lipoprotein association and protein oligomerization."; RL J. Biol. Chem. 268:15745-15750(1993). RN [25] RP INTERACTION WITH APP/A4 AMYLOID-BETA PEPTIDE, AND CHARACTERIZATION OF RP VARIANT AD2 ARG-130. RX PubMed=8367470; DOI=10.1073/pnas.90.17.8098; RA Strittmatter W.J., Weisgraber K.H., Huang D.Y., Dong L.M., Salvesen G.S., RA Pericak-Vance M., Schmechel D., Saunders A.M., Goldgaber D., Roses A.D.; RT "Binding of human apolipoprotein E to synthetic amyloid beta peptide: RT isoform-specific effects and implications for late-onset Alzheimer RT disease."; RL Proc. Natl. Acad. Sci. U.S.A. 90:8098-8102(1993). RN [26] RP INTERACTION WITH MAP2, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=7891887; DOI=10.1016/0304-3940(94)90204-6; RA Huang D.Y., Goedert M., Jakes R., Weisgraber K.H., Garner C.C., RA Saunders A.M., Pericak-Vance M.A., Schmechel D.E., Roses A.D., RA Strittmatter W.J.; RT "Isoform-specific interactions of apolipoprotein E with the microtubule- RT associated protein MAP2c: implications for Alzheimer's disease."; RL Neurosci. Lett. 182:55-58(1994). RN [27] RP INTERACTION WITH MAPT, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=7972031; DOI=10.1073/pnas.91.23.11183; RA Strittmatter W.J., Saunders A.M., Goedert M., Weisgraber K.H., Dong L.M., RA Jakes R., Huang D.Y., Pericak-Vance M., Schmechel D., Roses A.D.; RT "Isoform-specific interactions of apolipoprotein E with microtubule- RT associated protein tau: implications for Alzheimer disease."; RL Proc. Natl. Acad. Sci. U.S.A. 91:11183-11186(1994). RN [28] RP FUNCTION, AND LRP2-BINDING. RX PubMed=7768901; DOI=10.1074/jbc.270.22.13070; RA Kounnas M.Z., Loukinova E.B., Stefansson S., Harmony J.A.K., Brewer B.H., RA Strickland D.K., Argraves W.S.; RT "Identification of glycoprotein 330 as an endocytic receptor for RT apolipoprotein J/clusterin."; RL J. Biol. Chem. 270:13070-13075(1995). RN [29] RP FUNCTION IN NEURITE OUTGROWTH, LRP-BINDING, AND CHARACTERIZATION OF VARIANT RP AD2 ARG-130. RX PubMed=8939961; DOI=10.1074/jbc.271.47.30121; RA Fagan A.M., Bu G., Sun Y., Daugherty A., Holtzman D.M.; RT "Apolipoprotein E-containing high density lipoprotein promotes neurite RT outgrowth and is a ligand for the low density lipoprotein receptor-related RT protein."; RL J. Biol. Chem. 271:30121-30125(1996). RN [30] RP FUNCTION IN HDL CLEARANCE, AND HEPARAN SULFATE-BINDING. RX PubMed=9395455; DOI=10.1074/jbc.272.50.31285; RA Ji Z.S., Dichek H.L., Miranda R.D., Mahley R.W.; RT "Heparan sulfate proteoglycans participate in hepatic lipase and RT apolipoprotein E-mediated binding and uptake of plasma lipoproteins, RT including high density lipoproteins."; RL J. Biol. Chem. 272:31285-31292(1997). RN [31] RP FUNCTION, HEPARAN-SULFATE-BINDING, AND SUBCELLULAR LOCATION. RX PubMed=9488694; DOI=10.1074/jbc.273.10.5645; RA Burgess J.W., Gould D.R., Marcel Y.L.; RT "The HepG2 extracellular matrix contains separate heparinase- and lipid- RT releasable pools of ApoE. Implications for hepatic lipoprotein RT metabolism."; RL J. Biol. Chem. 273:5645-5654(1998). RN [32] RP TISSUE SPECIFICITY. RX PubMed=10027417; DOI=10.1016/s0002-9440(10)65305-9; RA Xu P.T., Gilbert J.R., Qiu H.L., Ervin J., Rothrock-Christian T.R., RA Hulette C., Schmechel D.E.; RT "Specific regional transcription of apolipoprotein E in human brain RT neurons."; RL Am. J. Pathol. 154:601-611(1999). RN [33] RP GLYCATION AT LYS-93, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=10452964; DOI=10.1016/s0925-4439(99)00047-2; RA Shuvaev V.V., Fujii J., Kawasaki Y., Itoh H., Hamaoka R., Barbier A., RA Ziegler O., Siest G., Taniguchi N.; RT "Glycation of apolipoprotein E impairs its binding to heparin: RT identification of the major glycation site."; RL Biochim. Biophys. Acta 1454:296-308(1999). RN [34] RP PTM, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=11447277; DOI=10.1073/pnas.151254698; RA Huang Y., Liu X.Q., Wyss-Coray T., Brecht W.J., Sanan D.A., Mahley R.W.; RT "Apolipoprotein E fragments present in Alzheimer's disease brains induce RT neurofibrillary tangle-like intracellular inclusions in neurons."; RL Proc. Natl. Acad. Sci. U.S.A. 98:8838-8843(2001). RN [35] RP FUNCTION, LRP8-BINDING, AND CHARACTERIZATION OF VARIANT CYS-176. RX PubMed=12950167; DOI=10.1021/bi027093c; RA Li X., Kypreos K., Zanni E.E., Zannis V.; RT "Domains of apoE required for binding to apoE receptor 2 and to RT phospholipids: implications for the functions of apoE in the brain."; RL Biochemistry 42:10406-10417(2003). RN [36] RP FUNCTION IN REVERSE CHOLESTEROL TRANSPORT, AND INTERACTION WITH ABCA1. RX PubMed=14754908; DOI=10.1194/jlr.m300418-jlr200; RA Krimbou L., Denis M., Haidar B., Carrier M., Marcil M., Genest J. Jr.; RT "Molecular interactions between apoE and ABCA1: impact on apoE RT lipidation."; RL J. Lipid Res. 45:839-848(2004). RN [37] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-212; THR-307 AND SER-308, AND RP STRUCTURE 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 [38] RP FUNCTION, LRP1-BINDING, AND REGION. RX PubMed=20030366; DOI=10.1021/bi9017208; RA Guttman M., Prieto J.H., Croy J.E., Komives E.A.; RT "Decoding of lipoprotein-receptor interactions: properties of ligand RT binding modules governing interactions with apolipoprotein E."; RL Biochemistry 49:1207-1216(2010). RN [39] RP GLYCOSYLATION AT SER-308. RX PubMed=20511397; DOI=10.1074/mcp.m900430-mcp200; RA Lee Y., Kockx M., Raftery M.J., Jessup W., Griffith R., Kritharides L.; RT "Glycosylation and sialylation of macrophage-derived human apolipoprotein E RT analyzed by SDS-PAGE and mass spectrometry: evidence for a novel site of RT glycosylation on Ser290."; RL Mol. Cell. Proteomics 9:1968-1981(2010). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [41] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22905912; DOI=10.1021/pr300539b; RA Rosenow A., Noben J.P., Jocken J., Kallendrusch S., Fischer-Posovszky P., RA Mariman E.C., Renes J.; RT "Resveratrol-induced changes of the human adipocyte secretion profile."; RL J. Proteome Res. 11:4733-4743(2012). RN [42] RP FUNCTION IN LIPOPROTEIN CLEARANCE, AND HEPARAN-SULFATE PROTEOGLYCANS RP BINDING. RX PubMed=23676495; DOI=10.1172/jci67398; RA Gonzales J.C., Gordts P.L., Foley E.M., Esko J.D.; RT "Apolipoproteins E and AV mediate lipoprotein clearance by hepatic RT proteoglycans."; RL J. Clin. Invest. 123:2742-2751(2013). RN [43] RP GLYCOSYLATION AT THR-26; THR-36 AND SER-314, AND IDENTIFICATION BY MASS RP 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). RN [44] RP FUNCTION IN CHOLESTEROL EFFLUX, AND INTERACTION WITH APP/A4 AMYLOID-BETA RP PEPTIDE. RX PubMed=23620513; DOI=10.1073/pnas.1220484110; RA Verghese P.B., Castellano J.M., Garai K., Wang Y., Jiang H., Shah A., RA Bu G., Frieden C., Holtzman D.M.; RT "ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta RT association in physiological conditions."; RL Proc. Natl. Acad. Sci. U.S.A. 110:E1807-E1816(2013). RN [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147, 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 HCV ENVELOPE GLYCOPROTEIN E2 (MICROBIAL INFECTION), AND RP FUNCTION (MICROBIAL INFECTION). RX PubMed=25122793; DOI=10.1128/jvi.01660-14; RA Lee J.Y., Acosta E.G., Stoeck I.K., Long G., Hiet M.S., Mueller B., RA Fackler O.T., Kallis S., Bartenschlager R.; RT "Apolipoprotein E likely contributes to a maturation step of infectious RT hepatitis C virus particles and interacts with viral envelope RT glycoproteins."; RL J. Virol. 88:12422-12437(2014). RN [47] RP PHOSPHORYLATION AT SER-147. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted phosphoproteome."; RL Cell 161:1619-1632(2015). RN [48] RP SUBCELLULAR LOCATION, AND INTERACTION WITH PMEL. RX PubMed=26387950; DOI=10.1016/j.celrep.2015.08.057; RA van Niel G., Bergam P., Di Cicco A., Hurbain I., Lo Cicero A., Dingli F., RA Palmulli R., Fort C., Potier M.C., Schurgers L.J., Loew D., Levy D., RA Raposo G.; RT "Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment RT Cells."; RL Cell Rep. 13:43-51(2015). RN [49] RP FUNCTION IN APP TRANSCRIPTION, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=28111074; DOI=10.1016/j.cell.2016.12.044; RA Huang Y.A., Zhou B., Wernig M., Suedhof T.C.; RT "ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and RT Abeta Secretion."; RL Cell 168:427-441(2017). RN [50] RP INTERACTION WITH HCV ENVELOPE GLYCOPROTEIN E2 (MICROBIAL INFECTION), AND RP FUNCTION (MICROBIAL INFECTION). RX PubMed=29695434; DOI=10.1128/jvi.00211-18; RA Kim J.Y., Ou J.J.; RT "Regulation of Apolipoprotein E Trafficking by Hepatitis C Virus-Induced RT Autophagy."; RL J. Virol. 92:e00211-e00218(2018). RN [51] RP FUNCTION, SUBCELLULAR LOCATION, AND ROLE IN TUMOR CELL INFILTRATION. RX PubMed=30333625; DOI=10.1038/s41586-018-0615-z; RA Deng M., Gui X., Kim J., Xie L., Chen W., Li Z., He L., Chen Y., Chen H., RA Luo W., Lu Z., Xie J., Churchill H., Xu Y., Zhou Z., Wu G., Yu C., John S., RA Hirayasu K., Nguyen N., Liu X., Huang F., Li L., Deng H., Tang H., RA Sadek A.H., Zhang L., Huang T., Zou Y., Chen B., Zhu H., Arase H., Xia N., RA Jiang Y., Collins R., You M.J., Homsi J., Unni N., Lewis C., Chen G.Q., RA Fu Y.X., Liao X.C., An Z., Zheng J., Zhang N., Zhang C.C.; RT "LILRB4 signalling in leukaemia cells mediates T cell suppression and RT tumour infiltration."; RL Nature 562:605-609(2018). RN [52] {ECO:0007744|PDB:1LPE} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 41-184, FUNCTION, AND REGION. RX PubMed=2063194; DOI=10.1126/science.2063194; RA Wilson C., Wardell M.R., Weisgraber K.H., Mahley R.W., Agard D.A.; RT "Three-dimensional structure of the LDL receptor-binding domain of human RT apolipoprotein E."; RL Science 252:1817-1822(1991). RN [53] {ECO:0007744|PDB:1LE4} RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 41-184 OF VARIANT AD2 ARG-130, RP CHARACTERIZATION OF VARIANT AD2 ARG-130, MUTAGENESIS OF ARG-79 AND GLU-127, RP AND REGION. RX PubMed=8071364; DOI=10.1016/s0021-9258(17)31797-0; RA Dong L.M., Wilson C., Wardell M.R., Simmons T., Mahley R.W., RA Weisgraber K.H., Agard D.A.; RT "Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein RT preferences of the E3 and E4 isoforms."; RL J. Biol. Chem. 269:22358-22365(1994). RN [54] {ECO:0007744|PDB:1LE2} RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 41-184 OF VARIANT CYS-176, AND RP CHARACTERIZATION OF VARIANT CYS-176. RX PubMed=7994571; DOI=10.1016/s0969-2126(00)00072-1; RA Wilson C., Mau T., Weisgraber K.H., Wardell M.R., Mahley R.W., Agard D.A.; RT "Salt bridge relay triggers defective LDL receptor binding by a mutant RT apolipoprotein."; RL Structure 2:713-718(1994). RN [55] {ECO:0007744|PDB:1NFN, ECO:0007744|PDB:1NFO} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 19-209 OF VARIANT CYS-176, RP MUTAGENESIS OF ASP-172, CHARACTERIZATION OF VARIANT CYS-176, FUNCTION, AND RP LDLR-BINDING. RX PubMed=8756331; DOI=10.1038/nsb0896-718; RA Dong L.-M., Parkin S., Trakhanov S.D., Rupp B., Simmons T., Arnold K.S., RA Newhouse Y.M., Innerarity T.L., Weisgraber K.H.; RT "Novel mechanism for defective receptor binding of apolipoprotein E2 in RT type III hyperlipoproteinemia."; RL Nat. Struct. Biol. 3:718-722(1996). RN [56] {ECO:0007744|PDB:1BZ4, ECO:0007744|PDB:1OR2, ECO:0007744|PDB:1OR3} RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 19-183. RX PubMed=10850798; DOI=10.1110/ps.9.5.886; RA Segelke B.W., Forstner M., Knapp M., Trakhanov S.D., Parkin S., RA Newhouse Y.M., Bellamy H.D., Weisgraber K.H., Rupp B.; RT "Conformational flexibility in the apolipoprotein E amino-terminal domain RT structure determined from three new crystal forms: implications for lipid RT binding."; RL Protein Sci. 9:886-897(2000). RN [57] {ECO:0007744|PDB:1B68} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 19-209 OF VARIANT AD2 ARG-130. RX PubMed=11258893; DOI=10.1021/bi002417n; RA Dong J., Peters-Libeu C.A., Weisgraber K.H., Segelke B.W., Rupp B., RA Capila I., Hernaiz M.J., LeBrun L.A., Linhardt R.J.; RT "Interaction of the N-terminal domain of apolipoprotein E4 with heparin."; RL Biochemistry 40:2826-2834(2001). RN [58] {ECO:0007744|PDB:2KNY} RP STRUCTURE BY NMR OF 147-167 IN COMPLEX WITH LRP1, FUNCTION, AND RP LRP1-BINDING. RX PubMed=20303980; DOI=10.1016/j.jmb.2010.03.022; RA Guttman M., Prieto J.H., Handel T.M., Domaille P.J., Komives E.A.; RT "Structure of the minimal interface between ApoE and LRP."; RL J. Mol. Biol. 398:306-319(2010). RN [59] RP VARIANT HLPP3 262-GLU-GLU-263 DELINS LYS-LYS. RX PubMed=2738044; DOI=10.1093/oxfordjournals.jbchem.a122618; RA Maeda H., Nakamura H., Kobori S., Okada M., Mori H., Niki H., Ogura T., RA Hiraga S.; RT "Identification of human apolipoprotein E variant gene: apolipoprotein E7 RT (Glu244,245----Lys244,245)."; RL J. Biochem. 105:51-54(1989). RN [60] RP VARIANT LYS-21. RX PubMed=2760009; DOI=10.1093/oxfordjournals.jbchem.a122692; RA Maeda H., Nakamura H., Kobori S., Okada M., Niki H., Ogura T., Hiraga S.; RT "Molecular cloning of a human apolipoprotein E variant: E5 (Glu-3-->Lys)."; RL J. Biochem. 105:491-493(1989). RN [61] RP VARIANTS HLPP3 ARG-130 AND GLU-VAL-GLN-ALA-MET-LEU-GLY-145 INS. RX PubMed=2556398; DOI=10.1016/s0021-9258(19)30067-5; RA Wardell M.R., Weisgraber K.H., Havekes L.M., Rall S.C. Jr.; RT "Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a RT tandem repeat of residues 121-127."; RL J. Biol. Chem. 264:21205-21210(1989). RN [62] RP VARIANT HLPP3 HIS-163. RX PubMed=2101409; DOI=10.2169/internalmedicine1962.29.587; RA Suehiro T., Yoshida K., Yamano T., Ohno F.; RT "Identification and characterization of a new variant of apolipoprotein E RT (apo E-Kochi)."; RL Jpn. J. Med. 29:587-594(1990). RN [63] RP VARIANT CYS-246. RX PubMed=2341812; RA Wardell M.R., Rall S.C. Jr., Brennan S.O., Nye E.R., George P.M., RA Janus E.D., Weisgraber K.H.; RT "Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 RT variant with normal receptor-binding activity."; RL J. Lipid Res. 31:535-543(1990). RN [64] RP VARIANT HLPP3 GLN-164. RX PubMed=2313204; RA Smit M., de Knijff P., van der Kooij-Meijs E., Groenendijk C., RA van den Maagdenberg A.M., Gevers Leuven J.A., Stalenhoef A.F., Stuyt P.M., RA Frants R.R., Havekes L.M.; RT "Genetic heterogeneity in familial dysbetalipoproteinemia. The RT E2(lys146----gln) variant results in a dominant mode of inheritance."; RL J. Lipid Res. 31:45-53(1990). RN [65] RP VARIANTS HLPP3 LYS-31 AND CYS-163. RX PubMed=1674745; DOI=10.1016/s0021-9258(18)99249-5; RA Lohse P., Mann W.A., Stein E.A., Brewer H.B. Jr.; RT "Apolipoprotein E-4 Philadelphia (Glu-13-->Lys,Arg-145-->Cys). Homozygosity RT for two rare point mutations in the apolipoprotein E gene combined with RT severe type III hyperlipoproteinemia."; RL J. Biol. Chem. 266:10479-10484(1991). RN [66] RP VARIANT APOE5 FRENCH-CANADIAN LYS-31. RX PubMed=1713245; RA Mailly F., Xu C.F., Xhignesse M., Lussier-Cacan S., Talmud P.J., RA Davignon J., Humphries S.E., Nestruck A.C.; RT "Characterization of a new apolipoprotein E5 variant detected in two RT French-Canadian subjects."; RL J. Lipid Res. 32:613-620(1991). RN [67] RP CHARACTERIZATION OF VARIANT LYS-21, FUNCTION, AND LDLR-BINDING. RX PubMed=1530612; DOI=10.1016/0006-291x(92)91321-g; RA Dong L.M., Yamamura T., Tajima S., Yamamoto A.; RT "Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3---- RT Lys) and its binding to low density lipoprotein receptors."; RL Biochem. Biophys. Res. Commun. 187:1180-1186(1992). RN [68] RP VARIANT HLPP3 228-TRP--HIS-317 DEL. RX PubMed=1361196; RA Lohse P., Brewer H.B. III, Meng M.S., Skarlatos S.I., LaRosa J.C., RA Brewer H.B. Jr.; RT "Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due RT to a premature stop codon in the apolipoprotein E gene."; RL J. Lipid Res. 33:1583-1590(1992). RN [69] RP VARIANTS GLU-254; GLY-269; GLU-270; HIS-292 AND ARG-314. RX PubMed=8488843; RA van den Maagdenberg A.M.J.M., Weng W., de Bruijn I.H., de Knijff P., RA Funke H., Smelt A.H.M., Leuven J.A.G., van 't Hooft F.M., Assmann G., RA Hofker M.H., Havekes L.M., Frants R.R.; RT "Characterization of five new mutants in the carboxyl-terminal domain of RT human apolipoprotein E: no cosegregation with severe hyperlipidemia."; RL Am. J. Hum. Genet. 52:937-946(1993). RN [70] RP VARIANTS LYS-99 AND ARG-130. RX PubMed=8125051; DOI=10.1002/elps.11501401164; RA Ruzicka V., Maerz W., Russ A., Fisher E., Mondorf W., Gross W.; RT "Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, RT Cys112->Arg) by polymerase chain reaction, restriction isotyping, and RT temperature gradient gel electrophoresis."; RL Electrophoresis 14:1032-1037(1993). RN [71] RP CHARACTERIZATION OF VARIANT GLU-VAL-GLN-ALA-MET-LEU-GLY-145 INS. RX PubMed=8468528; RA Fazio S., Horie Y., Weisgraber K.H., Havekes L.M., Rall S.C. Jr.; RT "Preferential association of apolipoprotein E Leiden with very low density RT lipoproteins of human plasma."; RL J. Lipid Res. 34:447-453(1993). RN [72] RP INVOLVEMENT IN AD2, AND VARIANT AD2 ARG-130. RX PubMed=8346443; DOI=10.1126/science.8346443; RA Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., RA Gaskell P.C., Small G.W., Roses A.D., Haines J.L., Pericak-Vance M.A.; RT "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's RT disease in late onset families."; RL Science 261:921-923(1993). RN [73] RP VARIANTS HLPP3 ARG-130; SER-154; CYS-160 AND CYS-176, AND VARIANT ASP-145. RX PubMed=8287539; RA Richard P., Thomas G., de Zulueta M.P., de Gennes J.-L., Thomas M., RA Cassaigne A., Bereziat G., Iron A.; RT "Common and rare genotypes of human apolipoprotein E determined by specific RT restriction profiles of polymerase chain reaction-amplified DNA."; RL Clin. Chem. 40:24-29(1994). RN [74] RP VARIANTS HLPP3 LYS-31; ARG-130 AND CYS-154, AND VARIANTS ARG-102 AND RP GLN-152. RX PubMed=7833947; DOI=10.1002/humu.1380040303; RA de Knijff P., van den Maagdenberg A.M.J.M., Frants R.R., Havekes L.M.; RT "Genetic heterogeneity of apolipoprotein E and its influence on plasma RT lipid and lipoprotein levels."; RL Hum. Mutat. 4:178-194(1994). RN [75] RP VARIANT HLPP3 GLU-164, CHARACTERIZATION OF VARIANT HLPP3 GLU-164 AND RP CYS-176, FUNCTION, LDLR-BINDING, AND HEPARIN-BINDING. RX PubMed=7635945; DOI=10.1172/jci118096; RA Mann W.A., Lohse P., Gregg R.E., Ronan R., Hoeg J.M., Zech L.A., RA Brewer H.B. Jr.; RT "Dominant expression of type III hyperlipoproteinemia. Pathophysiological RT insights derived from the structural and kinetic characteristics of ApoE-1 RT (Lys146-->Glu)."; RL J. Clin. Invest. 96:1100-1107(1995). RN [76] RP VARIANT GLN-242. RX PubMed=8664327; DOI=10.1016/0005-2760(96)00014-8; RA Moriyama K., Sasaki J., Takada Y., Arakawa F., Matsunaga A., Ito Y., RA Arakawa K.; RT "Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg- RT 224 --> Gln) in a hyperlipidemic patient with xanthomatosis."; RL Biochim. Biophys. Acta 1301:185-190(1996). RN [77] RP VARIANT LPG PRO-163. RX PubMed=9176854; DOI=10.1681/asn.v85820; RA Oikawa S., Matsunaga A., Saito T., Sato H., Seki T., Hoshi K., Hayasaka K., RA Kotake H., Midorikawa H., Sekikawa A., Hara S., Abe K., Toyota T., RA Jingami H., Nakamura H., Sasaki J.; RT "Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated RT with lipoprotein glomerulopathy."; RL J. Am. Soc. Nephrol. 8:820-823(1997). RN [78] RP VARIANTS ARG-130 AND GLY-269. RX PubMed=9360638; DOI=10.1016/s1383-5726(97)00009-5; RA Kang A.K., Jenkins D.J.A., Wolever T.M.S., Huff M.W., Maguire G.F., RA Connelly P.W., Hegele R.A.; RT "Apolipoprotein E R112; R251G: a carboxy-terminal variant found in patients RT with hyperlipidemia and coronary heart disease."; RL Mutat. Res. 382:57-65(1997). RN [79] RP VARIANT LPG CYS-43. RX PubMed=10432380; DOI=10.1046/j.1523-1755.1999.00572.x; RA Matsunaga A., Sasaki J., Komatsu T., Kanatsu K., Tsuji E., Moriyama K., RA Koga T., Arakawa K., Oikawa S., Saito T., Kita T., Doi T.; RT "A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein RT glomerulopathy."; RL Kidney Int. 56:421-427(1999). RN [80] RP CHARACTERIZATION OF VARIANT LPG PRO-163, AND CHARACTERIZATION OF VARIANT RP AD2 ARG-130. RX PubMed=10903326; DOI=10.1074/jbc.m005906200; RA Ishigaki Y., Oikawa S., Suzuki T., Usui S., Magoori K., Kim D.H., RA Suzuki H., Sasaki J., Sasano H., Okazaki M., Toyota T., Saito T., RA Yamamoto T.T.; RT "Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops RT lipoprotein glomerulopathy in ApoE-deficient mice."; RL J. Biol. Chem. 275:31269-31273(2000). RN [81] RP VARIANT SBHD LEU-167 DEL. RX PubMed=11095479; DOI=10.1210/jcem.85.11.6981; RA Nguyen T.T., Kruckeberg K.E., O'Brien J.F., Ji Z.-S., Karnes P.S., RA Crotty T.B., Hay I.D., Mahley R.W., O'Brien T.; RT "Familial splenomegaly: macrophage hypercatabolism of lipoproteins RT associated with apolipoprotein E mutation [apolipoprotein E (delta149 RT Leu)]."; RL J. Clin. Endocrinol. Metab. 85:4354-4358(2000). RN [82] RP VARIANT VAL-124. RX PubMed=12864777; DOI=10.1046/j.1365-2362.2003.01180.x; RA Miserez A.R., Scharnagl H., Muller P.Y., Mirsaidi R., Stahelin H.B., RA Monsch A., Marz W., Hoffmann M.M.; RT "Apolipoprotein E3Basel: new insights into a highly conserved protein RT region."; RL Eur. J. Clin. Invest. 33:677-685(2003). RN [83] RP VARIANTS ARG-130 AND CYS-176. RX PubMed=12966036; DOI=10.1093/hmg/ddg314; RA Morabia A., Cayanis E., Costanza M.C., Ross B.M., Flaherty M.S., RA Alvin G.B., Das K., Gilliam T.C.; RT "Association of extreme blood lipid profile phenotypic variation with 11 RT reverse cholesterol transport genes and 10 non-genetic cardiovascular RT disease risk factors."; RL Hum. Mol. Genet. 12:2733-2743(2003). RN [84] RP VARIANT SBHD LEU-167 DEL. RX PubMed=16094309; DOI=10.1038/sj.ejhg.5201480; RA Faivre L., Saugier-Veber P., Pais de Barros J.-P., Verges B., Couret B., RA Lorcerie B., Thauvin C., Charbonnier F., Huet F., Gambert P., Frebourg T., RA Duvillard L.; RT "Variable expressivity of the clinical and biochemical phenotype associated RT with the apolipoprotein E p.Leu149del mutation."; RL Eur. J. Hum. Genet. 13:1186-1191(2005). RN [85] RP VARIANT LPG CYS-43. RX PubMed=18077821; DOI=10.1056/nejmc072088; RA Rovin B.H., Roncone D., McKinley A., Nadasdy T., Korbet S.M., RA Schwartz M.M.; RT "APOE Kyoto mutation in European Americans with lipoprotein RT glomerulopathy."; RL N. Engl. J. Med. 357:2522-2524(2007). RN [86] RP VARIANT HIS-64, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22028381; DOI=10.1093/jmcb/mjr024; RA Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H., Lin X., RA Zeng R., Wu J.R.; RT "Quantitative detection of single amino acid polymorphisms by targeted RT proteomics."; RL J. Mol. Cell Biol. 3:309-315(2011). RN [87] RP VARIANT HLPP3 SER-154, AND VARIANT SBHD LEU-167 DEL. RX PubMed=22481068; DOI=10.1016/j.atherosclerosis.2012.03.011; RA Solanas-Barca M., de Castro-Oros I., Mateo-Gallego R., Cofan M., Plana N., RA Puzo J., Burillo E., Martin-Fuentes P., Ros E., Masana L., Pocovi M., RA Civeira F., Cenarro A.; RT "Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and RT a clinical diagnosis of familial combined hyperlipidemia."; RL Atherosclerosis 222:449-455(2012). RN [88] RP VARIANT SBHD LEU-167 DEL. RX PubMed=24267230; DOI=10.1016/j.atherosclerosis.2013.09.007; RA Awan Z., Choi H.Y., Stitziel N., Ruel I., Bamimore M.A., Husa R., RA Gagnon M.H., Wang R.H., Peloso G.M., Hegele R.A., Seidah N.G., RA Kathiresan S., Genest J.; RT "APOE p.Leu167del mutation in familial hypercholesterolemia."; RL Atherosclerosis 231:218-222(2013). RN [89] RP VARIANT SBHD LEU-167 DEL. RX PubMed=22949395; DOI=10.1002/humu.22215; RA Marduel M., Ouguerram K., Serre V., Bonnefont-Rousselot D., RA Marques-Pinheiro A., Erik Berge K., Devillers M., Luc G., Lecerf J.M., RA Tosolini L., Erlich D., Peloso G.M., Stitziel N., Nitchke P., Jais J.P., RA Abifadel M., Kathiresan S., Leren T.P., Rabes J.P., Boileau C., Varret M.; RT "Description of a large family with autosomal dominant hypercholesterolemia RT associated with the APOE p.Leu167del mutation."; RL Hum. Mutat. 34:83-87(2013). RN [90] RP VARIANTS PRO-46 AND ASP-145, VARIANT HLPP3 CYS-163, AND VARIANT SBHD RP LEU-167 DEL. RX PubMed=26802169; DOI=10.1194/jlr.p055699; RA Wintjens R., Bozon D., Belabbas K., Mbou F., Girardet J.P., Tounian P., RA Jolly M., Boccara F., Cohen A., Karsenty A., Dubern B., Carel J.C., RA Azar-Kolakez A., Feillet F., Labarthe F., Gorsky A.M., Horovitz A., RA Tamarindi C., Kieffer P., Lienhardt A., Lascols O., Di Filippo M., RA Dufernez F.; RT "Global molecular analysis and APOE mutations in a cohort of autosomal RT dominant hypercholesterolemia patients in France."; RL J. Lipid Res. 57:482-491(2016). RN [91] RP REVIEW, POLYMORPHISM, AND TISSUE SPECIFICITY. RX PubMed=25173806; DOI=10.1016/j.nbd.2014.08.025; RA Huang Y., Mahley R.W.; RT "Apolipoprotein E: structure and function in lipid metabolism, RT neurobiology, and Alzheimer's diseases."; RL Neurobiol. Dis. 72:3-12(2014). RN [92] RP REVIEW, FUNCTION, AND PTM. RX PubMed=29516132; DOI=10.1007/s00109-018-1632-y; RA Kockx M., Traini M., Kritharides L.; RT "Cell-specific production, secretion, and function of apolipoprotein E."; RL J. Mol. Med. 96:361-371(2018). RN [93] RP POLYMORPHISM, AND VARIANT ARG-130. RX PubMed=33450186; DOI=10.1016/j.stem.2020.12.018; RA Wang C., Zhang M., Garcia G. Jr., Tian E., Cui Q., Chen X., Sun G., RA Wang J., Arumugaswami V., Shi Y.; RT "ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response."; RL Cell Stem Cell 0:0-0(2021). CC -!- FUNCTION: APOE is an apolipoprotein, a protein associating with lipid CC particles, that mainly functions in lipoprotein-mediated lipid CC transport between organs via the plasma and interstitial fluids CC (PubMed:14754908, PubMed:1911868, PubMed:6860692). APOE is a core CC component of plasma lipoproteins and is involved in their production, CC conversion and clearance (PubMed:14754908, PubMed:1911868, CC PubMed:1917954, PubMed:23620513, PubMed:2762297, PubMed:6860692, CC PubMed:9395455). Apolipoproteins are amphipathic molecules that CC interact both with lipids of the lipoprotein particle core and the CC aqueous environment of the plasma (PubMed:2762297, PubMed:6860692, CC PubMed:9395455). As such, APOE associates with chylomicrons, CC chylomicron remnants, very low density lipoproteins (VLDL) and CC intermediate density lipoproteins (IDL) but shows a preferential CC binding to high-density lipoproteins (HDL) (PubMed:1911868, CC PubMed:6860692). It also binds a wide range of cellular receptors CC including the LDL receptor/LDLR, the LDL receptor-related proteins CC LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR CC that mediate the cellular uptake of the APOE-containing lipoprotein CC particles (PubMed:12950167, PubMed:1530612, PubMed:1917954, CC PubMed:20030366, PubMed:20303980, PubMed:2063194, PubMed:2762297, CC PubMed:7635945, PubMed:7768901, PubMed:8756331, PubMed:8939961). CC Finally, APOE also has a heparin-binding activity and binds heparan- CC sulfate proteoglycans on the surface of cells, a property that supports CC the capture and the receptor-mediated uptake of APOE-containing CC lipoproteins by cells (PubMed:23676495, PubMed:7635945, PubMed:9395455, CC PubMed:9488694). A main function of APOE is to mediate lipoprotein CC clearance through the uptake of chylomicrons, VLDLs, and HDLs by CC hepatocytes (PubMed:1911868, PubMed:1917954, PubMed:23676495, CC PubMed:29516132, PubMed:9395455). APOE is also involved in the CC biosynthesis by the liver of VLDLs as well as their uptake by CC peripheral tissues ensuring the delivery of triglycerides and energy CC storage in muscle, heart and adipose tissues (PubMed:2762297, CC PubMed:29516132). By participating in the lipoprotein-mediated CC distribution of lipids among tissues, APOE plays a critical role in CC plasma and tissues lipid homeostasis (PubMed:1917954, PubMed:2762297, CC PubMed:29516132). APOE is also involved in two steps of reverse CC cholesterol transport, the HDLs-mediated transport of cholesterol from CC peripheral tissues to the liver, and thereby plays an important role in CC cholesterol homeostasis (PubMed:14754908, PubMed:23620513, CC PubMed:9395455). First, it is functionally associated with ABCA1 in the CC biogenesis of HDLs in tissues (PubMed:14754908, PubMed:23620513). CC Second, it is enriched in circulating HDLs and mediates their uptake by CC hepatocytes (PubMed:9395455). APOE also plays an important role in CC lipid transport in the central nervous system, regulating neuron CC survival and sprouting (PubMed:25173806, PubMed:8939961). APOE is also CC involved in innate and adaptive immune responses, controlling for CC instance the survival of myeloid-derived suppressor cells (By CC similarity). Binds to the immune cell receptor LILRB4 CC (PubMed:30333625). APOE may also play a role in transcription CC regulation through a receptor-dependent and cholesterol-independent CC mechanism, that activates MAP3K12 and a non-canonical MAPK signal CC transduction pathway that results in enhanced AP-1-mediated CC transcription of APP (PubMed:28111074). {ECO:0000250|UniProtKB:P08226, CC ECO:0000269|PubMed:12950167, ECO:0000269|PubMed:14754908, CC ECO:0000269|PubMed:1530612, ECO:0000269|PubMed:1911868, CC ECO:0000269|PubMed:1917954, ECO:0000269|PubMed:20030366, CC ECO:0000269|PubMed:20303980, ECO:0000269|PubMed:2063194, CC ECO:0000269|PubMed:23620513, ECO:0000269|PubMed:23676495, CC ECO:0000269|PubMed:2762297, ECO:0000269|PubMed:28111074, CC ECO:0000269|PubMed:30333625, ECO:0000269|PubMed:6860692, CC ECO:0000269|PubMed:7635945, ECO:0000269|PubMed:7768901, CC ECO:0000269|PubMed:8756331, ECO:0000269|PubMed:8939961, CC ECO:0000269|PubMed:9395455, ECO:0000269|PubMed:9488694, CC ECO:0000303|PubMed:25173806, ECO:0000303|PubMed:29516132}. CC -!- FUNCTION: (Microbial infection) Through its interaction with HCV CC envelope glycoprotein E2, participates in the attachment of HCV to CC HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface CC and to the assembly, maturation and infectivity of HCV viral particles CC (PubMed:25122793, PubMed:29695434). This interaction is probably CC promoted via the up-regulation of cellular autophagy by the virus CC (PubMed:29695434). {ECO:0000269|PubMed:25122793, CC ECO:0000269|PubMed:29695434}. CC -!- SUBUNIT: Homotetramer (PubMed:8340399). May interact with ABCA1; CC functionally associated with ABCA1 in the biogenesis of HDLs CC (PubMed:14754908). May interact with APP/A4 amyloid-beta peptide; the CC interaction is extremely stable in vitro but its physiological CC significance is unclear (PubMed:23620513, PubMed:8367470). May interact CC with MAPT (PubMed:7972031). May interact with MAP2 (PubMed:7891887). In CC the cerebrospinal fluid, interacts with secreted SORL1 CC (PubMed:30448281). Interacts with PMEL; this allows the loading of PMEL CC luminal fragment on ILVs to induce fibril nucleation. CC {ECO:0000269|PubMed:14754908, ECO:0000269|PubMed:23620513, CC ECO:0000269|PubMed:26387950, ECO:0000269|PubMed:30448281, CC ECO:0000269|PubMed:7891887, ECO:0000269|PubMed:7972031, CC ECO:0000269|PubMed:8340399, ECO:0000269|PubMed:8367470}. CC -!- SUBUNIT: (Microbial infection) Interacts with hepatitis C virus (HCV) CC envelope glycoprotein E2; this interaction is required for HCV CC infectivity and production. {ECO:0000269|PubMed:25122793, CC ECO:0000269|PubMed:29695434}. CC -!- INTERACTION: CC P02649; Q9UIJ7: AK3; NbExp=3; IntAct=EBI-1222467, EBI-3916527; CC P02649; Q06481-5: APLP2; NbExp=3; IntAct=EBI-1222467, EBI-25646567; CC P02649; PRO_0000000093 [P05067]: APP; NbExp=4; IntAct=EBI-1222467, EBI-2431589; CC P02649; Q9HBG4: ATP6V0A4; NbExp=3; IntAct=EBI-1222467, EBI-25832286; CC P02649; Q9NUB4: C20orf141; NbExp=3; IntAct=EBI-1222467, EBI-9088162; CC P02649; P02748: C9; NbExp=2; IntAct=EBI-1222467, EBI-6677628; CC P02649; Q16543: CDC37; NbExp=3; IntAct=EBI-1222467, EBI-295634; CC P02649; P08603: CFH; NbExp=8; IntAct=EBI-1222467, EBI-1223708; CC P02649; Q9UBD9: CLCF1; NbExp=3; IntAct=EBI-1222467, EBI-2880701; CC P02649; Q8IUW6: CLSTN3; NbExp=3; IntAct=EBI-1222467, EBI-25832219; CC P02649; P26441: CNTF; NbExp=3; IntAct=EBI-1222467, EBI-1050897; CC P02649; Q9H6J7-2: CSTPP1; NbExp=3; IntAct=EBI-1222467, EBI-13328871; CC P02649; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-1222467, EBI-3508943; CC P02649; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-1222467, EBI-712452; CC P02649; Q9Y6C2-2: EMILIN1; NbExp=3; IntAct=EBI-1222467, EBI-11748557; CC P02649; Q3SYB3: FOXD4L6; NbExp=3; IntAct=EBI-1222467, EBI-6425864; CC P02649; Q8IY40: GRIK2; NbExp=3; IntAct=EBI-1222467, EBI-25832107; CC P02649; O75409: H2AP; NbExp=3; IntAct=EBI-1222467, EBI-6447217; CC P02649; P00738: HP; NbExp=7; IntAct=EBI-1222467, EBI-1220767; CC P02649; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-1222467, EBI-1108377; CC P02649; P01130: LDLR; NbExp=4; IntAct=EBI-1222467, EBI-988319; CC P02649; P09382: LGALS1; NbExp=3; IntAct=EBI-1222467, EBI-1048875; CC P02649; Q07954: LRP1; NbExp=23; IntAct=EBI-1222467, EBI-1046087; CC P02649; Q14114: LRP8; NbExp=2; IntAct=EBI-1222467, EBI-2681187; CC P02649; Q14114-3: LRP8; NbExp=3; IntAct=EBI-1222467, EBI-25832196; CC P02649; P11137-4: MAP2; NbExp=3; IntAct=EBI-1222467, EBI-25832133; CC P02649; P10636-6: MAPT; NbExp=3; IntAct=EBI-1222467, EBI-7796455; CC P02649; Q9Y3D2: MSRB2; NbExp=3; IntAct=EBI-1222467, EBI-9092052; CC P02649; P02795: MT2A; NbExp=3; IntAct=EBI-1222467, EBI-996616; CC P02649; Q53EL6: PDCD4; NbExp=3; IntAct=EBI-1222467, EBI-935824; CC P02649; Q9NS23-4: RASSF1; NbExp=3; IntAct=EBI-1222467, EBI-438710; CC P02649; P52756: RBM5; NbExp=3; IntAct=EBI-1222467, EBI-714003; CC P02649; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-1222467, EBI-21535400; CC P02649; Q8WTV0-2: SCARB1; NbExp=3; IntAct=EBI-1222467, EBI-21529758; CC P02649; P37840: SNCA; NbExp=11; IntAct=EBI-1222467, EBI-985879; CC P02649; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-1222467, EBI-2510414; CC P02649; P50502: ST13; NbExp=3; IntAct=EBI-1222467, EBI-357285; CC P02649; O75069: TMCC2; NbExp=5; IntAct=EBI-1222467, EBI-726731; CC P02649; Q13829: TNFAIP1; NbExp=3; IntAct=EBI-1222467, EBI-2505861; CC P02649; Q9NZC2: TREM2; NbExp=4; IntAct=EBI-1222467, EBI-14036387; CC P02649; Q6PID6: TTC33; NbExp=3; IntAct=EBI-1222467, EBI-2555404; CC P02649; Q8TBC4: UBA3; NbExp=3; IntAct=EBI-1222467, EBI-717567; CC P02649; Q9NYH9: UTP6; NbExp=3; IntAct=EBI-1222467, EBI-749211; CC P02649; P21796: VDAC1; NbExp=2; IntAct=EBI-1222467, EBI-354158; CC P02649; P17028: ZNF24; NbExp=3; IntAct=EBI-1222467, EBI-707773; CC P02649; PRO_0000037570 [P27958]; Xeno; NbExp=4; IntAct=EBI-1222467, EBI-6904269; CC PRO_0000001987; P10636: MAPT; NbExp=3; IntAct=EBI-9209835, EBI-366182; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:2498325, CC ECO:0000269|PubMed:30333625}. Secreted, extracellular space CC {ECO:0000269|PubMed:8340399}. Secreted, extracellular space, CC extracellular matrix {ECO:0000269|PubMed:9488694}. Extracellular CC vesicle {ECO:0000269|PubMed:26387950}. Endosome, multivesicular body CC {ECO:0000269|PubMed:26387950}. Note=In the plasma, APOE is associated CC with chylomicrons, chylomicrons remnants, VLDL, LDL and HDL CC lipoproteins (PubMed:1911868, PubMed:8340399). Lipid poor oligomeric CC APOE is associated with the extracellular matrix in a calcium- and CC heparan-sulfate proteoglycans-dependent manner (PubMed:9488694). CC Lipidation induces the release from the extracellular matrix CC (PubMed:9488694). Colocalizes with CD63 and PMEL at exosomes and in CC intraluminal vesicles within multivesicular endosomes. CC {ECO:0000269|PubMed:1911868, ECO:0000269|PubMed:26387950, CC ECO:0000269|PubMed:8340399, ECO:0000269|PubMed:9488694}. CC -!- TISSUE SPECIFICITY: Produced by several tissues and cell types and CC mainly found associated with lipid particles in the plasma, the CC interstitial fluid and lymph (PubMed:25173806). Mainly synthesized by CC liver hepatocytes (PubMed:25173806). Significant quantities are also CC produced in brain, mainly by astrocytes and glial cells in the cerebral CC cortex, but also by neurons in frontal cortex and hippocampus CC (PubMed:10027417, PubMed:3115992). It is also expressed by cells of the CC peripheral nervous system (PubMed:10027417, PubMed:25173806). Also CC expressed by adrenal gland, testis, ovary, skin, kidney, spleen and CC adipose tissue and macrophages in various tissues (PubMed:25173806). CC {ECO:0000269|PubMed:10027417, ECO:0000269|PubMed:3115992, CC ECO:0000303|PubMed:25173806}. CC -!- PTM: APOE exists as multiple glycosylated and sialylated glycoforms CC within cells and in plasma (PubMed:29516132). The extent of CC glycosylation and sialylation are tissue and context specific CC (PubMed:29516132). Plasma APOE undergoes desialylation and is less CC glycosylated and sialylated than the cellular form (PubMed:19838169, CC PubMed:20511397, PubMed:23234360, PubMed:2498325). Glycosylation is not CC required for proper expression and secretion (PubMed:2498325). O- CC glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Ser- CC 314 are minor glycosylation sites compared to Ser-308 (PubMed:19838169, CC PubMed:23234360). {ECO:0000269|PubMed:19838169, CC ECO:0000269|PubMed:20511397, ECO:0000269|PubMed:23234360, CC ECO:0000269|PubMed:2498325, ECO:0000303|PubMed:29516132}. CC -!- PTM: Glycated in plasma VLDL of normal subjects, and of hyperglycemic CC diabetic patients at a higher level (2-3 fold). CC {ECO:0000269|PubMed:10452964}. CC -!- PTM: Phosphorylated by FAM20C in the extracellular medium. CC {ECO:0000269|PubMed:26091039}. CC -!- PTM: Undergoes C-terminal proteolytic processing in neurons. C- CC terminally truncated APOE has a tendency to form neurotoxic CC intracellular neurofibrillary tangle-like inclusions in neurons. CC {ECO:0000269|PubMed:11447277}. CC -!- POLYMORPHISM: There are three common APOE alleles identified: CC APOE*2/APOE-epsilon2/E2, APOE*3/APOE-epsilon3/E3, and APOE*4/APOE- CC epsilon4/E4. The corresponding ApoE2, ApoE3 and ApoE4 isoforms CC differentially present Cys and Arg residues at positions 130 and 176. CC The most common allele in the human population is APOE*3 which sequence CC is the one displayed in that entry with a Cys at position 130 and an CC Arg at position 176. Common APOE variants influence lipoprotein CC metabolism in healthy individuals. Additional variants have been CC described and are described relative to the three common alleles. CC Allele APOE*4 is strongly associated with risk for severe COVID-19, CC increases susceptibility to SARS-CoV-2 infection in neurons and CC astrocytes (PubMed:33450186). {ECO:0000269|PubMed:2987927, CC ECO:0000269|PubMed:3243553, ECO:0000269|PubMed:33450186, CC ECO:0000269|PubMed:6325438, ECO:0000303|PubMed:25173806}. CC -!- DISEASE: Hyperlipoproteinemia 3 (HLPP3) [MIM:617347]: A disorder CC characterized by the accumulation of intermediate-density lipoprotein CC particles (IDL or broad-beta-lipoprotein) rich in cholesterol. Clinical CC features include xanthomas, yellowish lipid deposits in the palmar CC crease, or less specific on tendons and on elbows. The disorder rarely CC manifests before the third decade in men. In women, it is usually CC expressed only after the menopause. {ECO:0000269|PubMed:1361196, CC ECO:0000269|PubMed:1674745, ECO:0000269|PubMed:2101409, CC ECO:0000269|PubMed:22481068, ECO:0000269|PubMed:2313204, CC ECO:0000269|PubMed:2556398, ECO:0000269|PubMed:26802169, CC ECO:0000269|PubMed:2738044, ECO:0000269|PubMed:7635945, CC ECO:0000269|PubMed:7833947, ECO:0000269|PubMed:8287539}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. The vast majority of the patients are homozygous for APOE*2 CC alleles. More severe cases of HLPP3 have also been observed in CC individuals heterozygous for rare APOE variants. The influence of APOE CC on lipid levels is often suggested to have major implications for the CC risk of coronary artery disease (CAD). Individuals carrying the common CC APOE*4 variant are at higher risk of CAD. CC -!- DISEASE: Alzheimer disease 2 (AD2) [MIM:104310]: A late-onset form of CC Alzheimer disease. Alzheimer disease is a neurodegenerative disorder CC characterized by progressive dementia, loss of cognitive abilities, and CC deposition of fibrillar amyloid proteins as intraneuronal CC neurofibrillary tangles, extracellular amyloid plaques and vascular CC amyloid deposits. The major constituents of these plaques are CC neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that CC are produced by the proteolysis of the transmembrane APP protein. The CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, CC such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:10903326, ECO:0000269|PubMed:11258893, CC ECO:0000269|PubMed:11447277, ECO:0000269|PubMed:28111074, CC ECO:0000269|PubMed:2987927, ECO:0000269|PubMed:7891887, CC ECO:0000269|PubMed:7972031, ECO:0000269|PubMed:8071364, CC ECO:0000269|PubMed:8346443, ECO:0000269|PubMed:8367470, CC ECO:0000269|PubMed:8939961}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. The APOE*4 CC allele (APOE form E4) is genetically associated with the common late CC onset familial and sporadic forms of Alzheimer disease. Risk for AD CC increased from 20% to 90% and mean age at onset decreased from 84 to 68 CC years with increasing number of APOE*4 alleles in 42 families with late CC onset AD. Thus APOE*4 gene dose is a major risk factor for late onset CC AD and, in these families, homozygosity for APOE*4 was virtually CC sufficient to cause AD by age 80. The mechanism by which APOE*4 CC participates in pathogenesis is not known. CC {ECO:0000269|PubMed:8346443}. CC -!- DISEASE: Sea-blue histiocyte disease (SBHD) [MIM:269600]: Characterized CC by splenomegaly, mild thrombocytopenia and, in the bone marrow, CC numerous histiocytes containing cytoplasmic granules which stain bright CC blue with the usual hematologic stains. The syndrome is the consequence CC of an inherited metabolic defect analogous to Gaucher disease and other CC sphingolipidoses. {ECO:0000269|PubMed:11095479, CC ECO:0000269|PubMed:16094309, ECO:0000269|PubMed:22481068, CC ECO:0000269|PubMed:22949395, ECO:0000269|PubMed:24267230, CC ECO:0000269|PubMed:26802169}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Lipoprotein glomerulopathy (LPG) [MIM:611771]: Uncommon kidney CC disease characterized by proteinuria, progressive kidney failure, and CC distinctive lipoprotein thrombi in glomerular capillaries. CC {ECO:0000269|PubMed:10432380, ECO:0000269|PubMed:10903326, CC ECO:0000269|PubMed:18077821, ECO:0000269|PubMed:9176854}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: Binds to and activates LILRB4 on acute myeloid leukemia CC (AML) cells which leads to suppression of T cell proliferation and CC promotion of AML cell migration and infiltration. CC {ECO:0000269|PubMed:30333625}. CC -!- SIMILARITY: Belongs to the apolipoprotein A1/A4/E family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Apolipoprotein E entry; CC URL="https://en.wikipedia.org/wiki/Apolipoprotein_E"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Tangled - Issue 83 of June CC 2007; CC URL="https://www.proteinspotlight.org/back_issues/083"; 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; M12529; AAB59518.1; -; mRNA. DR EMBL; K00396; AAB59546.1; -; mRNA. DR EMBL; M10065; AAB59397.1; -; Genomic_DNA. DR EMBL; AF050154; AAD02505.1; -; Genomic_DNA. DR EMBL; AF261279; AAG27089.1; -; Genomic_DNA. DR EMBL; AK314898; BAG37412.1; -; mRNA. DR EMBL; FJ525876; ACN81314.1; -; Genomic_DNA. DR EMBL; BC003557; AAH03557.1; -; mRNA. DR EMBL; AB035149; BAA96080.1; -; Genomic_DNA. DR CCDS; CCDS12647.1; -. DR PIR; A92478; LPHUE. DR RefSeq; NP_000032.1; NM_000041.4. DR RefSeq; NP_001289617.1; NM_001302688.1. DR RefSeq; NP_001289618.1; NM_001302689.2. DR RefSeq; NP_001289619.1; NM_001302690.2. DR RefSeq; NP_001289620.1; NM_001302691.2. DR PDB; 1B68; X-ray; 2.00 A; A=19-209. DR PDB; 1BZ4; X-ray; 1.85 A; A=40-183. DR PDB; 1EA8; X-ray; 1.95 A; A=19-209. DR PDB; 1GS9; X-ray; 1.70 A; A=19-183. DR PDB; 1H7I; X-ray; 1.90 A; A=19-209. DR PDB; 1LE2; X-ray; 3.00 A; A=41-184. DR PDB; 1LE4; X-ray; 2.50 A; A=41-184. DR PDB; 1LPE; X-ray; 2.25 A; A=41-184. DR PDB; 1NFN; X-ray; 1.80 A; A=19-209. DR PDB; 1NFO; X-ray; 2.00 A; A=19-209. DR PDB; 1OEF; NMR; -; A=281-304. DR PDB; 1OEG; NMR; -; A=285-307. DR PDB; 1OR2; X-ray; 2.50 A; A=19-183. DR PDB; 1OR3; X-ray; 1.73 A; A=19-183. DR PDB; 2KC3; NMR; -; A=19-201. DR PDB; 2KNY; NMR; -; A=147-167. DR PDB; 2L7B; NMR; -; A=19-317. DR PDB; 6IWB; X-ray; 2.50 A; A/C=41-186. DR PDB; 6NCN; X-ray; 1.82 A; A=19-180. DR PDB; 6NCO; X-ray; 1.71 A; A=19-180. DR PDB; 6V7M; X-ray; 2.00 A; A=1-100, B=101-183. DR PDB; 7FCR; X-ray; 1.40 A; A=19-209. DR PDB; 7FCS; X-ray; 1.60 A; A=19-209. DR PDB; 7UVJ; X-ray; 1.99 A; A/B=40-183. DR PDB; 8AX8; X-ray; 1.55 A; A=19-317. DR PDB; 8AX9; X-ray; 1.55 A; A=19-317. DR PDB; 8CDY; X-ray; 1.90 A; A=19-317. DR PDB; 8CE0; X-ray; 1.75 A; A=19-317. DR PDB; 8GRX; EM; 3.00 A; A/C=41-180. DR PDBsum; 1B68; -. DR PDBsum; 1BZ4; -. DR PDBsum; 1EA8; -. DR PDBsum; 1GS9; -. DR PDBsum; 1H7I; -. DR PDBsum; 1LE2; -. DR PDBsum; 1LE4; -. DR PDBsum; 1LPE; -. DR PDBsum; 1NFN; -. DR PDBsum; 1NFO; -. DR PDBsum; 1OEF; -. DR PDBsum; 1OEG; -. DR PDBsum; 1OR2; -. DR PDBsum; 1OR3; -. DR PDBsum; 2KC3; -. DR PDBsum; 2KNY; -. DR PDBsum; 2L7B; -. DR PDBsum; 6IWB; -. DR PDBsum; 6NCN; -. DR PDBsum; 6NCO; -. DR PDBsum; 6V7M; -. DR PDBsum; 7FCR; -. DR PDBsum; 7FCS; -. DR PDBsum; 7UVJ; -. DR PDBsum; 8AX8; -. DR PDBsum; 8AX9; -. DR PDBsum; 8CDY; -. DR PDBsum; 8CE0; -. DR PDBsum; 8GRX; -. DR AlphaFoldDB; P02649; -. DR BMRB; P02649; -. DR EMDB; EMD-34216; -. DR EMDB; EMD-53251; -. DR EMDB; EMD-53269; -. DR EMDB; EMD-53271; -. DR EMDB; EMD-53272; -. DR EMDB; EMD-53273; -. DR EMDB; EMD-53280; -. DR EMDB; EMD-53289; -. DR EMDB; EMD-53292; -. DR EMDB; EMD-53293; -. DR SASBDB; P02649; -. DR SMR; P02649; -. DR BioGRID; 106845; 168. DR CORUM; P02649; -. DR DIP; DIP-1120N; -. DR FunCoup; P02649; 41. DR IntAct; P02649; 102. DR MINT; P02649; -. DR STRING; 9606.ENSP00000252486; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB11886; Infigratinib. DR DrugBank; DB00877; Sirolimus. DR DrugBank; DB00460; Verteporfin. DR DrugBank; DB01593; Zinc. DR DrugBank; DB14487; Zinc acetate. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR MoonDB; P02649; Predicted. DR TCDB; 9.B.445.2.1; the apolipoprotein a2 (alp-a2) family. DR CarbonylDB; P02649; -. DR GlyConnect; 648; 2 O-Linked glycans (5 sites). DR GlyCosmos; P02649; 8 sites, 5 glycans. DR GlyGen; P02649; 9 sites, 7 O-linked glycans (8 sites). DR iPTMnet; P02649; -. DR MetOSite; P02649; -. DR PhosphoSitePlus; P02649; -. DR SwissPalm; P02649; -. DR BioMuta; APOE; -. DR DMDM; 114039; -. DR CPTAC; non-CPTAC-1087; -. DR jPOST; P02649; -. DR MassIVE; P02649; -. DR PaxDb; 9606-ENSP00000252486; -. DR PeptideAtlas; P02649; -. DR ProteomicsDB; 51537; -. DR Pumba; P02649; -. DR ABCD; P02649; 7 sequenced antibodies. DR Antibodypedia; 3639; 1465 antibodies from 51 providers. DR DNASU; 348; -. DR YCharOS; P02649; Tested 14 antibodies from 8 manufacturers. DR Ensembl; ENST00000252486.9; ENSP00000252486.3; ENSG00000130203.11. DR GeneID; 348; -. DR KEGG; hsa:348; -. DR MANE-Select; ENST00000252486.9; ENSP00000252486.3; NM_000041.4; NP_000032.1. DR UCSC; uc002pab.4; human. DR AGR; HGNC:613; -. DR ClinPGx; PA55; -. DR CTD; 348; -. DR DisGeNET; 348; -. DR GeneCards; APOE; -. DR HGNC; HGNC:613; APOE. DR HPA; ENSG00000130203; Group enriched (adrenal gland, brain, liver). DR MalaCards; APOE; -. DR MIM; 104310; phenotype. DR MIM; 107741; gene. DR MIM; 269600; phenotype. DR MIM; 611771; phenotype. DR MIM; 617347; phenotype. DR OpenTargets; ENSG00000130203; -. DR Orphanet; 412; Dysbetalipoproteinemia. DR Orphanet; 329481; Lipoprotein glomerulopathy. DR VEuPathDB; HostDB:ENSG00000130203; -. DR eggNOG; ENOG502QVD6; Eukaryota. DR GeneTree; ENSGT00950000182929; -. DR HOGENOM; CLU_066029_0_0_1; -. DR InParanoid; P02649; -. DR OMA; GHMTDAR; -. DR OrthoDB; 9048614at2759; -. DR PAN-GO; P02649; 9 GO annotations based on evolutionary models. DR PhylomeDB; P02649; -. DR PathwayCommons; P02649; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-3000480; Scavenging by Class A Receptors. DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-8864260; Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors. DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR Reactome; R-HSA-8963888; Chylomicron assembly. DR Reactome; R-HSA-8963901; Chylomicron remodeling. DR Reactome; R-HSA-8964026; Chylomicron clearance. DR Reactome; R-HSA-8964058; HDL remodeling. DR Reactome; R-HSA-9029569; NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux. DR Reactome; R-HSA-975634; Retinoid metabolism and transport. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; P02649; -. DR SIGNOR; P02649; -. DR Agora; ENSG00000130203; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 348; 20 hits in 1163 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; APOE; human. DR EvolutionaryTrace; P02649; -. DR GeneWiki; Apolipoprotein_E; -. DR GenomeRNAi; 348; -. DR Pharos; P02649; Tbio. DR PRO; PR:P02649; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P02649; protein. DR Bgee; ENSG00000130203; Expressed in right adrenal gland cortex and 179 other cell types or tissues. DR ExpressionAtlas; P02649; baseline and differential. DR GO; GO:0072562; C:blood microparticle; HDA:UniProtKB. DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL. DR GO; GO:0034360; C:chylomicron remnant; IDA:ARUK-UCL. DR GO; GO:0030669; C:clathrin-coated endocytic vesicle membrane; TAS:Reactome. DR GO; GO:0005737; C:cytoplasm; TAS:UniProtKB. DR GO; GO:0030425; C:dendrite; NAS:BHF-UCL. DR GO; GO:0034365; C:discoidal high-density lipoprotein particle; TAS:ARUK-UCL. DR GO; GO:0005769; C:early endosome; TAS:Reactome. DR GO; GO:0071682; C:endocytic vesicle lumen; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:AgBase. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB. DR GO; GO:0031012; C:extracellular matrix; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:ARUK-UCL. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:1903561; C:extracellular vesicle; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO. DR GO; GO:0005794; C:Golgi apparatus; IDA:AgBase. DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:0034363; C:intermediate-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:1990777; C:lipoprotein particle; IDA:ARUK-UCL. DR GO; GO:0034362; C:low-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:0042470; C:melanosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0097487; C:multivesicular body, internal vesicle; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; NAS:BHF-UCL. DR GO; GO:0005634; C:nucleus; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0043083; C:synaptic cleft; IDA:SynGO. DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:0001540; F:amyloid-beta binding; IDA:UniProtKB. DR GO; GO:0016209; F:antioxidant activity; IDA:BHF-UCL. DR GO; GO:0120020; F:cholesterol transfer activity; IBA:GO_Central. DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL. DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; IDA:UniProtKB. DR GO; GO:0008201; F:heparin binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0008289; F:lipid binding; IDA:UniProtKB. DR GO; GO:0005319; F:lipid transporter activity; IDA:BHF-UCL. DR GO; GO:0071813; F:lipoprotein particle binding; IEA:Ensembl. DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IDA:UniProtKB. DR GO; GO:0046911; F:metal chelating activity; IDA:BHF-UCL. DR GO; GO:0060228; F:phosphatidylcholine-sterol O-acyltransferase activator activity; IDA:BHF-UCL. DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL. DR GO; GO:0046983; F:protein dimerization activity; IPI:ARUK-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:ARUK-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IDA:ARUK-UCL. DR GO; GO:0048018; F:receptor ligand activity; IDA:UniProt. DR GO; GO:0005102; F:signaling receptor binding; IPI:ARUK-UCL. DR GO; GO:0005198; F:structural molecule activity; TAS:ARUK-UCL. DR GO; GO:0048156; F:tau protein binding; IPI:BHF-UCL. DR GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; IDA:BHF-UCL. DR GO; GO:0055090; P:acylglycerol homeostasis; IBA:GO_Central. DR GO; GO:0097113; P:AMPA glutamate receptor clustering; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0048844; P:artery morphogenesis; IEA:Ensembl. DR GO; GO:0071402; P:cellular response to lipoprotein particle stimulus; IDA:UniProt. DR GO; GO:0006707; P:cholesterol catabolic process; IEA:Ensembl. DR GO; GO:0033344; P:cholesterol efflux; IDA:UniProtKB. DR GO; GO:0042632; P:cholesterol homeostasis; IDA:BHF-UCL. DR GO; GO:0008203; P:cholesterol metabolic process; IDA:BHF-UCL. DR GO; GO:0034382; P:chylomicron remnant clearance; IDA:UniProtKB. DR GO; GO:0007010; P:cytoskeleton organization; TAS:UniProtKB. DR GO; GO:0055089; P:fatty acid homeostasis; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0010467; P:gene expression; IEA:Ensembl. DR GO; GO:0034380; P:high-density lipoprotein particle assembly; IDA:UniProtKB. DR GO; GO:0034384; P:high-density lipoprotein particle clearance; IDA:BHF-UCL. DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IGI:BHF-UCL. DR GO; GO:0044794; P:host-mediated activation of viral process; IMP:AgBase. DR GO; GO:0071831; P:intermediate-density lipoprotein particle clearance; IDA:UniProtKB. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0046907; P:intracellular transport; TAS:UniProtKB. DR GO; GO:0010877; P:lipid transport involved in lipid storage; ISS:BHF-UCL. DR GO; GO:0042158; P:lipoprotein biosynthetic process; IDA:UniProtKB. DR GO; GO:0042159; P:lipoprotein catabolic process; IEA:Ensembl. DR GO; GO:0035641; P:locomotory exploration behavior; IMP:ARUK-UCL. DR GO; GO:0015909; P:long-chain fatty acid transport; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0007616; P:long-term memory; IGI:ARUK-UCL. DR GO; GO:0034374; P:low-density lipoprotein particle remodeling; IEA:Ensembl. DR GO; GO:0051651; P:maintenance of location in cell; IEA:Ensembl. DR GO; GO:0032438; P:melanosome organization; IMP:UniProtKB. DR GO; GO:1905907; P:negative regulation of amyloid fibril formation; ISS:UniProtKB. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030195; P:negative regulation of blood coagulation; IDA:BHF-UCL. DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ARUK-UCL. DR GO; GO:0045541; P:negative regulation of cholesterol biosynthetic process; IDA:BHF-UCL. DR GO; GO:0010596; P:negative regulation of endothelial cell migration; IMP:ARUK-UCL. DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IDA:BHF-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:ARUK-UCL. DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:BHF-UCL. DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IDA:ARUK-UCL. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0010977; P:negative regulation of neuron projection development; IDA:ARUK-UCL. DR GO; GO:0010544; P:negative regulation of platelet activation; IDA:BHF-UCL. DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0051248; P:negative regulation of protein metabolic process; IGI:ARUK-UCL. DR GO; GO:0050709; P:negative regulation of protein secretion; IMP:UniProtKB. DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; ISS:BHF-UCL. DR GO; GO:0090209; P:negative regulation of triglyceride metabolic process; IEA:Ensembl. DR GO; GO:0031175; P:neuron projection development; IDA:UniProtKB. DR GO; GO:0038060; P:nitric oxide-cGMP-mediated signaling; IDA:BHF-UCL. DR GO; GO:0097114; P:NMDA glutamate receptor clustering; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; TAS:ARUK-UCL. DR GO; GO:1900223; P:positive regulation of amyloid-beta clearance; ISS:UniProtKB. DR GO; GO:0010875; P:positive regulation of cholesterol efflux; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0090205; P:positive regulation of cholesterol metabolic process; IDA:BHF-UCL. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IDA:Alzheimers_University_of_Toronto. DR GO; GO:1902952; P:positive regulation of dendritic spine maintenance; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:ARUK-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB. DR GO; GO:0046889; P:positive regulation of lipid biosynthetic process; IDA:Alzheimers_University_of_Toronto. DR GO; GO:1903002; P:positive regulation of lipid transport across blood-brain barrier; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0140077; P:positive regulation of lipoprotein transport; IDA:ARUK-UCL. DR GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; IDA:BHF-UCL. DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL. DR GO; GO:0010976; P:positive regulation of neuron projection development; IDA:ARUK-UCL. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL. DR GO; GO:1902995; P:positive regulation of phospholipid efflux; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0017038; P:protein import; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0006898; P:receptor-mediated endocytosis; IDA:BHF-UCL. DR GO; GO:1905906; P:regulation of amyloid fibril formation; IDA:ARUK-UCL. DR GO; GO:1902991; P:regulation of amyloid precursor protein catabolic process; IDA:UniProtKB. DR GO; GO:1900221; P:regulation of amyloid-beta clearance; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0030516; P:regulation of axon extension; TAS:UniProtKB. DR GO; GO:2000822; P:regulation of behavioral fear response; IMP:ARUK-UCL. DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IDA:BHF-UCL. DR GO; GO:1905890; P:regulation of cellular response to very-low-density lipoprotein particle stimulus; IDA:ARUK-UCL. DR GO; GO:0090181; P:regulation of cholesterol metabolic process; IGI:ARUK-UCL. DR GO; GO:0045088; P:regulation of innate immune response; IEA:Ensembl. DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; TAS:UniProtKB. DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IMP:UniProtKB. DR GO; GO:0051246; P:regulation of protein metabolic process; IGI:ARUK-UCL. DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:ARUK-UCL. DR GO; GO:0061771; P:response to caloric restriction; IGI:ARUK-UCL. DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl. DR GO; GO:0000302; P:response to reactive oxygen species; NAS:UniProtKB. DR GO; GO:0043691; P:reverse cholesterol transport; IDA:BHF-UCL. DR GO; GO:0007271; P:synaptic transmission, cholinergic; TAS:UniProtKB. DR GO; GO:0070328; P:triglyceride homeostasis; ISS:BHF-UCL. DR GO; GO:0006641; P:triglyceride metabolic process; IDA:BHF-UCL. DR GO; GO:0071830; P:triglyceride-rich lipoprotein particle clearance; IMP:UniProtKB. DR GO; GO:0042311; P:vasodilation; IEA:Ensembl. DR GO; GO:0034447; P:very-low-density lipoprotein particle clearance; IDA:UniProtKB. DR GO; GO:0034372; P:very-low-density lipoprotein particle remodeling; IDA:BHF-UCL. DR GO; GO:0019068; P:virion assembly; IMP:AgBase. DR DisProt; DP04133; -. DR FunFam; 1.20.120.20:FF:000002; Apolipoprotein E; 1. DR FunFam; 1.20.120.20:FF:000003; Apolipoprotein E; 1. DR Gene3D; 1.20.120.20; Apolipoprotein; 2. DR InterPro; IPR000074; ApoA_E. DR InterPro; IPR050163; Apolipoprotein_A1/A4/E. DR PANTHER; PTHR18976; APOLIPOPROTEIN; 1. DR PANTHER; PTHR18976:SF2; APOLIPOPROTEIN E; 1. DR Pfam; PF01442; Apolipoprotein; 1. DR SUPFAM; SSF58113; Apolipoprotein A-I; 1. PE 1: Evidence at protein level; KW 3D-structure; Alzheimer disease; Amyloidosis; Cholesterol metabolism; KW Chylomicron; Direct protein sequencing; Disease variant; Endosome; KW Extracellular matrix; Glycation; Glycoprotein; HDL; Heparin-binding; KW Host-virus interaction; Hyperlipidemia; Lipid metabolism; Lipid transport; KW Lipid-binding; Neurodegeneration; Oxidation; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Secreted; Signal; KW Steroid metabolism; Sterol metabolism; Transport; VLDL. FT SIGNAL 1..18 FT /evidence="ECO:0000269|PubMed:7068630" FT CHAIN 19..317 FT /note="Apolipoprotein E" FT /id="PRO_0000001987" FT REPEAT 80..101 FT /note="1" FT REPEAT 102..123 FT /note="2" FT REPEAT 124..145 FT /note="3" FT REPEAT 146..167 FT /note="4" FT REPEAT 168..189 FT /note="5" FT REPEAT 190..211 FT /note="6" FT REPEAT 212..233 FT /note="7" FT REPEAT 234..255 FT /note="8" FT REGION 80..255 FT /note="8 X 22 AA approximate tandem repeats" FT REGION 158..168 FT /note="LDL and other lipoprotein receptors binding" FT /evidence="ECO:0000269|PubMed:20030366, FT ECO:0000269|PubMed:2063194" FT REGION 210..290 FT /note="Lipid-binding and lipoprotein association" FT /evidence="ECO:0000269|PubMed:2280190, FT ECO:0000269|PubMed:8071364" FT REGION 266..317 FT /note="Homooligomerization" FT /evidence="ECO:0000269|PubMed:8340399" FT REGION 278..290 FT /note="Specificity for association with VLDL" FT /evidence="ECO:0000269|PubMed:8071364" FT BINDING 162..165 FT /ligand="heparin" FT /ligand_id="ChEBI:CHEBI:28304" FT /evidence="ECO:0000269|PubMed:3947350" FT BINDING 229..236 FT /ligand="heparin" FT /ligand_id="ChEBI:CHEBI:28304" FT /evidence="ECO:0000269|PubMed:3947350" FT MOD_RES 143 FT /note="Methionine sulfoxide" FT /evidence="ECO:0000250|UniProtKB:P08226" FT MOD_RES 147 FT /note="Phosphoserine; by FAM20C" FT /evidence="ECO:0000269|PubMed:26091039, FT ECO:0007744|PubMed:24275569" FT CARBOHYD 26 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:23234360" FT CARBOHYD 36 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:23234360" FT CARBOHYD 93 FT /note="N-linked (Glc) (glycation) lysine" FT /evidence="ECO:0000269|PubMed:10452964" FT CARBOHYD 212 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:2498325" FT CARBOHYD 307 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169" FT CARBOHYD 308 FT /note="O-linked (GalNAc...) serine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:20511397" FT CARBOHYD 314 FT /note="O-linked (GalNAc...) serine" FT /evidence="ECO:0000269|PubMed:23234360" FT VARIANT 21 FT /note="E -> K (in ApoE5; associated with FT hyperlipoproteinemia and atherosclerosis; increased binding FT to LDL receptor; dbSNP:rs121918392)" FT /evidence="ECO:0000269|PubMed:1530612, FT ECO:0000269|PubMed:2760009" FT /id="VAR_000645" FT VARIANT 31 FT /note="E -> K (in HLPP3; ApoE4 Philadelphia, ApoE5 French- FT Canadian and ApoE5-type; only ApoE4 Philadelphia is FT associated with HLPP3; dbSNP:rs201672011)" FT /evidence="ECO:0000269|PubMed:1674745, FT ECO:0000269|PubMed:1713245, ECO:0000303|PubMed:7833947" FT /id="VAR_000646" FT VARIANT 43 FT /note="R -> C (in LPG; ApoE2 Kyoto; dbSNP:rs121918399)" FT /evidence="ECO:0000269|PubMed:10432380, FT ECO:0000269|PubMed:18077821" FT /id="VAR_042734" FT VARIANT 46 FT /note="L -> P (found in a patient with FT hypercholesterolemia; uncertain significance; ApoE4 FT Freiburg; dbSNP:rs769452)" FT /evidence="ECO:0000269|PubMed:11042151, FT ECO:0000269|PubMed:26802169" FT /id="VAR_000647" FT VARIANT 60 FT /note="T -> A (in ApoE3 Freiburg; dbSNP:rs28931576)" FT /id="VAR_000648" FT VARIANT 64 FT /note="Q -> H (confirmed at protein level; FT dbSNP:rs370594287)" FT /evidence="ECO:0000269|PubMed:22028381, ECO:0000269|Ref.10" FT /id="VAR_014114" FT VARIANT 99 FT /note="Q -> K (in ApoE5 Frankfurt; dbSNP:rs1180612218)" FT /evidence="ECO:0000269|PubMed:8125051" FT /id="VAR_000649" FT VARIANT 102 FT /note="P -> R (apoE5-type; no hyperlipidemia; FT dbSNP:rs11083750)" FT /evidence="ECO:0000269|PubMed:7833947" FT /id="VAR_000650" FT VARIANT 117 FT /note="A -> T (in ApoE3*; dbSNP:rs28931577)" FT /evidence="ECO:0000269|PubMed:6327682" FT /id="VAR_000651" FT VARIANT 124 FT /note="A -> V (in ApoE3 Basel; dbSNP:rs937063425)" FT /evidence="ECO:0000269|PubMed:12864777" FT /id="VAR_016789" FT VARIANT 130 FT /note="C -> R (in HLPP3 and AD2; ApoE4, ApoE3 Leiden, FT ApoE3**, ApoE5-Frankfurt and ApoE5-type; ApoE3 Leiden and FT ApoE3** are associated with HLPP3; ApoE4 is associated with FT AD2; changed protein structure; no effect on binding to LDL FT receptor; decreased association with HDL and enrichment in FT VLDL and IDL; may prevent the interaction with MAP2 and FT MAPT; changed interaction with APP/A4 amyloid-beta peptide; FT increased ability to induce APP transcription; increased C- FT terminal proteolytic processing in neurons; decreased FT function in neurite outgrowth; ApoE4 is associated with FT higher susceptibility to SARS-CoV-2 infection in neurons FT and astrocytes; dbSNP:rs429358)" FT /evidence="ECO:0000269|PubMed:10903326, FT ECO:0000269|PubMed:11042151, ECO:0000269|PubMed:11447277, FT ECO:0000269|PubMed:12966036, ECO:0000269|PubMed:2280190, FT ECO:0000269|PubMed:2556398, ECO:0000269|PubMed:28111074, FT ECO:0000269|PubMed:2987927, ECO:0000269|PubMed:7891887, FT ECO:0000269|PubMed:7972031, ECO:0000269|PubMed:8071364, FT ECO:0000269|PubMed:8125051, ECO:0000269|PubMed:8287539, FT ECO:0000269|PubMed:8346443, ECO:0000269|PubMed:8367470, FT ECO:0000269|PubMed:8939961, ECO:0000269|PubMed:9360638, FT ECO:0000303|PubMed:7833947" FT /id="VAR_000652" FT VARIANT 145 FT /note="G -> D (found in a patient with FT hypercholesterolemia; uncertain significance; ApoE1 FT Weisgraber; dbSNP:rs267606664)" FT /evidence="ECO:0000269|PubMed:26802169, FT ECO:0000269|PubMed:8287539" FT /id="VAR_000653" FT VARIANT 145 FT /note="G -> GEVQAMLG (in HLPP3; ApoE3 Leiden; no effect on FT glycosylation)" FT /evidence="ECO:0000269|PubMed:2556398, FT ECO:0000269|PubMed:8468528" FT /id="VAR_000654" FT VARIANT 152 FT /note="R -> Q (apoE2-type; no hyperlipidemia; FT dbSNP:rs28931578)" FT /evidence="ECO:0000269|PubMed:7833947" FT /id="VAR_000655" FT VARIANT 154 FT /note="R -> C (in HLPP3; ApoE2-type; dbSNP:rs121918393)" FT /evidence="ECO:0000303|PubMed:7833947" FT /id="VAR_000657" FT VARIANT 154 FT /note="R -> S (in HLPP3; ApoE2 Christchurch; decreased FT binding to LDL receptor; dbSNP:rs121918393)" FT /evidence="ECO:0000269|PubMed:22481068, FT ECO:0000269|PubMed:2831187, ECO:0000269|PubMed:8287539" FT /id="VAR_000656" FT VARIANT 160 FT /note="R -> C (in HLPP3; ApoE3**; dbSNP:rs387906567)" FT /evidence="ECO:0000269|PubMed:8287539" FT /id="VAR_000658" FT VARIANT 163 FT /note="R -> C (in HLPP3; also found in a patient with FT hypercholesterolemia; ApoE4 Philadelphia and ApoE2-type; FT dbSNP:rs769455)" FT /evidence="ECO:0000269|PubMed:11042151, FT ECO:0000269|PubMed:1674745, ECO:0000269|PubMed:26802169" FT /id="VAR_000659" FT VARIANT 163 FT /note="R -> H (in HLPP3; uncertain significance; ApoE FT Kochi; dbSNP:rs121918397)" FT /evidence="ECO:0000269|PubMed:2101409" FT /id="VAR_000660" FT VARIANT 163 FT /note="R -> P (in LPG; ApoE2 Sendai; decreased binding to FT LDL receptor; induces intraglomerular deposition of ApoE- FT containing lipoproteins; dbSNP:rs121918397)" FT /evidence="ECO:0000269|PubMed:10903326, FT ECO:0000269|PubMed:9176854" FT /id="VAR_042735" FT VARIANT 164 FT /note="K -> E (in HLPP3; ApoE1 Harrisburg; decreased FT binding to LDL receptor; probable dominant negative effect; FT decreased in vitro binding to heparin; dbSNP:rs121918394)" FT /evidence="ECO:0000269|PubMed:7635945" FT /id="VAR_000662" FT VARIANT 164 FT /note="K -> Q (in HLPP3; ApoE2**; dbSNP:rs121918394)" FT /evidence="ECO:0000269|PubMed:2313204" FT /id="VAR_000661" FT VARIANT 167 FT /note="Missing (in SBHD; also found in patients with a FT diagnosis of familial combined hyperlipidemia)" FT /evidence="ECO:0000269|PubMed:11095479, FT ECO:0000269|PubMed:16094309, ECO:0000269|PubMed:22481068, FT ECO:0000269|PubMed:22949395, ECO:0000269|PubMed:24267230, FT ECO:0000269|PubMed:26802169" FT /id="VAR_035015" FT VARIANT 170 FT /note="A -> P (in ApoE3*; decreased binding to LDL FT receptor; dbSNP:rs267606662)" FT /evidence="ECO:0000269|PubMed:2831187, FT ECO:0000269|PubMed:6327682" FT /id="VAR_000663" FT VARIANT 176 FT /note="R -> C (in HLPP3; ApoE2, ApoE2 Fukuoka, ApoE1 FT Weisgraber and ApoE3**; ApoE3** is associated with HLPP3; FT changed protein structure; decreased binding to LDLR and FT other lipoprotein receptors; decreased in vitro binding to FT heparin; no effect on distribution among plasma FT lipoproteins; dbSNP:rs7412)" FT /evidence="ECO:0000269|PubMed:11042151, FT ECO:0000269|PubMed:12950167, ECO:0000269|PubMed:12966036, FT ECO:0000269|PubMed:2280190, ECO:0000269|PubMed:3243553, FT ECO:0000269|PubMed:7635945, ECO:0000269|PubMed:7994571, FT ECO:0000269|PubMed:8287539, ECO:0000269|PubMed:8756331" FT /id="VAR_000664" FT VARIANT 228..317 FT /note="Missing (in HLPP3; ApoE3 Washington)" FT /evidence="ECO:0000269|PubMed:1361196" FT /id="VAR_081136" FT VARIANT 242 FT /note="R -> Q (in ApoE2 Fukuoka; dbSNP:rs267606663)" FT /evidence="ECO:0000269|PubMed:8664327" FT /id="VAR_000665" FT VARIANT 246 FT /note="R -> C (in ApoE2 Dunedin; dbSNP:rs121918395)" FT /evidence="ECO:0000269|PubMed:2341812" FT /id="VAR_000666" FT VARIANT 254 FT /note="V -> E (in ApoE2 WG; dbSNP:rs199768005)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000667" FT VARIANT 262..263 FT /note="EE -> KK (in HLPP3; ApoE7 Suita)" FT /evidence="ECO:0000269|PubMed:2738044" FT /id="VAR_000668" FT VARIANT 269 FT /note="R -> G (in ApoE3 HB; dbSNP:rs267606661)" FT /evidence="ECO:0000269|PubMed:8488843, FT ECO:0000269|PubMed:9360638" FT /id="VAR_000669" FT VARIANT 270 FT /note="L -> E (in ApoE1 HE; requires 2 nucleotide FT substitutions)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000670" FT VARIANT 292 FT /note="R -> H (in ApoE4 PD; dbSNP:rs121918398)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000671" FT VARIANT 314 FT /note="S -> R (in ApoE4 HG; dbSNP:rs28931579)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000672" FT MUTAGEN 79 FT /note="R->T: Changes the plasma lipoprotein distribution of FT ApoE4 to the HDL." FT /evidence="ECO:0000269|PubMed:8071364" FT MUTAGEN 127 FT /note="E->A: No effect on plasma lipoprotein distribution." FT /evidence="ECO:0000269|PubMed:8071364" FT MUTAGEN 157 FT /note="S->R: Increased binding to LDL receptor; when FT associated with A-167." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 158 FT /note="H->A: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 161 FT /note="K->A: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 162 FT /note="L->P: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 167 FT /note="L->A: Increased binding to LDL receptor; when FT associated with R-157." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 168 FT /note="R->A: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 172 FT /note="D->A: Restores the LDL receptor binding activity of FT ApoE2." FT /evidence="ECO:0000269|PubMed:8756331" FT MUTAGEN 212 FT /note="T->A: Loss of O-glycosylation." FT /evidence="ECO:0000269|PubMed:2498325" FT STRAND 22..24 FT /evidence="ECO:0007829|PDB:2KC3" FT HELIX 31..39 FT /evidence="ECO:0007829|PDB:2KC3" FT TURN 40..42 FT /evidence="ECO:0007829|PDB:2KC3" FT HELIX 43..60 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 63..70 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 73..96 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 97..99 FT /evidence="ECO:0007829|PDB:7FCR" FT STRAND 103..105 FT /evidence="ECO:0007829|PDB:7UVJ" FT HELIX 107..142 FT /evidence="ECO:0007829|PDB:7FCR" FT TURN 143..145 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 149..180 FT /evidence="ECO:0007829|PDB:7FCR" FT TURN 187..190 FT /evidence="ECO:0007829|PDB:2KC3" FT HELIX 193..198 FT /evidence="ECO:0007829|PDB:2KC3" FT STRAND 200..202 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 209..217 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 228..241 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 257..283 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 286..303 FT /evidence="ECO:0007829|PDB:1OEF" FT STRAND 307..309 FT /evidence="ECO:0007829|PDB:2L7B" SQ SEQUENCE 317 AA; 36154 MW; 91AFC04210A30689 CRC64; MKVLWAALLV TFLAGCQAKV EQAVETEPEP ELRQQTEWQS GQRWELALGR FWDYLRWVQT LSEQVQEELL SSQVTQELRA LMDETMKELK AYKSELEEQL TPVAEETRAR LSKELQAAQA RLGADMEDVC GRLVQYRGEV QAMLGQSTEE LRVRLASHLR KLRKRLLRDA DDLQKRLAVY QAGAREGAER GLSAIRERLG PLVEQGRVRA ATVGSLAGQP LQERAQAWGE RLRARMEEMG SRTRDRLDEV KEQVAEVRAK LEEQAQQIRL QAEAFQARLK SWFEPLVEDM QRQWAGLVEK VQAAVGTSAA PVPSDNH // ID HMGB1_HUMAN Reviewed; 215 AA. AC P09429; A5D8W9; Q14321; Q5T7C3; Q6IBE1; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 3. DT 28-JAN-2026, entry version 248. DE RecName: Full=High mobility group protein B1; DE AltName: Full=High mobility group protein 1; DE Short=HMG-1; GN Name=HMGB1 {ECO:0000312|HGNC:HGNC:4983}; Synonyms=HMG1; 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=2922262; DOI=10.1093/nar/17.3.1197; RA Wen L., Huang J.K., Johnson B.H., Reeck G.R.; RT "A human placental cDNA clone that encodes nonhistone chromosomal protein RT HMG-1."; RL Nucleic Acids Res. 17:1197-1214(1989). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8661151; DOI=10.1006/geno.1996.0369; RA Ferrari S., Finelli P., Rocchi M., Bianchi M.E.; RT "The active gene that encodes human high mobility group 1 protein (HMG1) RT contains introns and maps to chromosome 13."; RL Genomics 35:367-371(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ARG-11; GLU-149 AND GLY-190. RX PubMed=9036861; RX DOI=10.1002/(sici)1097-0215(19970220)74:1<1::aid-ijc1>3.0.co;2-6; RA Xiang Y.-Y., Wang D.-Y., Tanaka M., Suzuki M., Kiyokawa E., Igarashi H., RA Niato Y., Shen Q., Sugimura H.; RT "Expression of high-mobility group-1 mRNA in human gastrointestinal RT adenocarcinoma and corresponding non-cancerous mucosa."; RL Int. J. Cancer 74:1-6(1997). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=17610420; DOI=10.1111/j.1399-0039.2007.00854.x; RA Kornblit B., Munthe-Fog L., Petersen S., Madsen H., Vindeloev L., RA Garred P.; RT "The genetic variation of the human HMGB1 gene."; RL Tissue Antigens 70:151-156(2007). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RA He F.T., Yang Z.H., Ji Q., Li R., Peng J., Jiang Y., Zhong X.; RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases. RN [6] 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Small intestine; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLN-156. RG SeattleSNPs variation discovery resource; RL Submitted (JUL-2007) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057823; DOI=10.1038/nature02379; RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L., RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., RA Frankish A.G., Frankland J., French L., Garner P., Garnett J., RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., RA Rogers J., Ross M.T.; RT "The DNA sequence and analysis of human chromosome 13."; RL Nature 428:522-528(2004). RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, Cervix, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [14] RP PROTEIN SEQUENCE OF 58-65 AND 113-127. RC TISSUE=Mammary carcinoma; RX PubMed=9150946; DOI=10.1002/elps.1150180342; RA Rasmussen R.K., Ji H., Eddes J.S., Moritz R.L., Reid G.E., Simpson R.J., RA Dorow D.S.; RT "Two-dimensional electrophoretic analysis of human breast carcinoma RT proteins: mapping of proteins that bind to the SH3 domain of mixed lineage RT kinase MLK2."; RL Electrophoresis 18:588-598(1997). RN [15] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=11154118; RA Rouhiainen A., Imai S., Rauvala H., Parkkinen J.; RT "Occurrence of amphoterin (HMG1) as an endogenous protein of human RT platelets that is exported to the cell surface upon platelet activation."; RL Thromb. Haemost. 84:1087-1094(2000). RN [16] RP SUBCELLULAR LOCATION. RX PubMed=12231511; DOI=10.1093/embo-reports/kvf198; RA Gardella S., Andrei C., Ferrera D., Lotti L.V., Torrisi M.R., Bianchi M.E., RA Rubartelli A.; RT "The nuclear protein HMGB1 is secreted by monocytes via a non-classical, RT vesicle-mediated secretory pathway."; RL EMBO Rep. 3:995-1001(2002). RN [17] RP SUBCELLULAR LOCATION. RX PubMed=14532127; DOI=10.1093/emboj/cdg516; RA Bonaldi T., Talamo F., Scaffidi P., Ferrera D., Porto A., Bachi A., RA Rubartelli A., Agresti A., Bianchi M.E.; RT "Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it RT towards secretion."; RL EMBO J. 22:5551-5560(2003). RN [18] RP FUNCTION, AND DOMAIN. RX PubMed=12765338; DOI=10.1007/bf03402105; RA Li J., Kokkola R., Tabibzadeh S., Yang R., Ochani M., Qiang X., RA Harris H.E., Czura C.J., Wang H., Ulloa L., Wang H., Warren H.S., RA Moldawer L.L., Fink M.P., Andersson U., Tracey K.J., Yang H.; RT "Structural basis for the proinflammatory cytokine activity of high RT mobility group box 1."; RL Mol. Med. 9:37-45(2003). RN [19] RP FUNCTION, AND INTERACTION WITH MSH2. RX PubMed=15014079; DOI=10.1074/jbc.m401931200; RA Yuan F., Gu L., Guo S., Wang C., Li G.M.; RT "Evidence for involvement of HMGB1 protein in human DNA mismatch repair."; RL J. Biol. Chem. 279:20935-20940(2004). RN [20] RP INVOLVEMENT IN INFLAMMATORY DISEASES. RX PubMed=14695889; DOI=10.1073/pnas.2434651100; RA Yang H., Ochani M., Li J., Qiang X., Tanovic M., Harris H.E., Susarla S.M., RA Ulloa L., Wang H., DiRaimo R., Czura C.J., Wang H., Roth J., Warren H.S., RA Fink M.P., Fenton M.J., Andersson U., Tracey K.J.; RT "Reversing established sepsis with antagonists of endogenous high-mobility RT group box 1."; RL Proc. Natl. Acad. Sci. U.S.A. 101:296-301(2004). RN [21] RP FUNCTION. RX PubMed=16143102; DOI=10.1016/j.cell.2005.06.027; RA Zhang Y., Yuan F., Presnell S.R., Tian K., Gao Y., Tomkinson A.E., Gu L., RA Li G.-M.; RT "Reconstitution of 5'-directed human mismatch repair in a purified RT system."; RL Cell 122:693-705(2005). RN [22] RP INTERACTION WITH THBD. RX PubMed=15841214; DOI=10.1172/jci22782; RA Abeyama K., Stern D.M., Ito Y., Kawahara K., Yoshimoto Y., Tanaka M., RA Uchimura T., Ida N., Yamazaki Y., Yamada S., Yamamoto Y., Yamamoto H., RA Iino S., Taniguchi N., Maruyama I.; RT "The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 RT protein, a novel antiinflammatory mechanism."; RL J. Clin. Invest. 115:1267-1274(2005). RN [23] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=15944249; DOI=10.4049/jimmunol.174.12.7506; RA Dumitriu I.E., Baruah P., Valentinis B., Voll R.E., Herrmann M., RA Nawroth P.P., Arnold B., Bianchi M.E., Manfredi A.A., Rovere-Querini P.; RT "Release of high mobility group box 1 by dendritic cells controls T cell RT activation via the receptor for advanced glycation end products."; RL J. Immunol. 174:7506-7515(2005). RN [24] RP FUNCTION. RX PubMed=15607795; DOI=10.1016/j.molimm.2004.07.023; RA DeMarco R.A., Fink M.P., Lotze M.T.; RT "Monocytes promote natural killer cell interferon gamma production in RT response to the endogenous danger signal HMGB1."; RL Mol. Immunol. 42:433-444(2005). RN [25] RP SUBCELLULAR LOCATION. RX PubMed=16855214; DOI=10.1152/ajpcell.00616.2005; RA Bell C.W., Jiang W., Reich C.F., Pisetsky D.S.; RT "The extracellular release of HMGB1 during apoptotic cell death."; RL Am. J. Physiol. 291:C1318-C1325(2006). RN [26] RP DISULFIDE BRIDGE, AND REDOX FORMS. RX PubMed=16962095; DOI=10.1016/j.yexcr.2006.07.020; RA Hoppe G., Talcott K.E., Bhattacharya S.K., Crabb J.W., Sears J.E.; RT "Molecular basis for the redox control of nuclear transport of the RT structural chromatin protein Hmgb1."; RL Exp. Cell Res. 312:3526-3538(2006). RN [27] RP PHOSPHORYLATION, MUTAGENESIS OF SER-35; SER-39; SER-42; SER-46; SER-53 AND RP SER-181, SUBCELLULAR LOCATION, AND INTERACTION WITH KPNA1. RX PubMed=17114460; DOI=10.4049/jimmunol.177.11.7889; RA Youn J.H., Shin J.S.; RT "Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that RT redirects it toward secretion."; RL J. Immunol. 177:7889-7897(2006). RN [28] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-106. RX PubMed=18631454; DOI=10.1016/j.immuni.2008.05.013; RA Kazama H., Ricci J.E., Herndon J.M., Hoppe G., Green D.R., Ferguson T.A.; RT "Induction of immunological tolerance by apoptotic cells requires caspase- RT dependent oxidation of high-mobility group box-1 protein."; RL Immunity 29:21-32(2008). RN [29] RP FUNCTION. RX PubMed=17803946; DOI=10.1016/j.molcel.2007.06.029; RA Prasad R., Liu Y., Deterding L.J., Poltoratsky V.P., Kedar P.S., RA Horton J.K., Kanno S., Asagoshi K., Hou E.W., Khodyreva S.N., Lavrik O.I., RA Tomer K.B., Yasui A., Wilson S.H.; RT "HMGB1 is a cofactor in mammalian base excision repair."; RL Mol. Cell 27:829-841(2007). RN [30] RP FUNCTION, TISSUE SPECIFICITY, AND INVOLVEMENT IN AUTOIMMUNE DISEASES. RX PubMed=19064698; DOI=10.1084/jem.20081165; RA Urbonaviciute V., Furnrohr B.G., Meister S., Munoz L., Heyder P., RA De Marchis F., Bianchi M.E., Kirschning C., Wagner H., Manfredi A.A., RA Kalden J.R., Schett G., Rovere-Querini P., Herrmann M., Voll R.E.; RT "Induction of inflammatory and immune responses by HMGB1-nucleosome RT complexes: implications for the pathogenesis of SLE."; RL J. Exp. Med. 205:3007-3018(2008). RN [31] RP FUNCTION, AND INTERACTION WITH IL1B. RX PubMed=18250463; DOI=10.4049/jimmunol.180.4.2531; RA Sha Y., Zmijewski J., Xu Z., Abraham E.; RT "HMGB1 develops enhanced proinflammatory activity by binding to RT cytokines."; RL J. Immunol. 180:2531-2537(2008). RN [32] RP FUNCTION. RX PubMed=18354232; DOI=10.4049/jimmunol.180.7.5067; RA Youn J.H., Oh Y.J., Kim E.S., Choi J.E., Shin J.S.; RT "High mobility group box 1 protein binding to lipopolysaccharide RT facilitates transfer of lipopolysaccharide to CD14 and enhances RT lipopolysaccharide-mediated TNF-alpha production in human monocytes."; RL J. Immunol. 180:5067-5074(2008). RN [33] RP INTERACTION WITH HNF1A. RX PubMed=18160415; DOI=10.1093/nar/gkm1131; RA Yu M., Wang J., Li W., Yuan Y.Z., Li C.Y., Qian X.H., Xu W.X., Zhan Y.Q., RA Yang X.M.; RT "Proteomic screen defines the hepatocyte nuclear factor 1alpha-binding RT partners and identifies HMGB1 as a new cofactor of HNF1alpha."; RL Nucleic Acids Res. 36:1209-1219(2008). RN [34] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35 AND SER-100, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [35] RP REDOX FORMS, AND SUBCELLULAR LOCATION. RX PubMed=19811284; DOI=10.1080/08916930902831803; RA Urbonaviciute V., Meister S., Furnrohr B.G., Frey B., Guckel E., Schett G., RA Herrmann M., Voll R.E.; RT "Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during RT apoptosis."; RL Autoimmunity 42:305-307(2009). RN [36] RP FUNCTION, AND INTERACTION WITH XPA AND XPC. RX PubMed=19446504; DOI=10.1016/j.dnarep.2009.04.001; RA Lange S.S., Reddy M.C., Vasquez K.M.; RT "Human HMGB1 directly facilitates interactions between nucleotide excision RT repair proteins on triplex-directed psoralen interstrand crosslinks."; RL DNA Repair 8:865-872(2009). RN [37] RP REVIEW ON FUNCTION RELATED TO DNA REPAIR. RX PubMed=19360789; DOI=10.1002/mc.20544; RA Lange S.S., Vasquez K.M.; RT "HMGB1: the jack-of-all-trades protein is a master DNA repair mechanic."; RL Mol. Carcinog. 48:571-580(2009). RN [38] RP FUNCTION, INTERACTION WITH CD24, AND LIGAND FOR CD24:SIGLEC10 RECEPTOR RP COMPLEX. RX PubMed=19264983; DOI=10.1126/science.1168988; RA Chen G.Y., Tang J., Zheng P., Liu Y.; RT "CD24 and Siglec-10 selectively repress tissue damage-induced immune RT responses."; RL Science 323:1722-1725(2009). RN [39] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-30, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [40] RP REVIEW ON FUNCTION RELATED TO DNA-BINDING. RX PubMed=20123072; DOI=10.1016/j.bbagrm.2009.09.008; RA Stros M.; RT "HMGB proteins: interactions with DNA and chromatin."; RL Biochim. Biophys. Acta 1799:101-113(2010). RN [41] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH BECN1. RX PubMed=20819940; DOI=10.1083/jcb.200911078; RA Tang D., Kang R., Livesey K.M., Cheh C.W., Farkas A., Loughran P., RA Hoppe G., Bianchi M.E., Tracey K.J., Zeh H.J. III, Lotze M.T.; RT "Endogenous HMGB1 regulates autophagy."; RL J. Cell Biol. 190:881-892(2010). RN [42] RP FUNCTION, LIGAND FOR TLR4:LY96 RECEPTOR COMPLEX, AND DOMAIN. RX PubMed=20547845; DOI=10.1073/pnas.1003893107; RA Yang H., Hreggvidsdottir H.S., Palmblad K., Wang H., Ochani M., Li J., RA Lu B., Chavan S., Rosas-Ballina M., Al-Abed Y., Akira S., Bierhaus A., RA Erlandsson-Harris H., Andersson U., Tracey K.J.; RT "A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 RT and activation of macrophage cytokine release."; RL Proc. Natl. Acad. Sci. U.S.A. 107:11942-11947(2010). RN [43] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35, 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 [44] RP FUNCTION. RX PubMed=21395369; DOI=10.1089/ars.2010.3666; RA Tang D., Kang R., Livesey K.M., Zeh H.J., Lotze M.T.; RT "High mobility group box 1 (HMGB1) activates an autophagic response to RT oxidative stress."; RL Antioxid. Redox Signal. 15:2185-2195(2011). RN [45] 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 [46] RP LPS-BINDING. RX PubMed=21660935; DOI=10.1002/eji.201141391; RA Youn J.H., Kwak M.S., Wu J., Kim E.S., Ji Y., Min H.J., Yoo J.H., RA Choi J.E., Cho H.S., Shin J.S.; RT "Identification of lipopolysaccharide-binding peptide regions within HMGB1 RT and their effects on subclinical endotoxemia in a mouse model."; RL Eur. J. Immunol. 41:2753-2762(2011). RN [47] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35, 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 [48] RP FUNCTION (MICROBIAL INFECTION), INTERACTION WITH INFLUENZA A VIRUS PROTEIN RP NP (MICROBIAL INFECTION), AND SUBCELLULAR LOCATION. RX PubMed=22696656; DOI=10.1128/jvi.00789-12; RA Moisy D., Avilov S.V., Jacob Y., Laoide B.M., Ge X., Baudin F., Naffakh N., RA Jestin J.L.; RT "HMGB1 protein binds to influenza virus nucleoprotein and promotes viral RT replication."; RL J. Virol. 86:9122-9133(2012). RN [49] RP FUNCTION. RX PubMed=22473704; DOI=10.1093/intimm/dxs051; RA Wild C.A., Bergmann C., Fritz G., Schuler P., Hoffmann T.K., Lotfi R., RA Westendorf A., Brandau S., Lang S.; RT "HMGB1 conveys immunosuppressive characteristics on regulatory and RT conventional T cells."; RL Int. Immunol. 24:485-494(2012). RN [50] RP FUNCTION, AND INTERACTION WITH CXCL12. RX PubMed=22370717; DOI=10.1084/jem.20111739; RA Schiraldi M., Raucci A., Munoz L.M., Livoti E., Celona B., Venereau E., RA Apuzzo T., De Marchis F., Pedotti M., Bachi A., Thelen M., Varani L., RA Mellado M., Proudfoot A., Bianchi M.E., Uguccioni M.; RT "HMGB1 promotes recruitment of inflammatory cells to damaged tissues by RT forming a complex with CXCL12 and signaling via CXCR4."; RL J. Exp. Med. 209:551-563(2012). RN [51] RP REDOX FORMS, AND SUBCELLULAR LOCATION. RX PubMed=22869893; DOI=10.1084/jem.20120189; RA Venereau E., Casalgrandi M., Schiraldi M., Antoine D.J., Cattaneo A., RA De Marchis F., Liu J., Antonelli A., Preti A., Raeli L., Shams S.S., RA Yang H., Varani L., Andersson U., Tracey K.J., Bachi A., Uguccioni M., RA Bianchi M.E.; RT "Mutually exclusive redox forms of HMGB1 promote cell recruitment or RT proinflammatory cytokine release."; RL J. Exp. Med. 209:1519-1528(2012). RN [52] RP ACETYLATION. RX PubMed=22801494; DOI=10.1038/nature11290; RA Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbaeck P., RA Valdes-Ferrer S.I., Olofsson P.S., Kalb T., Roth J., Zou Y., RA Erlandsson-Harris H., Yang H., Ting J.P., Wang H., Andersson U., RA Antoine D.J., Chavan S.S., Hotamisligil G.S., Tracey K.J.; RT "Novel role of PKR in inflammasome activation and HMGB1 release."; RL Nature 488:670-674(2012). RN [53] RP INVOLVEMENT IN CANCER THERAPY. RX PubMed=23040637; DOI=10.1016/j.ejca.2012.09.016; RA Luo Y., Chihara Y., Fujimoto K., Sasahira T., Kuwada M., Fujiwara R., RA Fujii K., Ohmori H., Kuniyasu H.; RT "High mobility group box 1 released from necrotic cells enhances regrowth RT and metastasis of cancer cells that have survived chemotherapy."; RL Eur. J. Cancer 49:741-751(2013). RN [54] RP REVIEW ON FUNCTION RELATED TO ADAPTIVE IMMUNITY. RX PubMed=23519706; DOI=10.3389/fimmu.2013.00068; RA Li G., Liang X., Lotze M.T.; RT "HMGB1: The central cytokine for all lymphoid cells."; RL Front. Immunol. 4:68-68(2013). RN [55] RP FUNCTION, AND INTERACTION WITH HTT. RX PubMed=23303669; DOI=10.4049/jimmunol.1202472; RA Min H.J., Ko E.A., Wu J., Kim E.S., Kwon M.K., Kwak M.S., Choi J.E., RA Lee J.E., Shin J.S.; RT "Chaperone-like activity of high-mobility group box 1 protein and its role RT in reducing the formation of polyglutamine aggregates."; RL J. Immunol. 190:1797-1806(2013). RN [56] RP REVIEW ON FUNCTION RELATED TO INFLAMMATION. RX PubMed=23446148; DOI=10.1189/jlb.1212662; RA Yang H., Antoine D.J., Andersson U., Tracey K.J.; RT "The many faces of HMGB1: molecular structure-functional activity in RT inflammation, apoptosis, and chemotaxis."; RL J. Leukoc. Biol. 93:865-873(2013). RN [57] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35, 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 [58] RP REVIEW. RX PubMed=23994764; DOI=10.1016/j.semcancer.2013.08.002; RA Li G., Tang D., Lotze M.T.; RT "Menage a Trois in stress: DAMPs, redox and autophagy."; RL Semin. Cancer Biol. 23:380-390(2013). RN [59] RP FUNCTION. RX PubMed=24971542; DOI=10.1016/j.bbrc.2014.06.074; RA Liu L., Yang M., Kang R., Dai Y., Yu Y., Gao F., Wang H., Sun X., Li X., RA Li J., Wang H., Cao L., Tang D.; RT "HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome activation RT through RAGE."; RL Biochem. Biophys. Res. Commun. 450:851-856(2014). RN [60] RP FUNCTION, MUTAGENESIS OF ASP-67, INTERACTION WITH AGER, DOMAIN, AND RP PROTEOLYTIC CLEAVAGE. RX PubMed=24474694; DOI=10.1074/jbc.m113.541474; RA LeBlanc P.M., Doggett T.A., Choi J., Hancock M.A., Durocher Y., Frank F., RA Nagar B., Ferguson T.A., Saleh M.; RT "An immunogenic peptide in the A-box of HMGB1 protein reverses apoptosis- RT induced tolerance through RAGE receptor."; RL J. Biol. Chem. 289:7777-7786(2014). RN [61] 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 [62] RP NOMENCLATURE OF REDOX FORMS. RX PubMed=24531895; DOI=10.2119/molmed.2014.00022; RA Antoine D.J., Harris H.E., Andersson U., Tracey K.J., Bianchi M.E.; RT "A systematic nomenclature for the redox states of high mobility group box RT (HMGB) proteins."; RL Mol. Med. 20:135-137(2014). RN [63] RP REVIEW ON INVOLVEMENT IN DISEASES AND THERAPEUTIC TARGET. RX PubMed=24220159; DOI=10.1016/j.pharmthera.2013.11.001; RA Musumeci D., Roviello G.N., Montesarchio D.; RT "An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1- RT related pathologies."; RL Pharmacol. Ther. 141:347-357(2014). RN [64] RP FUNCTION. RX PubMed=25549101; DOI=10.1371/journal.pone.0115809; RA Lee L.C., Chen C.M., Wang P.R., Su M.T., Lee-Chen G.J., Chang C.Y.; RT "Role of high mobility group box 1 (HMGB1) in SCA17 pathogenesis."; RL PLoS ONE 9:E115809-E115809(2014). RN [65] RP REVIEW ON FUNCTION RELATED TO INNATE IMMUNITY. RX PubMed=25048472; DOI=10.3349/ymj.2014.55.5.1165; RA Lee S.A., Kwak M.S., Kim S., Shin J.S.; RT "The role of high mobility group box 1 in innate immunity."; RL Yonsei Med. J. 55:1165-1176(2014). RN [66] RP INVOLVEMENT AUTOIMMUNE DISEASES. RX PubMed=26078984; DOI=10.1155/2015/946748; RA Lu M., Yu S., Xu W., Gao B., Xiong S.; RT "HMGB1 promotes systemic lupus erythematosus by enhancing macrophage RT inflammatory response."; RL J. Immunol. Res. 2015:946748-946748(2015). RN [67] RP FUNCTION. RX PubMed=25660311; DOI=10.1159/000369972; RA Kwak M.S., Lim M., Lee Y.J., Lee H.S., Kim Y.H., Youn J.H., Choi J.E., RA Shin J.S.; RT "HMGB1 binds to lipoteichoic acid and enhances TNF-alpha and IL-6 RT production through HMGB1-mediated transfer of lipoteichoic acid to CD14 and RT TLR2."; RL J. Innate Immun. 7:405-416(2015). RN [68] 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 [69] RP FUNCTION, INTERACTION WITH ADENOVIRUS PROTEIN PVII (MICROBIAL INFECTION), RP AND SUBCELLULAR LOCATION. RX PubMed=27362237; DOI=10.1038/nature18317; RA Avgousti D.C., Herrmann C., Kulej K., Pancholi N.J., Sekulic N., RA Petrescu J., Molden R.C., Blumenthal D., Paris A.J., Reyes E.D., RA Ostapchuk P., Hearing P., Seeholzer S.H., Worthen G.S., Black B.E., RA Garcia B.A., Weitzman M.D.; RT "A core viral protein binds host nucleosomes to sequester immune danger RT signals."; RL Nature 535:173-177(2016). RN [70] RP ADP-RIBOSYLATION AT SER-181. RX PubMed=28190768; DOI=10.1016/j.molcel.2017.01.003; RA Bonfiglio J.J., Fontana P., Zhang Q., Colby T., Gibbs-Seymour I., RA Atanassov I., Bartlett E., Zaja R., Ahel I., Matic I.; RT "Serine ADP-ribosylation depends on HPF1."; RL Mol. Cell 0:0-0(2017). RN [71] RP SUBCELLULAR LOCATION, AND TRANSGLUTAMINATION AT LYS-28; LYS-43; LYS-44; RP LYS-68; LYS-177; LYS-180; LYS-182; LYS-183 AND LYS-184. RX PubMed=29618516; DOI=10.1074/jbc.ra117.001078; RA Willis W.L., Wang L., Wada T.T., Gardner M., Abdouni O., Hampton J., RA Valiente G., Young N., Ardoin S., Agarwal S., Freitas M.A., Wu L.C., RA Jarjour W.N.; RT "The proinflammatory protein HMGB1 is a substrate of transglutaminase-2 and RT forms high-molecular weight complexes with autoantigens."; RL J. Biol. Chem. 293:8394-8409(2018). RN [72] RP FUNCTION, FUNCTION (MICROBIAL INFECTION), SUBCELLULAR LOCATION, AND RP INDUCTION BY SARS-COV2 (MICROBIAL INFECTION). RX PubMed=33147444; DOI=10.1016/j.cell.2020.10.028; RA Wei J., Alfajaro M.M., DeWeirdt P.C., Hanna R.E., Lu-Culligan W.J., RA Cai W.L., Strine M.S., Zhang S.M., Graziano V.R., Schmitz C.O., Chen J.S., RA Mankowski M.C., Filler R.B., Ravindra N.G., Gasque V., de Miguel F.J., RA Patil A., Chen H., Oguntuyo K.Y., Abriola L., Surovtseva Y.V., RA Orchard R.C., Lee B., Lindenbach B.D., Politi K., van Dijk D., Kadoch C., RA Simon M.D., Yan Q., Doench J.G., Wilen C.B.; RT "Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 RT Infection."; RL Cell 184:76-91.e13(2021). RN [73] RP FUNCTION, AND INTERACTION WITH AGER. RX PubMed=34743181; DOI=10.1038/s41420-021-00729-0; RA Wang G., Jin S., Huang W., Li Y., Wang J., Ling X., Huang Y., Hu Y., Li C., RA Meng Y., Li X.; RT "LPS-induced macrophage HMGB1-loaded extracellular vesicles trigger RT hepatocyte pyroptosis by activating the NLRP3 inflammasome."; RL Cell. Death. Discov. 7:337-337(2021). RN [74] RP FUNCTION (MICROBIAL INFECTION). RX PubMed=34922257; DOI=10.1016/j.virol.2021.12.002; RA Reinhart N.M., Akinyemi I.A., Frey T.R., Xu H., Agudelo C., Brathwaite J., RA Burton E.M., Burgula S., McIntosh M.T., Bhaduri-McIntosh S.; RT "The danger molecule HMGB1 cooperates with the NLRP3 inflammasome to RT sustain expression of the EBV lytic switch protein in Burkitt lymphoma RT cells."; RL Virology 566:136-142(2022). RN [75] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=36585612; DOI=10.1186/s10020-022-00596-0; RA Shin J., Kim Y.H., Lee B., Chang J.H., Choi H.Y., Lee H., Song K.C., RA Kwak M.S., Choi J.E., Shin J.S.; RT "USP13 regulates HMGB1 stability and secretion through its deubiquitinase RT activity."; RL Mol. Med. 28:164-164(2022). RN [76] RP FUNCTION (MICROBIAL INFECTION), AND SUBCELLULAR LOCATION. RX PubMed=34971702; DOI=10.1016/j.virusres.2021.198668; RA Chaudhary N., Srivastava S., Dave U., Ojha A., Guchhait P., Chandele A., RA Patel A.K.; RT "High-mobility group box 1 protein promotes dengue virus replication by RT interacting with untranslated regions of viral genome."; RL Virus Res. 309:198668-198668(2022). RN [77] RP FUNCTION (MICROBIAL INFECTION), INTERACTION WITH SARS-COV-2 ORF3A, AND RP SUBCELLULAR LOCATION (MICROBIAL INFECTION). RX PubMed=35239449; DOI=10.1080/15548627.2022.2039992; RA Zhang X., Yang Z., Pan T., Long X., Sun Q., Wang P.H., Li X., Kuang E.; RT "SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulophagy and RT triggers sequential ER stress and inflammatory responses during SARS-CoV-2 RT infection."; RL Autophagy 0:0-0(2022). RN [78] RP STRUCTURE BY NMR OF 1-166. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the tandem HMG box domain from human high mobility RT group protein B1."; RL Submitted (FEB-2008) to the PDB data bank. RN [79] RP STRUCTURE BY NMR OF 2-84 IN COMPLEX WITH TP53, FUNCTION, AND DOMAIN. RX PubMed=23063560; DOI=10.1016/j.str.2012.09.004; RA Rowell J.P., Simpson K.L., Stott K., Watson M., Thomas J.O.; RT "HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 transactivation RT domain interaction, regulated by the acidic tail."; RL Structure 20:2014-2024(2012). RN [80] RP STRUCTURE BY NMR OF 1-84. RX PubMed=24427810; DOI=10.1016/j.bbrc.2013.10.085; RA Wang J., Tochio N., Takeuchi A., Uewaki J., Kobayashi N., Tate S.; RT "Redox-sensitive structural change in the A-domain of HMGB1 and its RT implication for the binding to cisplatin modified DNA."; RL Biochem. Biophys. Res. Commun. 441:701-706(2013). CC -!- FUNCTION: Multifunctional redox sensitive protein with various roles in CC different cellular compartments. In the nucleus is one of the major CC chromatin-associated non-histone proteins and acts as a DNA chaperone CC involved in replication, transcription, chromatin remodeling, V(D)J CC recombination, DNA repair and genome stability (PubMed:33147444). CC Proposed to be an universal biosensor for nucleic acids. Promotes host CC inflammatory response to sterile and infectious signals and is involved CC in the coordination and integration of innate and adaptive immune CC responses. In the cytoplasm functions as a sensor and/or chaperone for CC immunogenic nucleic acids implicating the activation of TLR9-mediated CC immune responses, and mediates autophagy. Acts as a danger-associated CC molecular pattern (DAMP) molecule that amplifies immune responses CC during tissue injury (PubMed:27362237). Released to the extracellular CC environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform CC 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and CC activates cells through engagement of multiple surface receptors CC (PubMed:34743181). In the extracellular compartment fully reduced HMGB1 CC (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively CC secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic CC cells) promotes immunological tolerance (PubMed:23446148, CC PubMed:23519706, PubMed:23994764, PubMed:25048472). Has proangiogdenic CC activity (By similarity). May be involved in platelet activation (By CC similarity). Binds to phosphatidylserine and phosphatidylethanolamide CC (By similarity). Bound to RAGE mediates signaling for neuronal CC outgrowth (By similarity). May play a role in accumulation of expanded CC polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP CC (PubMed:23303669, PubMed:25549101). {ECO:0000250|UniProtKB:P10103, CC ECO:0000250|UniProtKB:P12682, ECO:0000250|UniProtKB:P63158, CC ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:23303669, CC ECO:0000269|PubMed:25549101, ECO:0000269|PubMed:27362237, CC ECO:0000269|PubMed:33147444, ECO:0000269|PubMed:34743181, CC ECO:0000305|PubMed:23446148, ECO:0000305|PubMed:23519706, CC ECO:0000305|PubMed:23994764, ECO:0000305|PubMed:25048472}. CC -!- FUNCTION: Nuclear functions are attributed to fully reduced HGMB1. CC Associates with chromatin and binds DNA with a preference to non- CC canonical DNA structures such as single-stranded DNA, DNA-containing CC cruciforms or bent structures, supercoiled DNA and ZDNA. Can bent DNA CC and enhance DNA flexibility by looping thus providing a mechanism to CC promote activities on various gene promoters by enhancing transcription CC factor binding and/or bringing distant regulatory sequences into close CC proximity (PubMed:20123072). May have an enhancing role in nucleotide CC excision repair (NER) (By similarity). However, effects in NER using in CC vitro systems have been reported conflictingly (PubMed:19360789, CC PubMed:19446504). May be involved in mismatch repair (MMR) and base CC excision repair (BER) pathways (PubMed:15014079, PubMed:16143102, CC PubMed:17803946). May be involved in double strand break repair such as CC non-homologous end joining (NHEJ) (By similarity). Involved in V(D)J CC recombination by acting as a cofactor of the RAG complex: acts by CC stimulating cleavage and RAG protein binding at the 23 bp spacer of CC conserved recombination signal sequences (RSS) (By similarity). In CC vitro can displace histone H1 from highly bent DNA (By similarity). Can CC restructure the canonical nucleosome leading to relaxation of CC structural constraints for transcription factor-binding (By CC similarity). Enhances binding of sterol regulatory element-binding CC proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and CC increases their transcriptional activities (By similarity). Facilitates CC binding of TP53 to DNA (PubMed:23063560). Proposed to be involved in CC mitochondrial quality control and autophagy in a transcription- CC dependent fashion implicating HSPB1; however, this function has been CC questioned (By similarity). Can modulate the activity of the telomerase CC complex and may be involved in telomere maintenance (By similarity). CC {ECO:0000250|UniProtKB:P10103, ECO:0000250|UniProtKB:P63158, CC ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:15014079, CC ECO:0000269|PubMed:16143102, ECO:0000269|PubMed:17803946, CC ECO:0000269|PubMed:19446504, ECO:0000269|PubMed:23063560, CC ECO:0000305|PubMed:19360789, ECO:0000305|PubMed:20123072}. CC -!- FUNCTION: In the cytoplasm proposed to dissociate the BECN1:BCL2 CC complex via competitive interaction with BECN1 leading to autophagy CC activation (PubMed:20819940). Involved in oxidative stress-mediated CC autophagy (PubMed:21395369). Can protect BECN1 and ATG5 from calpain- CC mediated cleavage and thus proposed to control their proautophagic and CC proapoptotic functions and to regulate the extent and severity of CC inflammation-associated cellular injury (By similarity). In myeloid CC cells has a protective role against endotoxemia and bacterial infection CC by promoting autophagy (By similarity). Involved in endosomal CC translocation and activation of TLR9 in response to CpG-DNA in CC macrophages (By similarity). {ECO:0000250|UniProtKB:P63158, CC ECO:0000269|PubMed:20819940, ECO:0000269|PubMed:21395369}. CC -!- FUNCTION: In the extracellular compartment (following either active CC secretion or passive release) involved in regulation of the CC inflammatory response. Fully reduced HGMB1 (which subsequently gets CC oxidized after release) in association with CXCL12 mediates the CC recruitment of inflammatory cells during the initial phase of tissue CC injury; the CXCL12:HMGB1 complex triggers CXCR4 homodimerization CC (PubMed:22370717). Induces the migration of monocyte-derived immature CC dendritic cells and seems to regulate adhesive and migratory functions CC of neutrophils implicating AGER/RAGE and ITGAM (By similarity). Can CC bind to various types of DNA and RNA including microbial unmethylated CC CpG-DNA to enhance the innate immune response to nucleic acids. CC Proposed to act in promiscuous DNA/RNA sensing which cooperates with CC subsequent discriminative sensing by specific pattern recognition CC receptors (By similarity). Promotes extracellular DNA-induced AIM2 CC inflammasome activation implicating AGER/RAGE (PubMed:24971542). CC Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, CC TLR2, TLR4 and probably TREM1, thus activating their signal CC transduction pathways. Mediates the release of cytokines/chemokines CC such as TNF, IL-1, IL-6, IL-8, CCL2, CCL3, CCL4 and CXCL10 CC (PubMed:12765338, PubMed:18354232, PubMed:19264983, PubMed:20547845, CC PubMed:24474694). Promotes secretion of interferon-gamma by macrophage- CC stimulated natural killer (NK) cells in concert with other cytokines CC like IL-2 or IL-12 (PubMed:15607795). TLR4 is proposed to be the CC primary receptor promoting macrophage activation and signaling through CC TLR4 seems to implicate LY96/MD-2 (PubMed:20547845). In bacterial CC LPS- or LTA-mediated inflammatory responses binds to the endotoxins and CC transfers them to CD14 for signaling to the respective TLR4:LY96 and CC TLR2 complexes (PubMed:18354232, PubMed:21660935, PubMed:25660311). CC Contributes to tumor proliferation by association with ACER/RAGE (By CC similarity). Can bind to IL1-beta and signals through the IL1R1:IL1RAP CC receptor complex (PubMed:18250463). Binding to class A CpG activates CC cytokine production in plasmacytoid dendritic cells implicating TLR9, CC MYD88 and AGER/RAGE and can activate autoreactive B cells. Via HMGB1- CC containing chromatin immune complexes may also promote B cell responses CC to endogenous TLR9 ligands through a B-cell receptor (BCR)-dependent CC and ACER/RAGE-independent mechanism (By similarity). Inhibits CC phagocytosis of apoptotic cells by macrophages; the function is CC dependent on poly-ADP-ribosylation and involves binding to CC phosphatidylserine on the cell surface of apoptotic cells (By CC similarity). In adaptive immunity may be involved in enhancing immunity CC through activation of effector T cells and suppression of regulatory T CC (TReg) cells (PubMed:15944249, PubMed:22473704). In contrast, without CC implicating effector or regulatory T-cells, required for tumor CC infiltration and activation of T-cells expressing the lymphotoxin CC LTA:LTB heterotrimer thus promoting tumor malignant progression (By CC similarity). Also reported to limit proliferation of T-cells (By CC similarity). Released HMGB1:nucleosome complexes formed during CC apoptosis can signal through TLR2 to induce cytokine production CC (PubMed:19064698). Involved in induction of immunological tolerance by CC apoptotic cells; its pro-inflammatory activities when released by CC apoptotic cells are neutralized by reactive oxygen species (ROS)- CC dependent oxidation specifically on Cys-106 (PubMed:18631454). During CC macrophage activation by activated lymphocyte-derived self apoptotic CC DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes (By CC similarity). {ECO:0000250|UniProtKB:P10103, CC ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159, CC ECO:0000269|PubMed:12765338, ECO:0000269|PubMed:15607795, CC ECO:0000269|PubMed:15944249, ECO:0000269|PubMed:18250463, CC ECO:0000269|PubMed:18354232, ECO:0000269|PubMed:18631454, CC ECO:0000269|PubMed:19064698, ECO:0000269|PubMed:19264983, CC ECO:0000269|PubMed:20547845, ECO:0000269|PubMed:21660935, CC ECO:0000269|PubMed:22370717, ECO:0000269|PubMed:22473704, CC ECO:0000269|PubMed:24474694, ECO:0000269|PubMed:24971542, CC ECO:0000269|PubMed:25660311, ECO:0000269|Ref.8}. CC -!- FUNCTION: (Microbial infection) Critical for entry of human CC coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus CC NL63/HCoV-NL63 (PubMed:33147444). Regulates the expression of the pro- CC viral genes ACE2 and CTSL through chromatin modulation CC (PubMed:33147444). Required for SARS-CoV-2 ORF3A-induced reticulophagy CC which induces endoplasmic reticulum stress and inflammatory responses CC and facilitates viral infection (PubMed:35239449). CC {ECO:0000269|PubMed:33147444, ECO:0000269|PubMed:35239449}. CC -!- FUNCTION: (Microbial infection) Associates with the influenza A viral CC protein NP in the nucleus of infected cells, promoting viral growth and CC enhancing the activity of the viral polymerase. CC {ECO:0000269|PubMed:22696656}. CC -!- FUNCTION: (Microbial infection) Promotes Epstein-Barr virus (EBV) CC latent-to-lytic switch by sustaining the expression of the viral CC transcription factor BZLF1 that acts as a molecular switch to induce CC the transition from the latent to the lytic or productive phase of the CC virus cycle. Mechanistically, participates in EBV reactivation through CC the NLRP3 inflammasome. {ECO:0000269|PubMed:34922257}. CC -!- FUNCTION: (Microbial infection) Facilitates dengue virus propagation CC via interaction with the untranslated regions of viral genome. In turn, CC this interaction with viral RNA may regulate secondary structure of CC dengue RNA thus facilitating its recognition by the replication CC complex. {ECO:0000269|PubMed:34971702}. CC -!- SUBUNIT: Interacts (fully reduced HMGB1) with CXCL12; probably in a 1:2 CC ratio involving two molecules of CXCL12, each interacting with one HMG CC box of HMGB1; inhibited by glycyrrhizin (PubMed:22370717). Associates CC with the TLR4:LY96 receptor complex (PubMed:20547845). Component of the CC RAG complex composed of core components RAG1 and RAG2, and associated CC component HMGB1 or HMGB2 (By similarity). Interacts (in cytoplasm upon CC starvation) with BECN1; inhibits the interaction of BECN1 and BCL2 CC leading to promotion of autophagy (PubMed:20819940). Interacts with CC KPNA1; involved in nuclear import (PubMed:17114460). Interacts with CC SREBF1, TLR2, TLR4, TLR9, PTPRZ1, APEX1, FEN1, POLB, TERT (By CC similarity). Interacts with IL1B, AGER, MSH2, XPA, XPC, HNF1A, TP53 CC (PubMed:15014079, PubMed:18160415, PubMed:18250463, PubMed:19446504, CC PubMed:23063560, PubMed:24474694). Interacts with CD24; the probable CC CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue CC damage immune response (PubMed:19264983). Interacts with THBD; prevents CC HGMB1 interaction with ACER/RAGE and inhibits HGMB1 pro-inflammatory CC activity (PubMed:15841214). Interacts with HAVCR2; impairs HMGB1 CC binding to B-DNA and likely HMGB1-mediated innate immune response (By CC similarity). Interacts with XPO1; mediating nuclear export (By CC similarity). Interacts with HTT (wild-type and mutant HTT with expanded CC polyglutamine repeat) (PubMed:23303669). Interacts with receptor CC RAGE/AGER (PubMed:34743181). {ECO:0000250|UniProtKB:P63158, CC ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:15014079, CC ECO:0000269|PubMed:15841214, ECO:0000269|PubMed:17114460, CC ECO:0000269|PubMed:17803946, ECO:0000269|PubMed:18160415, CC ECO:0000269|PubMed:18250463, ECO:0000269|PubMed:19264983, CC ECO:0000269|PubMed:19446504, ECO:0000269|PubMed:20547845, CC ECO:0000269|PubMed:20819940, ECO:0000269|PubMed:22370717, CC ECO:0000269|PubMed:23063560, ECO:0000269|PubMed:23303669, CC ECO:0000269|PubMed:24474694, ECO:0000269|PubMed:34743181}. CC -!- SUBUNIT: (Microbial infection) Interacts with adenovirus protein pVII; CC this interaction immobilizes HMGB1 on chromatin, thus preventing its CC release from cell and subsequent inflammation activation. CC {ECO:0000269|PubMed:27362237}. CC -!- SUBUNIT: (Microbial infection) Interacts with SARS-CoV-2 ORF3A protein; CC the interaction promotes association of HMGB1 with BECN1, promoting CC reticulophagy which induces endoplasmic reticulum stress and CC inflammatory responses and facilitates viral infection. CC {ECO:0000269|PubMed:35239449}. CC -!- SUBUNIT: (Microbial infection) Interacts with influenza A virus protein CC NP; this interaction promotes viral replication. CC {ECO:0000269|PubMed:22696656}. CC -!- INTERACTION: CC P09429; Q15109: AGER; NbExp=3; IntAct=EBI-389432, EBI-1646426; CC P09429; Q6RW13: AGTRAP; NbExp=3; IntAct=EBI-389432, EBI-741181; CC P09429; P05067: APP; NbExp=3; IntAct=EBI-389432, EBI-77613; CC P09429; Q14457: BECN1; NbExp=2; IntAct=EBI-389432, EBI-949378; CC P09429; O95273: CCNDBP1; NbExp=3; IntAct=EBI-389432, EBI-748961; CC P09429; Q00839: HNRNPU; NbExp=3; IntAct=EBI-389432, EBI-351126; CC P09429; P42858: HTT; NbExp=13; IntAct=EBI-389432, EBI-466029; CC P09429; P08729: KRT7; NbExp=6; IntAct=EBI-389432, EBI-297833; CC P09429; P43246: MSH2; NbExp=2; IntAct=EBI-389432, EBI-355888; CC P09429; P09874: PARP1; NbExp=2; IntAct=EBI-389432, EBI-355676; CC P09429; Q96T23: RSF1; NbExp=3; IntAct=EBI-389432, EBI-926768; CC P09429; P23497: SP100; NbExp=3; IntAct=EBI-389432, EBI-751145; CC P09429; P84103: SRSF3; NbExp=3; IntAct=EBI-389432, EBI-372557; CC P09429; P04637: TP53; NbExp=9; IntAct=EBI-389432, EBI-366083; CC P09429; Q96B54: ZNF428; NbExp=3; IntAct=EBI-389432, EBI-9995882; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12231511, CC ECO:0000269|PubMed:17114460, ECO:0000269|PubMed:20819940, CC ECO:0000269|PubMed:22696656, ECO:0000269|PubMed:22869893, CC ECO:0000269|PubMed:27362237, ECO:0000269|PubMed:29618516, CC ECO:0000269|PubMed:33147444}. Chromosome {ECO:0000250|UniProtKB:P10103, CC ECO:0000250|UniProtKB:P63159, ECO:0000305}. Cytoplasm CC {ECO:0000269|PubMed:11154118, ECO:0000269|PubMed:12231511, CC ECO:0000269|PubMed:17114460, ECO:0000269|PubMed:20819940, CC ECO:0000269|PubMed:22869893, ECO:0000269|PubMed:29618516, CC ECO:0000269|PubMed:33147444, ECO:0000269|PubMed:34971702}. Secreted CC {ECO:0000250|UniProtKB:P63158, ECO:0000269|PubMed:12231511, CC ECO:0000269|PubMed:14532127, ECO:0000269|PubMed:15944249, CC ECO:0000269|PubMed:19811284, ECO:0000269|PubMed:22869893, CC ECO:0000269|PubMed:33147444}. Cell membrane CC {ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159, CC ECO:0000269|PubMed:11154118}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159, CC ECO:0000269|PubMed:11154118}; Extracellular side CC {ECO:0000250|UniProtKB:P63158, ECO:0000250|UniProtKB:P63159, CC ECO:0000269|PubMed:11154118}. Endosome {ECO:0000250|UniProtKB:P63158}. CC Endoplasmic reticulum-Golgi intermediate compartment CC {ECO:0000250|UniProtKB:P63158}. Note=In basal state predominantly CC nuclear. Shuttles between the cytoplasm and the nucleus CC (PubMed:12231511, PubMed:17114460). Translocates from the nucleus to CC the cytoplasm upon autophagy stimulation (PubMed:20819940). Release CC from macrophages in the extracellular milieu requires the activation of CC NLRC4 or NLRP3 inflammasomes (By similarity). Passively released to the CC extracellular milieu from necrotic cells by diffusion, involving the CC fully reduced HGMB1 which subsequently gets oxidized (PubMed:19811284). CC Also released from apoptotic cells (PubMed:16855214, PubMed:18631454). CC Active secretion from a variety of immune and non-immune cells such as CC macrophages, monocytes, neutrophils, dendritic cells and natural killer CC cells in response to various stimuli such as LPS and cytokines involves CC a nonconventional secretory process via secretory lysosomes CC (PubMed:12231511, PubMed:14532127, PubMed:15944249). Secreted by plasma CC cells in response to LPS (By similarity). Found on the surface of CC activated platelets (PubMed:11154118). An increased chromatin CC association is observed when associated with the adenovirus protein CC pVII (PubMed:27362237). {ECO:0000250|UniProtKB:P63158, CC ECO:0000269|PubMed:11154118, ECO:0000269|PubMed:12231511, CC ECO:0000269|PubMed:14532127, ECO:0000269|PubMed:15944249, CC ECO:0000269|PubMed:16855214, ECO:0000269|PubMed:17114460, CC ECO:0000269|PubMed:18631454, ECO:0000269|PubMed:19811284, CC ECO:0000269|PubMed:20819940, ECO:0000269|PubMed:27362237, CC ECO:0000305|PubMed:20123072}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum CC {ECO:0000269|PubMed:35239449}. Note=(Microbial infection) SARS-COV-2 CC ORF3A promotes HMGB1 translocation from the nucleus to the cytoplasm CC where it is recruited by and colocalizes with ORF3A at the endoplasmic CC reticulum. {ECO:0000269|PubMed:35239449}. CC -!- TISSUE SPECIFICITY: Ubiquitous. Expressed in platelets CC (PubMed:11154118). {ECO:0000269|PubMed:11154118}. CC -!- INDUCTION: (Microbial infection) Protein levels increase upon infection CC by human coronavirus SARS-CoV-2. {ECO:0000269|PubMed:33147444}. CC -!- DOMAIN: HMG box 2 mediates pro-inflammatory cytokine-stimulating CC activity and binding to TLR4 (PubMed:12765338, PubMed:20547845). CC However, not involved in mediating immunogenic activity in the context CC of apoptosis-induced immune tolerance (PubMed:24474694). CC {ECO:0000269|PubMed:12765338, ECO:0000269|PubMed:20547845, CC ECO:0000269|PubMed:24474694}. CC -!- DOMAIN: The acidic C-terminal domain forms a flexible structure which CC can reversibly interact intramolecularily with the HMG boxes and CC modulate binding to DNA and other proteins (PubMed:23063560). CC {ECO:0000250|UniProtKB:P63159, ECO:0000305|PubMed:23063560}. CC -!- PTM: Phosphorylated at serine residues. Phosphorylation in both NLS CC regions is required for cytoplasmic translocation followed by secretion CC (PubMed:17114460). {ECO:0000269|PubMed:17114460}. CC -!- PTM: Acetylated on multiple sites upon stimulation with LPS CC (PubMed:22801494). Acetylation on lysine residues in the nuclear CC localization signals (NLS 1 and NLS 2) leads to cytoplasmic CC localization and subsequent secretion (By similarity). Acetylation on CC Lys-3 results in preferential binding to DNA ends and impairs DNA CC bending activity (By similarity). {ECO:0000250|UniProtKB:P10103, CC ECO:0000250|UniProtKB:P63159, ECO:0000269|PubMed:22801494}. CC -!- PTM: Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys- CC 106 and a possible intramolecular disulfide bond involving Cys-23 and CC Cys-45 give rise to different redox forms with specific functional CC activities in various cellular compartments: 1- fully reduced HMGB1 CC (HMGB1C23hC45hC106h), 2- disulfide HMGB1 (HMGB1C23-C45C106h) and CC 3- sulfonyl HMGB1 (HMGB1C23soC45soC106so). CC {ECO:0000269|PubMed:16962095, ECO:0000269|PubMed:19811284, CC ECO:0000269|PubMed:22869893, ECO:0000305|PubMed:24531895}. CC -!- PTM: Poly-ADP-ribosylated by PARP1 when secreted following stimulation CC with LPS (By similarity). {ECO:0000250|UniProtKB:P63158}. CC -!- PTM: In vitro cleavage by CASP1 is liberating a HMG box 1-containing CC peptide which may mediate immunogenic activity; the peptide antagonizes CC apoptosis-induced immune tolerance (PubMed:24474694). Can be CC proteolytically cleaved by a thrombin:thrombomodulin complex; reduces CC binding to heparin and pro-inflammatory activities (By similarity). CC {ECO:0000250|UniProtKB:P10103, ECO:0000269|PubMed:24474694}. CC -!- PTM: Forms covalent cross-links mediated by transglutaminase TGM2, CC between a glutamine and the epsilon-amino group of a lysine residue, CC forming homopolymers and heteropolymers. {ECO:0000269|PubMed:29618516}. CC -!- MISCELLANEOUS: Proposed to contribute to the pathogenesis of various CC chronic inflammatory and autoimmune diseases, and cancer. High serum CC levels are found in several inflammatory events including sepsis, CC rheumatoid arthritis, artherosclerosis chronic kidney disease, systemic CC lupus erythematosus (SLE). Seems to be implicated in other diseases CC characterized by cell death and damage, including diabetes and CC Alzheimer's disease. Its nucleosome-associated release during secondary CC necrosis may play a role in SLE (PubMed:19064698). During chemotherapy CC can mediate regrowth and metastasis of remaining cells in a AGER/RAGE- CC dependent manner (PubMed:23040637). Purified HMG box 1 acts as a CC specific antagonist to HGMB1 pro-inflammatory activities CC (PubMed:14695889). {ECO:0000269|PubMed:14695889, CC ECO:0000269|PubMed:23040637, ECO:0000305, ECO:0000305|PubMed:19064698, CC ECO:0000305|PubMed:24220159, ECO:0000305|PubMed:26078984}. CC -!- SIMILARITY: Belongs to the HMGB family. {ECO:0000305}. CC -!- CAUTION: Inconsistent experimental results may reflect the use of CC inconsistently defined redox forms. A recombinant fully reduced form CC has been used in a number of experiments. However, the redox states of CC HMGB1 administered in vivo, may interconvert among each other. Purified CC HMGB1 by itself has only weak pro-inflammatory activity. {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; X12597; CAA31110.1; -; mRNA. DR EMBL; U51677; AAB08987.1; -; Genomic_DNA. DR EMBL; D63874; BAA09924.1; -; mRNA. DR EMBL; EF157968; ABM47301.1; -; Genomic_DNA. DR EMBL; AY377859; AAQ91389.1; -; mRNA. DR EMBL; AK291494; BAF84183.1; -; mRNA. DR EMBL; AK122825; BAG53745.1; -; mRNA. DR EMBL; CR749614; CAH18408.1; -; mRNA. DR EMBL; CR456863; CAG33144.1; -; mRNA. DR EMBL; BT006940; AAP35586.1; -; mRNA. DR EMBL; BT020159; AAV38961.1; -; mRNA. DR EMBL; EU012027; ABS29271.1; -; Genomic_DNA. DR EMBL; AL353648; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471075; EAX08457.1; -; Genomic_DNA. DR EMBL; BC003378; AAH03378.1; -; mRNA. DR EMBL; BC030981; AAH30981.1; -; mRNA. DR EMBL; BC066889; AAH66889.1; -; mRNA. DR EMBL; BC067732; AAH67732.1; -; mRNA. DR EMBL; BC141844; AAI41845.1; -; mRNA. DR CCDS; CCDS9335.1; -. DR PIR; S02826; S02826. DR RefSeq; NP_001300821.1; NM_001313892.2. DR RefSeq; NP_001300822.1; NM_001313893.1. DR RefSeq; NP_001357269.1; NM_001370340.1. DR RefSeq; NP_001357270.1; NM_001370341.1. DR RefSeq; NP_002119.1; NM_002128.7. DR RefSeq; XP_024305109.1; XM_024449341.2. DR RefSeq; XP_054230460.1; XM_054374485.1. DR PDB; 2LY4; NMR; -; A=2-84. DR PDB; 2RTU; NMR; -; A=1-84. DR PDB; 2YRQ; NMR; -; A=1-166. DR PDB; 6CG0; EM; 3.17 A; N=15-140. DR PDB; 6CIJ; EM; 3.90 A; N=1-163. DR PDB; 6CIK; X-ray; 3.15 A; N=1-163. DR PDB; 6CIL; X-ray; 4.15 A; N=1-163. DR PDB; 6CIM; X-ray; 3.60 A; N=1-163. DR PDB; 6OEM; EM; 3.60 A; H/N=15-155. DR PDB; 6OEN; EM; 4.30 A; H/N=1-163. DR PDB; 6OEO; EM; 3.69 A; N=1-163. DR PDB; 8I9M; EM; 5.19 A; A=89-163. DR PDB; 9CG9; EM; 2.94 A; K=1-215. DR PDBsum; 2LY4; -. DR PDBsum; 2RTU; -. DR PDBsum; 2YRQ; -. DR PDBsum; 6CG0; -. DR PDBsum; 6CIJ; -. DR PDBsum; 6CIK; -. DR PDBsum; 6CIL; -. DR PDBsum; 6CIM; -. DR PDBsum; 6OEM; -. DR PDBsum; 6OEN; -. DR PDBsum; 6OEO; -. DR PDBsum; 8I9M; -. DR PDBsum; 9CG9; -. DR AlphaFoldDB; P09429; -. DR BMRB; P09429; -. DR EMDB; EMD-20030; -. DR EMDB; EMD-20031; -. DR EMDB; EMD-20032; -. DR EMDB; EMD-35276; -. DR EMDB; EMD-45578; -. DR EMDB; EMD-7470; -. DR EMDB; EMD-7480; -. DR PCDDB; P09429; -. DR SMR; P09429; -. DR BioGRID; 109389; 481. DR CORUM; P09429; -. DR DIP; DIP-24195N; -. DR FunCoup; P09429; 1876. DR IntAct; P09429; 280. DR MINT; P09429; -. DR STRING; 9606.ENSP00000345347; -. DR BindingDB; P09429; -. DR ChEMBL; CHEMBL2311236; -. DR DrugBank; DB00608; Chloroquine. DR DrugBank; DB05869; Ethyl pyruvate. DR DrugCentral; P09429; -. DR GuidetoPHARMACOLOGY; 3279; -. DR MoonProt; P09429; -. DR GlyCosmos; P09429; 2 sites, 1 glycan. DR GlyGen; P09429; 6 sites, 3 N-linked glycans (2 sites), 1 O-linked glycan (3 sites). DR iPTMnet; P09429; -. DR MetOSite; P09429; -. DR PhosphoSitePlus; P09429; -. DR SwissPalm; P09429; -. DR BioMuta; HMGB1; -. DR DMDM; 123369; -. DR jPOST; P09429; -. DR MassIVE; P09429; -. DR PaxDb; 9606-ENSP00000345347; -. DR PeptideAtlas; P09429; -. DR ProteomicsDB; 52217; -. DR Pumba; P09429; -. DR TopDownProteomics; P09429; -. DR ABCD; P09429; 24 sequenced antibodies. DR Antibodypedia; 3132; 1697 antibodies from 47 providers. DR CPTC; P09429; 1 antibody. DR DNASU; 3146; -. DR Ensembl; ENST00000339872.8; ENSP00000343040.4; ENSG00000189403.16. DR Ensembl; ENST00000341423.10; ENSP00000345347.5; ENSG00000189403.16. DR Ensembl; ENST00000399494.5; ENSP00000382417.1; ENSG00000189403.16. DR Ensembl; ENST00000405805.5; ENSP00000384678.1; ENSG00000189403.16. DR GeneID; 3146; -. DR KEGG; hsa:3146; -. DR MANE-Select; ENST00000341423.10; ENSP00000345347.5; NM_002128.7; NP_002119.1. DR UCSC; uc001usx.5; human. DR AGR; HGNC:4983; -. DR ClinPGx; PA188; -. DR CTD; 3146; -. DR DisGeNET; 3146; -. DR GeneCards; HMGB1; -. DR HGNC; HGNC:4983; HMGB1. DR HPA; ENSG00000189403; Low tissue specificity. DR MalaCards; HMGB1; -. DR MIM; 163905; gene. DR OpenTargets; ENSG00000189403; -. DR VEuPathDB; HostDB:ENSG00000189403; -. DR eggNOG; KOG0381; Eukaryota. DR GeneTree; ENSGT00950000183120; -. DR InParanoid; P09429; -. DR OMA; PHSANEV; -. DR OrthoDB; 9484645at2759; -. DR PAN-GO; P09429; 2 GO annotations based on evolutionary models. DR PhylomeDB; P09429; -. DR PathwayCommons; P09429; -. DR Reactome; R-HSA-1236974; ER-Phagosome pathway. DR Reactome; R-HSA-140342; Apoptosis induced DNA fragmentation. DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane. DR Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation. DR Reactome; R-HSA-5602498; MyD88 deficiency (TLR2/4). DR Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4). DR Reactome; R-HSA-5620971; Pyroptosis. DR Reactome; R-HSA-5686938; Regulation of TLR by endogenous ligand. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-879415; Advanced glycosylation endproduct receptor signaling. DR Reactome; R-HSA-933542; TRAF6 mediated NF-kB activation. DR SignaLink; P09429; -. DR SIGNOR; P09429; -. DR Agora; ENSG00000189403; -. DR BioGRID-ORCS; 3146; 313 hits in 1115 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR ChiTaRS; HMGB1; human. DR EvolutionaryTrace; P09429; -. DR GeneWiki; HMGB1; -. DR GenomeRNAi; 3146; -. DR Pharos; P09429; Tchem. DR PRO; PR:P09429; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; P09429; protein. DR Bgee; ENSG00000189403; Expressed in ventricular zone and 181 other cell types or tissues. DR ExpressionAtlas; P09429; baseline and differential. DR GO; GO:0035868; C:alphav-beta3 integrin-HMGB1 complex; IDA:BHF-UCL. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0000793; C:condensed chromosome; IDA:UniProtKB. DR GO; GO:0005769; C:early endosome; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome. DR GO; GO:0043005; C:neuron projection; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0034774; C:secretory granule lumen; TAS:Reactome. DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB. DR GO; GO:0000405; F:bubble DNA binding; ISS:AgBase. DR GO; GO:0019958; F:C-X-C chemokine binding; IDA:UniProtKB. DR GO; GO:0010858; F:calcium-dependent protein kinase regulator activity; IEA:Ensembl. DR GO; GO:0042056; F:chemoattractant activity; ISS:UniProtKB. DR GO; GO:0005125; F:cytokine activity; ISS:UniProtKB. DR GO; GO:0003684; F:damaged DNA binding; IDA:UniProtKB. DR GO; GO:0008301; F:DNA binding, bending; IMP:UniProtKB. DR GO; GO:0070182; F:DNA polymerase binding; IDA:UniProtKB. DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0003690; F:double-stranded DNA binding; ISS:UniProtKB. DR GO; GO:0003725; F:double-stranded RNA binding; IEA:Ensembl. DR GO; GO:0000400; F:four-way junction DNA binding; ISS:AgBase. DR GO; GO:0005178; F:integrin binding; IDA:BHF-UCL. DR GO; GO:0001530; F:lipopolysaccharide binding; IDA:UniProtKB. DR GO; GO:0016829; F:lyase activity; IDA:UniProtKB. DR GO; GO:0001786; F:phosphatidylserine binding; IDA:UniProtKB. DR GO; GO:0030295; F:protein kinase activator activity; IEA:Ensembl. DR GO; GO:0050786; F:RAGE receptor binding; ISS:UniProtKB. DR GO; GO:0048018; F:receptor ligand activity; IDA:UniProt. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; ISS:UniProtKB. DR GO; GO:0003727; F:single-stranded RNA binding; IEA:Ensembl. DR GO; GO:0097100; F:supercoiled DNA binding; ISS:AgBase. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB. DR GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB. DR GO; GO:0002218; P:activation of innate immune response; IDA:UniProtKB. DR GO; GO:0043277; P:apoptotic cell clearance; IDA:UniProtKB. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0006284; P:base-excision repair; IEA:Ensembl. DR GO; GO:0098761; P:cellular response to interleukin-7; IEA:Ensembl. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISS:ARUK-UCL. DR GO; GO:0006338; P:chromatin remodeling; IBA:GO_Central. DR GO; GO:0002407; P:dendritic cell chemotaxis; ISS:UniProtKB. DR GO; GO:0032392; P:DNA geometric change; ISS:AgBase. DR GO; GO:0006310; P:DNA recombination; ISS:UniProtKB. DR GO; GO:0006265; P:DNA topological change; ISS:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB. DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; ISS:UniProtKB. DR GO; GO:0035767; P:endothelial cell chemotaxis; IEA:Ensembl. DR GO; GO:0001935; P:endothelial cell proliferation; IEA:Ensembl. DR GO; GO:0001654; P:eye development; IEA:Ensembl. DR GO; GO:0005980; P:glycogen catabolic process; IEA:Ensembl. DR GO; GO:0031507; P:heterochromatin formation; IGI:GO_Central. DR GO; GO:0006954; P:inflammatory response; IDA:CACAO. DR GO; GO:0002437; P:inflammatory response to antigenic stimulus; IEP:UniProtKB. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0030324; P:lung development; IEA:Ensembl. DR GO; GO:0002281; P:macrophage activation involved in immune response; IEA:Ensembl. DR GO; GO:0030099; P:myeloid cell differentiation; IEA:Ensembl. DR GO; GO:0001773; P:myeloid dendritic cell activation; ISS:UniProtKB. DR GO; GO:0002318; P:myeloid progenitor cell differentiation; IEA:Ensembl. DR GO; GO:2000426; P:negative regulation of apoptotic cell clearance; IDA:BHF-UCL. DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:CACAO. DR GO; GO:0043371; P:negative regulation of CD4-positive, alpha-beta T cell differentiation; IDA:UniProtKB. DR GO; GO:0017055; P:negative regulation of RNA polymerase II transcription preinitiation complex assembly; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0032689; P:negative regulation of type II interferon production; IDA:UniProtKB. DR GO; GO:0031175; P:neuron projection development; ISS:UniProtKB. DR GO; GO:0097350; P:neutrophil clearance; IDA:UniProtKB. DR GO; GO:0002270; P:plasmacytoid dendritic cell activation; IEA:Ensembl. DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; IMP:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB. DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IMP:BHF-UCL. DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IDA:CACAO. DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IDA:UniProtKB. DR GO; GO:2001200; P:positive regulation of dendritic cell differentiation; IMP:UniProtKB. DR GO; GO:0043388; P:positive regulation of DNA binding; IDA:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0045819; P:positive regulation of glycogen catabolic process; IEA:Ensembl. DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IEA:Ensembl. DR GO; GO:0032728; P:positive regulation of interferon-beta production; IEA:Ensembl. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl. DR GO; GO:0032732; P:positive regulation of interleukin-1 production; IDA:UniProtKB. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IDA:UniProtKB. DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IMP:UniProtKB. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:UniProtKB. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:CACAO. DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB. DR GO; GO:0032425; P:positive regulation of mismatch repair; IDA:UniProtKB. DR GO; GO:0071639; P:positive regulation of monocyte chemotactic protein-1 production; IEA:Ensembl. DR GO; GO:0090026; P:positive regulation of monocyte chemotaxis; IDA:UniProtKB. DR GO; GO:0045639; P:positive regulation of myeloid cell differentiation; IEA:Ensembl. DR GO; GO:1905455; P:positive regulation of myeloid progenitor cell differentiation; IEA:Ensembl. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:1903672; P:positive regulation of sprouting angiogenesis; IEA:Ensembl. DR GO; GO:0034137; P:positive regulation of toll-like receptor 2 signaling pathway; IEA:Ensembl. DR GO; GO:0034145; P:positive regulation of toll-like receptor 4 signaling pathway; IEA:Ensembl. DR GO; GO:0034165; P:positive regulation of toll-like receptor 9 signaling pathway; ISS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:UniProtKB. DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IMP:BHF-UCL. DR GO; GO:0046598; P:positive regulation of viral entry into host cell; IMP:UniProtKB. DR GO; GO:0090303; P:positive regulation of wound healing; IEA:Ensembl. DR GO; GO:2000819; P:regulation of nucleotide-excision repair; IEA:Ensembl. DR GO; GO:0032072; P:regulation of restriction endodeoxyribonuclease activity; IDA:UniProtKB. DR GO; GO:0002840; P:regulation of T cell mediated immune response to tumor cell; ISS:UniProtKB. DR GO; GO:0002643; P:regulation of tolerance induction; IDA:UniProtKB. DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl. DR GO; GO:0035711; P:T-helper 1 cell activation; IDA:UniProtKB. DR GO; GO:0045063; P:T-helper 1 cell differentiation; IMP:UniProtKB. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0033151; P:V(D)J recombination; IDA:UniProtKB. DR CDD; cd21978; HMG-box_HMGB_rpt1; 1. DR CDD; cd21979; HMG-box_HMGB_rpt2; 1. DR DisProt; DP01493; -. DR FunFam; 1.10.30.10:FF:000006; High mobility group protein B1; 1. DR FunFam; 1.10.30.10:FF:000015; high mobility group protein B1; 1. DR Gene3D; 1.10.30.10; High mobility group box domain; 2. DR IDEAL; IID00297; -. DR InterPro; IPR009071; HMG_box_dom. DR InterPro; IPR036910; HMG_box_dom_sf. DR InterPro; IPR017967; HMG_boxA_CS. DR InterPro; IPR050342; HMGB. DR PANTHER; PTHR48112:SF35; HIGH MOBILITY GROUP PROTEIN B1; 1. DR PANTHER; PTHR48112; HIGH MOBILITY GROUP PROTEIN DSP1; 1. DR Pfam; PF00505; HMG_box; 1. DR Pfam; PF09011; HMG_box_2; 1. DR PRINTS; PR00886; HIGHMOBLTY12. DR SMART; SM00398; HMG; 2. DR SUPFAM; SSF47095; HMG-box; 2. DR PROSITE; PS00353; HMG_BOX_1; 1. DR PROSITE; PS50118; HMG_BOX_2; 2. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Adaptive immunity; ADP-ribosylation; Autophagy; KW Cell membrane; Chemotaxis; Chromosome; Cytoplasm; KW Direct protein sequencing; Disulfide bond; DNA damage; DNA recombination; KW DNA repair; DNA-binding; Endoplasmic reticulum; Endosome; KW Host-virus interaction; Immunity; Inflammatory response; Innate immunity; KW Isopeptide bond; Membrane; Nucleus; Oxidation; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Secreted. FT CHAIN 1..215 FT /note="High mobility group protein B1" FT /id="PRO_0000048526" FT DNA_BIND 9..79 FT /note="HMG box 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00267" FT DNA_BIND 95..163 FT /note="HMG box 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00267" FT REGION 1..97 FT /note="Sufficient for interaction with HAVCR2" FT /evidence="ECO:0000250|UniProtKB:P63158" FT REGION 3..15 FT /note="LPS binding (delipidated)" FT /evidence="ECO:0000269|PubMed:21660935" FT REGION 76..95 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 80..96 FT /note="LPS binding (Lipid A)" FT /evidence="ECO:0000269|PubMed:21660935" FT REGION 89..108 FT /note="Cytokine-stimulating activity" FT /evidence="ECO:0000269|PubMed:12765338" FT REGION 150..183 FT /note="Binding to AGER/RAGE" FT /evidence="ECO:0000250|UniProtKB:P63159" FT REGION 161..215 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 27..43 FT /note="Nuclear localization signal (NLS) 1" FT /evidence="ECO:0000250|UniProtKB:P63159" FT MOTIF 178..184 FT /note="Nuclear localization signal (NLS) 2" FT /evidence="ECO:0000250|UniProtKB:P63159" FT COMPBIAS 83..94 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 161..179 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 187..215 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 1..10 FT /ligand="heparin" FT /ligand_id="ChEBI:CHEBI:28304" FT /evidence="ECO:0000250|UniProtKB:P10103" FT SITE 10..11 FT /note="Cleavage; by thrombin:thrombomodulin" FT /evidence="ECO:0000250|UniProtKB:P10103" FT SITE 67..68 FT /note="Cleavage; by CASP1" FT /evidence="ECO:0000269|PubMed:24474694" FT MOD_RES 3 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 7 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 8 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 12 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 23 FT /note="Cysteine sulfonic acid (-SO3H); alternate" FT /evidence="ECO:0000250|UniProtKB:P63159" FT MOD_RES 28 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 29 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 30 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 35 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 43 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P63158" FT MOD_RES 45 FT /note="Cysteine sulfonic acid (-SO3H); alternate" FT /evidence="ECO:0000250|UniProtKB:P63159" FT MOD_RES 90 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P63158" FT MOD_RES 100 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 106 FT /note="Cysteine sulfonic acid (-SO3H)" FT /evidence="ECO:0000250|UniProtKB:P63159" FT MOD_RES 127 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 128 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 141 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P63158" FT MOD_RES 172 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 173 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 177 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 180 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 181 FT /note="ADP-ribosylserine" FT /evidence="ECO:0000269|PubMed:28190768" FT MOD_RES 182 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 183 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 184 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT MOD_RES 185 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P10103" FT DISULFID 23..45 FT /note="In disulfide HMGB1; alternate" FT /evidence="ECO:0000250|UniProtKB:P63159" FT CROSSLNK 28 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT CROSSLNK 43 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT CROSSLNK 44 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT CROSSLNK 68 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT CROSSLNK 180 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT CROSSLNK 182 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT CROSSLNK 183 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT CROSSLNK 184 FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain FT with Q-?)" FT /evidence="ECO:0000269|PubMed:29618516" FT VARIANT 11 FT /note="G -> R (in gastric-carcinoma cell line)" FT /evidence="ECO:0000269|PubMed:9036861" FT /id="VAR_046451" FT VARIANT 149 FT /note="A -> E (in gastric-carcinoma cell line)" FT /evidence="ECO:0000269|PubMed:9036861" FT /id="VAR_046452" FT VARIANT 156 FT /note="E -> Q" FT /evidence="ECO:0000269|Ref.10" FT /id="VAR_046453" FT VARIANT 190 FT /note="D -> G (in gastric-carcinoma cell line)" FT /evidence="ECO:0000269|PubMed:9036861" FT /id="VAR_046454" FT MUTAGEN 35 FT /note="S->A: Greatly reduces phosphorylation, nuclear FT localization; when associated with A-39; A-42; A-46; A-53 FT and A-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 35 FT /note="S->E: Cytoplasmic localization (phosphorylation FT mimicking); when associated with E-39; E-42; E-46; E-53 and FT E-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 39 FT /note="S->A: Greatly reduces phosphorylation, nuclear FT localization; when associated with A-35; A-42; A-46; A-53 FT and A-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 39 FT /note="S->E: Cytoplasmic localization (phosphorylation FT mimicking); when associated with E-35; E-42; E-46; E-53 and FT E-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 42 FT /note="S->A: Greatly reduces phosphorylation, nuclear FT localization; when associated with A-35; A-39; A-46; A-53 FT and A-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 42 FT /note="S->E: Cytoplasmic localization (phosphorylation FT mimicking); when associated with E-35; E-39; E-46; E-53 and FT E-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 46 FT /note="S->A: Greatly reduces phosphorylation, nuclear FT localization; when associated with A-35; A-39; A-42; A-53 FT and A-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 46 FT /note="S->E: Cytoplasmic localization (phosphorylation FT mimicking); when associated with E-35; E-39; E-42; E-53 and FT E-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 53 FT /note="S->A: Greatly reduces phosphorylation, nuclear FT localization; when associated with A-35; A-39; A-42; A-46 FT and A-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 53 FT /note="S->E: Cytoplasmic localization (phosphorylation FT mimicking); when associated with E-35; E-39; E-42; E-46 and FT E-181." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 67 FT /note="D->A: Abolishes cleavage by CASP1 and impairs FT ability to antagonize apoptosis-induced immune tolerance." FT /evidence="ECO:0000269|PubMed:24474694" FT MUTAGEN 106 FT /note="C->S: Inhibits oxidation-dependent inactivation of FT immunostimmulatory activity in apoptotic cells." FT /evidence="ECO:0000269|PubMed:18631454" FT MUTAGEN 181 FT /note="S->A: Greatly reduces phosphorylation, nuclear FT localization; when associated with A-35; A-39; A-42; A-46 FT and A-53." FT /evidence="ECO:0000269|PubMed:17114460" FT MUTAGEN 181 FT /note="S->E: Cytoplasmic localization (phosphorylation FT mimicking); when associated with E-35; E-39; E-42; E-46 and FT E-53." FT /evidence="ECO:0000269|PubMed:17114460" FT CONFLICT 143 FT /note="P -> H (in Ref. 13; AAI41845)" FT /evidence="ECO:0000305" FT CONFLICT 215 FT /note="E -> D (in Ref. 8; CAG33144)" FT /evidence="ECO:0000305" FT STRAND 1..3 FT /evidence="ECO:0007829|PDB:2YRQ" FT STRAND 6..8 FT /evidence="ECO:0007829|PDB:2YRQ" FT HELIX 20..30 FT /evidence="ECO:0007829|PDB:6CIK" FT STRAND 31..33 FT /evidence="ECO:0007829|PDB:6CIK" FT HELIX 38..47 FT /evidence="ECO:0007829|PDB:6CIK" FT HELIX 54..76 FT /evidence="ECO:0007829|PDB:2LY4" FT STRAND 92..94 FT /evidence="ECO:0007829|PDB:2YRQ" FT HELIX 101..116 FT /evidence="ECO:0007829|PDB:6CIK" FT STRAND 118..120 FT /evidence="ECO:0007829|PDB:2YRQ" FT HELIX 122..135 FT /evidence="ECO:0007829|PDB:6CIK" FT HELIX 138..140 FT /evidence="ECO:0007829|PDB:2YRQ" FT HELIX 142..157 FT /evidence="ECO:0007829|PDB:6CIK" SQ SEQUENCE 215 AA; 24894 MW; 8A868CF277D417B5 CRC64; MGKGDPKKPR GKMSSYAFFV QTCREEHKKK HPDASVNFSE FSKKCSERWK TMSAKEKGKF EDMAKADKAR YEREMKTYIP PKGETKKKFK DPNAPKRPPS AFFLFCSEYR PKIKGEHPGL SIGDVAKKLG EMWNNTAADD KQPYEKKAAK LKEKYEKDIA AYRAKGKPDA AKKGVVKAEK SKKKKEEEED EEDEEDEEEE EDEEDEDEEE DDDDE // ID SORL_HUMAN Reviewed; 2214 AA. AC Q92673; B2RNX7; Q92856; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 28-JAN-2026, entry version 232. DE RecName: Full=Sortilin-related receptor; DE AltName: Full=Low-density lipoprotein receptor relative with 11 ligand-binding repeats; DE Short=LDLR relative with 11 ligand-binding repeats; DE Short=LR11 {ECO:0000303|PubMed:14764453}; DE AltName: Full=SorLA-1 {ECO:0000303|PubMed:8940146}; DE AltName: Full=Sorting protein-related receptor containing LDLR class A repeats; DE Short=SorLA {ECO:0000303|PubMed:16531402}; DE Flags: Precursor; GN Name=SORL1; Synonyms=C11orf32; 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], VARIANTS GLU-1074 AND ILE-1967, AND TISSUE RP SPECIFICITY. RC TISSUE=Brain; RX PubMed=9157966; DOI=10.1161/01.atv.17.5.996; RA Morwald S., Yamazaki H., Bujo H., Kusunoki J., Kanaki T., Seimiya K., RA Morisaki N., Nimpf J., Schneider W.J., Saito Y.; RT "A novel mosaic protein containing LDL receptor elements is highly RT conserved in humans and chickens."; RL Arterioscler. Thromb. Vasc. Biol. 17:996-1002(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 82-91; 114-121; 405-415 AND RP 2019-2030, VARIANTS GLU-1074 AND ILE-1967, TISSUE SPECIFICITY, AND RP INTERACTION WITH LRPAP1. RC TISSUE=Brain; RX PubMed=8940146; DOI=10.1074/jbc.271.49.31379; RA Jacobsen L., Madsen P., Moestrup S.K., Lund A.H., Tommerup N., Nykjaer A., RA Sottrup-Jensen L., Gliemann J., Petersen C.M.; RT "Molecular characterization of a novel human hybrid-type receptor that RT binds the alpha2-macroglobulin receptor-associated protein."; RL J. Biol. Chem. 271:31379-31383(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS GLU-1074 AND RP ILE-1967. 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 MRNA], AND VARIANTS GLU-1074 AND ILE-1967. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP INTERACTION WITH HA, INDUCTION BY HA, SUBCELLULAR LOCATION, AND CLEAVAGE OF RP THE PROPEPTIDE. RX PubMed=11082041; DOI=10.1242/jcs.113.24.4475; RA Hampe W., Riedel I.B., Lintzel J., Bader C.O., Franke I., Schaller H.C.; RT "Ectodomain shedding, translocation and synthesis of SorLA are stimulated RT by its ligand head activator."; RL J. Cell Sci. 113:4475-4485(2000). RN [7] RP PROTEIN SEQUENCE OF 82-86, CLEAVAGE OF THE PROPEPTIDE, INTERACTION WITH HA; RP LRPAP1; NTS AND PROPEPTIDE, SUBCELLULAR LOCATION, GLYCOSYLATION, AND RP MUTAGENESIS OF 78-ARG--ARG-81. RX PubMed=11294867; DOI=10.1074/jbc.m100857200; RA Jacobsen L., Madsen P., Jacobsen C., Nielsen M.S., Gliemann J., RA Petersen C.M.; RT "Activation and functional characterization of the mosaic receptor RT SorLA/LR11."; RL J. Biol. Chem. 276:22788-22796(2001). RN [8] RP INTERACTION WITH HA; LRPAP1 AND PROPEPTIDE. RX PubMed=12530537; DOI=10.1515/bc.2002.193; RA Lintzel J., Franke I., Riedel I.B., Schaller H.C., Hampe W.; RT "Characterization of the VPS10 domain of SorLA/LR11 as binding site for the RT neuropeptide HA."; RL Biol. Chem. 383:1727-1733(2002). RN [9] RP INTERACTION WITH GGA1 AND GGA2. RX PubMed=11821067; DOI=10.1016/s0014-5793(01)03299-9; RA Jacobsen L., Madsen P., Nielsen M.S., Geraerts W.P.M., Gliemann J., RA Smit A.B., Petersen C.M.; RT "The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines RT minimum requirements for GGA binding."; RL FEBS Lett. 511:155-158(2002). RN [10] RP SUBCELLULAR LOCATION, AND INTERACTION WITH LRPAP1; PDGFB; PLAT; PLAU AND RP SERPINE1. RX PubMed=15053742; DOI=10.1042/bj20040149; RA Gliemann J., Hermey G., Nykjaer A., Petersen C.M., Jacobsen C., RA Andreasen P.A.; RT "The mosaic receptor sorLA/LR11 binds components of the plasminogen- RT activating system and platelet-derived growth factor-BB similarly to LRP1 RT (low-density lipoprotein receptor-related protein), but mediates slow RT internalization of bound ligand."; RL Biochem. J. 381:203-212(2004). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PLAUR. RX PubMed=14764453; DOI=10.1161/01.res.0000120862.79154.0f; RA Zhu Y., Bujo H., Yamazaki H., Ohwaki K., Jiang M., Hirayama S., Kanaki T., RA Shibasaki M., Takahashi K., Schneider W.J., Saito Y.; RT "LR11, an LDL receptor gene family member, is a novel regulator of smooth RT muscle cell migration."; RL Circ. Res. 94:752-758(2004). RN [12] RP INTERACTION WITH LRPAP1; GDNF AND PROPEPTIDE. RX PubMed=15364913; DOI=10.1074/jbc.m408873200; RA Westergaard U.B., Soerensen E.S., Hermey G., Nielsen M.S., Nykjaer A., RA Kirkegaard K., Jacobsen C., Gliemann J., Madsen P., Petersen C.M.; RT "Functional organization of the sortilin Vps10p domain."; RL J. Biol. Chem. 279:50221-50229(2004). RN [13] RP FUNCTION IN APP TRAFFICKING, SUBCELLULAR LOCATION, INTERACTION WITH APP, RP AND TISSUE SPECIFICITY. RX PubMed=16174740; DOI=10.1073/pnas.0503689102; RA Andersen O.M., Reiche J., Schmidt V., Gotthardt M., Spoelgen R., Behlke J., RA von Arnim C.A., Breiderhoff T., Jansen P., Wu X., Bales K.R., Cappai R., RA Masters C.L., Gliemann J., Mufson E.J., Hyman B.T., Paul S.M., Nykjaer A., RA Willnow T.E.; RT "Neuronal sorting protein-related receptor sorLA/LR11 regulates processing RT of the amyloid precursor protein."; RL Proc. Natl. Acad. Sci. U.S.A. 102:13461-13466(2005). RN [14] RP INTERACTION WITH PDGFB, SUBCELLULAR LOCATION, AND SHEDDING BY ADAM17. RX PubMed=16393139; DOI=10.1042/bj20051364; RA Hermey G., Sjoegaard S.S., Petersen C.M., Nykjaer A., Gliemann J.; RT "Tumour necrosis factor alpha-converting enzyme mediates ectodomain RT shedding of Vps10p-domain receptor family members."; RL Biochem. J. 395:285-293(2006). RN [15] RP SUBCELLULAR LOCATION, CLEAVAGE BY PSEN1, AND MUTAGENESIS OF RP 2163-ARG-ARG-2164. RX PubMed=16531402; DOI=10.1074/jbc.m601660200; RA Boehm C., Seibel N.M., Henkel B., Steiner H., Haass C., Hampe W.; RT "SorLA signaling by regulated intramembrane proteolysis."; RL J. Biol. Chem. 281:14547-14553(2006). RN [16] RP FUNCTION, AND INTERACTION WITH APP AND BACE1. RX PubMed=16407538; DOI=10.1523/jneurosci.3882-05.2006; RA Spoelgen R., von Arnim C.A., Thomas A.V., Peltan I.D., Koker M., Deng A., RA Irizarry M.C., Andersen O.M., Willnow T.E., Hyman B.T.; RT "Interaction of the cytosolic domains of sorLA/LR11 with the amyloid RT precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme."; RL J. Neurosci. 26:418-428(2006). RN [17] RP INTERACTION WITH APOA5. RX PubMed=17326667; DOI=10.1021/bi7000533; RA Nilsson S.K., Lookene A., Beckstead J.A., Gliemann J., Ryan R.O., RA Olivecrona G.; RT "Apolipoprotein A-V interaction with members of the low density lipoprotein RT receptor gene family."; RL Biochemistry 46:3896-3904(2007). RN [18] RP FUNCTION, INTERACTION WITH APP; GGA1 AND PACS1, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF 2190-ASP--ASP-2198 AND 2208-ASP--MET-2211. RX PubMed=17855360; DOI=10.1074/jbc.m705073200; RA Schmidt V., Sporbert A., Rohe M., Reimer T., Rehm A., Andersen O.M., RA Willnow T.E.; RT "SorLA/LR11 regulates processing of amyloid precursor protein via RT interaction with adaptors GGA and PACS-1."; RL J. Biol. Chem. 282:32956-32964(2007). RN [19] RP FUNCTION, INTERACTION WITH PACS1; AP-1 COMPLEX AND AP-2 COMPLEX, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 2172-PHE--TYR-2177; RP 2190-ASP--ALA-2214; 2190-ASP--ASP-2198; 2201-MET-ILE-2202 AND RP 2211-MET--ALA-2214. RX PubMed=17646382; DOI=10.1128/mcb.00815-07; RA Nielsen M.S., Gustafsen C., Madsen P., Nyengaard J.R., Hermey G., Bakke O., RA Mari M., Schu P., Pohlmann R., Dennes A., Petersen C.M.; RT "Sorting by the cytoplasmic domain of the amyloid precursor protein binding RT receptor SorLA."; RL Mol. Cell. Biol. 27:6842-6851(2007). RN [20] RP FUNCTION, AND INTERACTION WITH APOA5. RX PubMed=18603531; DOI=10.1074/jbc.m802721200; RA Nilsson S.K., Christensen S., Raarup M.K., Ryan R.O., Nielsen M.S., RA Olivecrona G.; RT "Endocytosis of apolipoprotein A-V by members of the low density RT lipoprotein receptor and the VPS10p domain receptor families."; RL J. Biol. Chem. 283:25920-25927(2008). RN [21] RP LACK OF ASSOCIATION WITH SUSCEPTIBILITY TO LATE-ONSET ALZHEIMER DISEASE. RX PubMed=18562096; DOI=10.1016/j.neulet.2008.05.082; RA Minster R.L., DeKosky S.T., Kamboh M.I.; RT "No association of SORL1 SNPs with Alzheimer's disease."; RL Neurosci. Lett. 440:190-192(2008). RN [22] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-99; ASN-1733; ASN-2010; RP ASN-2076 AND ASN-2092. 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 [23] RP INTERACTION WITH STK39. RX PubMed=20385770; DOI=10.1128/mcb.01560-09; RA Reiche J., Theilig F., Rafiqi F.H., Carlo A.S., Militz D., Mutig K., RA Todiras M., Christensen E.I., Ellison D.H., Bader M., Nykjaer A., RA Bachmann S., Alessi D., Willnow T.E.; RT "SORLA/SORL1 functionally interacts with SPAK to control renal activation RT of Na(+)-K(+)-Cl(-) cotransporter 2."; RL Mol. Cell. Biol. 30:3027-3037(2010). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114, 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 [25] RP INVOLVEMENT IN AD. RX PubMed=21220680; DOI=10.1001/archneurol.2010.346; RG Genetic and Environmental Risk in Alzheimer Disease 1 Consortium; RA Reitz C., Cheng R., Rogaeva E., Lee J.H., Tokuhiro S., Zou F., Bettens K., RA Sleegers K., Tan E.K., Kimura R., Shibata N., Arai H., Kamboh M.I., RA Prince J.A., Maier W., Riemenschneider M., Owen M., Harold D., RA Hollingworth P., Cellini E., Sorbi S., Nacmias B., Takeda M., RA Pericak-Vance M.A., Haines J.L., Younkin S., Williams J., RA van Broeckhoven C., Farrer L.A., St George-Hyslop P.H., Mayeux R.; RT "Meta-analysis of the association between variants in SORL1 and Alzheimer RT disease."; RL Arch. Neurol. 68:99-106(2011). RN [26] RP PHOSPHORYLATION AT SER-2206, INTERACTION WITH ROCK2, AND TISSUE RP SPECIFICITY. RX PubMed=21147781; DOI=10.1074/jbc.m110.167239; RA Herskowitz J.H., Seyfried N.T., Gearing M., Kahn R.A., Peng J., Levey A.I., RA Lah J.J.; RT "Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA RT alters amyloid-beta production."; RL J. Biol. Chem. 286:6117-6127(2011). RN [27] RP FUNCTION, INTERACTION WITH GDNF, AND SUBCELLULAR LOCATION. RX PubMed=21994944; DOI=10.1074/jbc.m111.246413; RA Geng Z., Xu F.Y., Huang S.H., Chen Z.Y.; RT "Sorting protein-related receptor SorLA controls regulated secretion of RT glial cell line-derived neurotrophic factor."; RL J. Biol. Chem. 286:41871-41882(2011). RN [28] RP FUNCTION, INTERACTION WITH LPL, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP AND MUTAGENESIS OF 2211-MET--ALA-2214. RX PubMed=21385844; DOI=10.1242/jcs.072538; RA Klinger S.C., Glerup S., Raarup M.K., Mari M.C., Nyegaard M., Koster G., RA Prabakaran T., Nilsson S.K., Kjaergaard M.M., Bakke O., Nykjaer A., RA Olivecrona G., Petersen C.M., Nielsen M.S.; RT "SorLA regulates the activity of lipoprotein lipase by intracellular RT trafficking."; RL J. Cell Sci. 124:1095-1105(2011). RN [29] RP FUNCTION, INTERACTION WITH GDNF; GFRA1; GFRA2; GFRA3 AND GFRA4, AND RP SUBCELLULAR LOCATION. RX PubMed=23333276; DOI=10.1016/j.celrep.2012.12.011; RA Glerup S., Lume M., Olsen D., Nyengaard J.R., Vaegter C.B., Gustafsen C., RA Christensen E.I., Kjolby M., Hay-Schmidt A., Bender D., Madsen P., RA Saarma M., Nykjaer A., Petersen C.M.; RT "SorLA controls neurotrophic activity by sorting of GDNF and its receptors RT GFRalpha1 and RET."; RL Cell Rep. 3:186-199(2013). RN [30] RP FUNCTION, INTERACTION WITH PLAUR, AND INDUCTION BY HYPOXIA. RX PubMed=23486467; DOI=10.1074/jbc.m112.442491; RA Nishii K., Nakaseko C., Jiang M., Shimizu N., Takeuchi M., Schneider W.J., RA Bujo H.; RT "The soluble form of LR11 protein is a regulator of hypoxia-induced, RT urokinase-type plasminogen activator receptor (uPAR)-mediated adhesion of RT immature hematological cells."; RL J. Biol. Chem. 288:11877-11886(2013). RN [31] RP INVOLVEMENT IN AD. RX PubMed=23565137; DOI=10.1371/journal.pone.0058618; RG Alzheimer Disease Genetics Consortium; RA Miyashita A., Koike A., Jun G., Wang L.S., Takahashi S., Matsubara E., RA Kawarabayashi T., Shoji M., Tomita N., Arai H., Asada T., Harigaya Y., RA Ikeda M., Amari M., Hanyu H., Higuchi S., Ikeuchi T., Nishizawa M., RA Suga M., Kawase Y., Akatsu H., Kosaka K., Yamamoto T., Imagawa M., RA Hamaguchi T., Yamada M., Moriaha T., Takeda M., Takao T., Nakata K., RA Fujisawa Y., Sasaki K., Watanabe K., Nakashima K., Urakami K., Ooya T., RA Takahashi M., Yuzuriha T., Serikawa K., Yoshimoto S., Nakagawa R., RA Kim J.W., Ki C.S., Won H.H., Na D.L., Seo S.W., Mook-Jung I., RA St George-Hyslop P., Mayeux R., Haines J.L., Pericak-Vance M.A., RA Yoshida M., Nishida N., Tokunaga K., Yamamoto K., Tsuji S., Kanazawa I., RA Ihara Y., Schellenberg G.D., Farrer L.A., Kuwano R.; RT "SORL1 is genetically associated with late-onset Alzheimer's disease in RT Japanese, Koreans and Caucasians."; RL PLoS ONE 8:E58618-E58618(2013). RN [32] RP FUNCTION. RX PubMed=23977241; DOI=10.1371/journal.pone.0072164; RA Rohe M., Hartl D., Fjorback A.N., Klose J., Willnow T.E.; RT "SORLA-mediated trafficking of TrkB enhances the response of neurons to RT BDNF."; RL PLoS ONE 8:E72164-E72164(2013). RN [33] 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 [34] RP FUNCTION, INTERACTION WITH APP AND PROPEPTIDE, AND CHARACTERIZATION OF RP VARIANT AD ARG-511. RX PubMed=24523320; DOI=10.1126/scitranslmed.3007747; RA Caglayan S., Takagi-Niidome S., Liao F., Carlo A.S., Schmidt V., RA Burgert T., Kitago Y., Fuechtbauer E.M., Fuechtbauer A., Holtzman D.M., RA Takagi J., Willnow T.E.; RT "Lysosomal sorting of amyloid-beta by the SORLA receptor is impaired by a RT familial Alzheimer's disease mutation."; RL Sci. Transl. Med. 6:223RA20-223RA20(2014). RN [35] RP POTENTIAL ASSOCIATION WITH BODY MASS INDEX. RX PubMed=26584636; DOI=10.1038/ncomms9951; RA Whittle A.J., Jiang M., Peirce V., Relat J., Virtue S., Ebinuma H., RA Fukamachi I., Yamaguchi T., Takahashi M., Murano T., Tatsuno I., RA Takeuchi M., Nakaseko C., Jin W., Jin Z., Campbell M., Schneider W.J., RA Vidal-Puig A., Bujo H.; RT "Soluble LR11/SorLA represses thermogenesis in adipose tissue and RT correlates with BMI in humans."; RL Nat. Commun. 6:8951-8951(2015). RN [36] RP FUNCTION, INTERACTION WITH INSR, AND POTENTIAL ASSOCIATION WITH BODY MASS RP INDEX. RX PubMed=27322061; DOI=10.1172/jci84708; RA Schmidt V., Schulz N., Yan X., Schuermann A., Kempa S., Kern M., RA Blueher M., Poy M.N., Olivecrona G., Willnow T.E.; RT "SORLA facilitates insulin receptor signaling in adipocytes and exacerbates RT obesity."; RL J. Clin. Invest. 126:2706-2720(2016). RN [37] RP FUNCTION, AND INTERACTION WITH CLCF1; CRLF1; CNTFR AND LRPAP1. RX PubMed=26858303; DOI=10.1128/mcb.00917-15; RA Larsen J.V., Kristensen A.M., Pallesen L.T., Bauer J., Vaegter C.B., RA Nielsen M.S., Madsen P., Petersen C.M.; RT "Cytokine-like factor 1, an essential facilitator of cardiotrophin-like RT cytokine:ciliary neurotrophic factor receptor alpha signaling and sorLA- RT mediated turnover."; RL Mol. Cell. Biol. 36:1272-1286(2016). RN [38] RP FUNCTION, INTERACTION WITH IL6 AND IL6R, AND SHEDDING FROM THE CELL RP SURFACE. RX PubMed=28265003; DOI=10.1128/mcb.00641-16; RA Larsen J.V., Petersen C.M.; RT "SorLA in Interleukin-6 Signaling and Turnover."; RL Mol. Cell. Biol. 37:0-0(2017). RN [39] RP INTERACTION WITH APOE. RX PubMed=30448281; DOI=10.1016/j.cca.2018.11.024; RA Yano K., Hirayama S., Misawa N., Furuta A., Ueno T., Motoi Y., Seino U., RA Ebinuma H., Ikeuchi T., Schneider W.J., Bujo H., Miida T.; RT "Soluble LR11 competes with amyloid beta in binding to cerebrospinal fluid- RT high-density lipoprotein."; RL Clin. Chim. Acta 489:29-34(2019). RN [40] RP FUNCTION, INTERACTION WITH ERBB2, AND SUBCELLULAR LOCATION. RX PubMed=31138794; DOI=10.1038/s41467-019-10275-0; RA Pietilae M., Sahgal P., Peuhu E., Jaentti N.Z., Paatero I., Naervae E., RA Al-Akhrass H., Lilja J., Georgiadou M., Andersen O.M., Padzik A., Sihto H., RA Joensuu H., Blomqvist M., Saarinen I., Bostroem P.J., Taimen P., Ivaska J.; RT "SORLA regulates endosomal trafficking and oncogenic fitness of HER2."; RL Nat. Commun. 10:2340-2340(2019). RN [41] RP INTERACTION WITH GGA1 AND HSPA12A, AND MUTAGENESIS OF 2190-ASP-ASP-2191; RP 2194-GLU--ASP-2198; 2203-THR-GLY-2204; 2205-PHE-SER-2206; 2207-ASP-ASP-2208 RP AND 2209-VAL-PRO-2210. RX PubMed=30679749; DOI=10.1038/s41598-018-37336-6; RA Madsen P., Isaksen T.J., Siupka P., Toth A.E., Nyegaard M., Gustafsen C., RA Nielsen M.S.; RT "HSPA12A targets the cytoplasmic domain and affects the trafficking of the RT Amyloid Precursor Protein receptor SorLA."; RL Sci. Rep. 9:611-611(2019). RN [42] RP STRUCTURE BY NMR OF 1651-1745. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the second FN3 domain of human SORLA/LR11."; RL Submitted (OCT-2006) to the PDB data bank. RN [43] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 2202-2214 IN COMPLEX WITH GGA1, RP AND INTERACTION WITH GGA1. RX PubMed=20015111; DOI=10.1111/j.1600-0854.2009.01017.x; RA Cramer J.F., Gustafsen C., Behrens M.A., Oliveira C.L., Pedersen J.S., RA Madsen P., Petersen C.M., Thirup S.S.; RT "GGA autoinhibition revisited."; RL Traffic 11:259-273(2010). RN [44] RP VARIANTS [LARGE SCALE ANALYSIS] SER-120; LEU-1581 AND VAL-1972. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [45] RP POSSIBLE ASSOCIATION WITH SUSCEPTIBILITY TO LATE-ONSET ALZHEIMER DISEASE, RP AND VARIANT THR-528. RX PubMed=18407551; DOI=10.1002/humu.20725; RA Bettens K., Brouwers N., Engelborghs S., De Deyn P.P., Van Broeckhoven C., RA Sleegers K.; RT "SORL1 is genetically associated with increased risk for late-onset RT Alzheimer disease in the Belgian population."; RL Hum. Mutat. 29:769-770(2008). RN [46] RP VARIANTS AD CYS-141; ARG-511; SER-924; SER-1358 AND ASP-1681. RX PubMed=22472873; DOI=10.1038/mp.2012.15; RG PHRC GMAJ Collaborators; RA Pottier C., Hannequin D., Coutant S., Rovelet-Lecrux A., Wallon D., RA Rousseau S., Legallic S., Paquet C., Bombois S., Pariente J., RA Thomas-Anterion C., Michon A., Croisile B., Etcharry-Bouyx F., Berr C., RA Dartigues J.F., Amouyel P., Dauchel H., Boutoleau-Bretonniere C., RA Thauvin C., Frebourg T., Lambert J.C., Campion D.; RT "High frequency of potentially pathogenic SORL1 mutations in autosomal RT dominant early-onset Alzheimer disease."; RL Mol. Psychiatry 17:875-879(2012). CC -!- FUNCTION: Sorting receptor that directs several proteins to their CC correct location within the cell (Probable). Along with AP-1 complex, CC involved Golgi apparatus - endosome sorting (PubMed:17646382). Sorting CC receptor for APP, regulating its intracellular trafficking and CC processing into amyloidogenic-beta peptides. Retains APP in the trans- CC Golgi network, hence preventing its transit through late endosomes CC where amyloid beta peptides Abeta40 and Abeta42 are generated CC (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320). CC May also sort newly produced amyloid-beta peptides to lysosomes for CC catabolism (PubMed:24523320). Does not affect APP trafficking from the CC endoplasmic reticulum to Golgi compartments (PubMed:17855360). Sorting CC receptor for the BDNF receptor NTRK2/TRKB that facilitates NTRK2 CC trafficking between synaptic plasma membranes, postsynaptic densities CC and cell soma, hence positively regulates BDNF signaling by controlling CC the intracellular location of its receptor (PubMed:23977241). Sorting CC receptor for GDNF that promotes GDNF regulated, but not constitutive CC secretion (PubMed:21994944). Sorting receptor for the GDNF-GFRA1 CC complex, directing it from the cell surface to endosomes. GDNF is then CC targeted to lysosomes and degraded, while its receptor GFRA1 recycles CC back to the cell membrane, resulting in a GDNF clearance pathway. The CC SORL1-GFRA1 complex further targets RET for endocytosis, but not for CC degradation, affecting GDNF-induced neurotrophic activities CC (PubMed:23333276). Sorting receptor for ERBB2/HER2. Regulates ERBB2 CC subcellular distribution by promoting its recycling after CC internalization from endosomes back to the plasma membrane, hence CC stimulating phosphoinositide 3-kinase (PI3K)-dependent ERBB2 signaling. CC In ERBB2-dependent cancer cells, promotes cell proliferation CC (PubMed:31138794). Sorting receptor for lipoprotein lipase LPL. CC Promotes LPL localization to endosomes and later to the lysosomes, CC leading to degradation of newly synthesized LPL (PubMed:21385844). CC Potential sorting receptor for APOA5, inducing APOA5 internalization to CC early endosomes, then to late endosomes, wherefrom a portion is sent to CC lysosomes and degradation, another portion is sorted to the trans-Golgi CC network (PubMed:18603531). Sorting receptor for the insulin receptor CC INSR. Promotes recycling of internalized INSR via the Golgi apparatus CC back to the cell surface, thereby preventing lysosomal INSR catabolism, CC increasing INSR cell surface expression and strengthening insulin CC signal reception in adipose tissue. Does not affect INSR CC internalization (PubMed:27322061). Plays a role in renal ion CC homeostasis, controlling the phospho-regulation of SLC12A1/NKCC2 by CC STK39/SPAK kinase and PPP3CB/calcineurin A beta phosphatase, possibly CC through intracellular sorting of STK39 and PPP3CB (By similarity). CC Stimulates, via the N-terminal ectodomain, the proliferation and CC migration of smooth muscle cells, possibly by increasing cell surface CC expression of the urokinase receptor uPAR/PLAUR. This may promote CC extracellular matrix proteolysis and hence facilitate cell migration CC (PubMed:14764453). By acting on the migration of intimal smooth muscle CC cells, may accelerate intimal thickening following vascular injury CC (PubMed:14764453). Promotes adhesion of monocytes (PubMed:23486467). CC Stimulates proliferation and migration of monocytes/macrophages (By CC similarity). Through its action on intimal smooth muscle cells and CC macrophages, may accelerate intimal thickening and macrophage foam cell CC formation in the process of atherosclerosis (By similarity). Regulates CC hypoxia-enhanced adhesion of hematopoietic stem and progenitor cells to CC the bone marrow stromal cells via a PLAUR-mediated pathway. This CC function is mediated by the N-terminal ectodomain (PubMed:23486467). CC Metabolic regulator, which functions to maintain the adequate balance CC between lipid storage and oxidation in response to changing CC environmental conditions, such as temperature and diet. The N-terminal CC ectodomain negatively regulates adipose tissue energy expenditure, CC acting through the inhibition the BMP/Smad pathway (By similarity). May CC regulate signaling by the heterodimeric neurotrophic cytokine CLCF1- CC CRLF1 bound to the CNTFR receptor by promoting the endocytosis of the CC tripartite complex CLCF1-CRLF1-CNTFR and lysosomal degradation CC (PubMed:26858303). May regulate IL6 signaling, decreasing cis CC signaling, possibly by interfering with IL6-binding to membrane-bound CC IL6R, while up-regulating trans signaling via soluble IL6R CC (PubMed:28265003). {ECO:0000250|UniProtKB:O88307, CC ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:16407538, ECO:0000269|PubMed:17646382, CC ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:18603531, CC ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:21994944, CC ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:23486467, CC ECO:0000269|PubMed:23977241, ECO:0000269|PubMed:24523320, CC ECO:0000269|PubMed:26858303, ECO:0000269|PubMed:27322061, CC ECO:0000269|PubMed:28265003, ECO:0000269|PubMed:31138794, ECO:0000305}. CC -!- SUBUNIT: After maturation cleavage, interacts (via N-terminus) with its CC own propeptide; this interaction prevents interaction with other CC ligands, including CRLF1, GDNF, GFRA1, IL6 and IL6R (PubMed:11294867, CC PubMed:12530537, PubMed:15364913, PubMed:23333276, PubMed:24523320). CC Interacts (via N-terminal ectodomain) with APP, forming a 1:1 CC stoichiometric complex, including with isoforms APP695, APP751 and CC APP770; this interaction retains APP in the trans-Golgi network and CC reduces processing into soluble APP-alpha and amyloid-beta peptides CC (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320). CC Also interacts with APP C-terminal fragment C99 and with Abeta40 CC (PubMed:16407538). Interacts with beta-secretase BACE1/BACE; this CC interaction may affect BACE1-binding to APP and hence reduce BACE1- CC dependent APP cleavage (PubMed:16407538). Interacts with LRPAP1/RAP CC (PubMed:11294867, PubMed:12530537, PubMed:14764453, PubMed:15053742, CC PubMed:15364913, PubMed:26858303, PubMed:8940146). Interacts (via C- CC terminal cytosolic domain) with GGA1 and GGA2 (via N-terminal VHS CC domain) (PubMed:11821067, PubMed:17855360, PubMed:20015111, CC PubMed:30679749). Interacts with PACS1 (PubMed:17646382, CC PubMed:17855360). May interact (via the N-terminal ectodomain) with the CC morphogenetic neuropeptide, also called head activator or HA; this CC interaction is impaired in the presence of propeptide (PubMed:11082041, CC PubMed:11294867, PubMed:12530537). Interacts with neurotensin/NTS CC (PubMed:11294867). Interacts (via the N-terminal ectodomain) with PDGFB CC homodimer (PubMed:15053742, PubMed:16393139). Interacts (via N-terminal CC ectodomain) with the uPA receptor PLAUR; this interaction decreases CC PLAUR internalization (PubMed:14764453, PubMed:23486467). Interacts CC (via N-terminal ectodomain) with uPA/PLAU and PAI1/SERPINE1, either CC individually or in complex with each other, leading to endocytosis; CC this interaction is abolished in the presence of LRPAP1 CC (PubMed:15053742). Also interacts with the ternary complex composed of CC PLAUR-PLAU-PAI1 (PubMed:15053742). Also interacts with tPA/PLAT either CC alone or in complex with SERPINE1 (PubMed:15053742). Interacts (via C- CC terminus) with AP-1 and AP-2 complexes (PubMed:17646382). Interacts CC with BMPR1A and BMPR1B (By similarity). Interacts with lipoprotein CC lipase LPL; this interaction is optimal in slightly acidic conditions CC (PubMed:21385844). Interacts (via N-terminal ectodomain) with GDNF (via CC propeptide) and GDNF receptor alpha-1/GFRA1, either individually or in CC complex with each other (PubMed:15364913, PubMed:21994944, CC PubMed:23333276). The interaction with GDNF occurs mostly CC intracellularly (PubMed:21994944). Also interacts with other GDNF CC receptor alpha family members, including GFRA2, GFRA3 and GFRA4 CC (PubMed:23333276). Interacts with the insulin receptor INSR; this CC interaction strongly increases the surface exposure of INSR CC (PubMed:27322061). Interacts (via cytosolic C-terminus) with STK39/SPAK CC (PubMed:20385770). Interacts (via N-terminal ectodomain) with the CC heterodimeric complex CRLF1-CLC; within this complex, the interaction CC is mediated predominantly by the CRLF1 moiety (PubMed:26858303). CC Interacts with CNTFR, as well as with the tripartite signaling complex CC formed by CRLF1, CLC and CNTFR (PubMed:26858303). Interacts (via N- CC terminal ectodomain) with IL6; this interaction leads to IL6 CC internalization and lysosomal degradation (PubMed:28265003). Binding of CC SOLRL1 secreted N-terminal ectodomain to IL6 may increase IL6 trans CC signaling (PubMed:28265003). Interacts with secreted IL6R; this CC interaction leads to IL6R internalization (PubMed:28265003). Also CC interacts with transmembrane IL6R; this interaction does not affect CC IL6R subcellular location (PubMed:28265003). Interacts with APOE CC (PubMed:30448281). Interacts with apolipoprotein E-rich beta-VLDL (By CC similarity). Interacts with APOA5; this interaction leads to APOA5 CC internalization and is abolished by heparin (PubMed:17326667, CC PubMed:18603531). Interaction with APOA5 results in enhanced binding to CC chylomicrons (PubMed:17326667). Interacts with ROCK2 (PubMed:21147781). CC Interacts (via cytosolic C-terminus) with PPP3CB/calcineurin A beta (By CC similarity). Interacts with NTRK2/TRKB; this interaction facilitates CC NTRK2 trafficking between synaptic plasma membranes, postsynaptic CC densities and cell soma, hence positively regulates BDNF signaling (By CC similarity). Interacts (via cytosolic C-terminus) with HSPA12A in an CC ADP-dependent manner; this interaction affects SORL1 internalization CC and subcellular localization (PubMed:30679749). Interacts (via N- CC terminal ectodomain) with ERBB2/HER2 (PubMed:31138794). CC {ECO:0000250|UniProtKB:O88307, ECO:0000250|UniProtKB:Q95209, CC ECO:0000269|PubMed:11082041, ECO:0000269|PubMed:11294867, CC ECO:0000269|PubMed:11821067, ECO:0000269|PubMed:12530537, CC ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:15053742, CC ECO:0000269|PubMed:15364913, ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:16393139, ECO:0000269|PubMed:16407538, CC ECO:0000269|PubMed:17326667, ECO:0000269|PubMed:17646382, CC ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:18603531, CC ECO:0000269|PubMed:20015111, ECO:0000269|PubMed:20385770, CC ECO:0000269|PubMed:21147781, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, CC ECO:0000269|PubMed:23486467, ECO:0000269|PubMed:24523320, CC ECO:0000269|PubMed:26858303, ECO:0000269|PubMed:27322061, CC ECO:0000269|PubMed:28265003, ECO:0000269|PubMed:30448281, CC ECO:0000269|PubMed:30679749, ECO:0000269|PubMed:31138794, CC ECO:0000269|PubMed:8940146}. CC -!- INTERACTION: CC Q92673; P05067: APP; NbExp=5; IntAct=EBI-1171329, EBI-77613; CC Q92673; P05067-4: APP; NbExp=8; IntAct=EBI-1171329, EBI-302641; CC Q92673; PRO_0000000091 [P05067]: APP; NbExp=4; IntAct=EBI-1171329, EBI-3894543; CC Q92673; PRO_0000000093 [P05067]: APP; NbExp=3; IntAct=EBI-1171329, EBI-2431589; CC Q92673; P83916: CBX1; NbExp=3; IntAct=EBI-1171329, EBI-78129; CC Q92673; P43681: CHRNA4; NbExp=3; IntAct=EBI-1171329, EBI-7132379; CC Q92673; P26992: CNTFR; NbExp=7; IntAct=EBI-1171329, EBI-743758; CC Q92673; O75462: CRLF1; NbExp=3; IntAct=EBI-1171329, EBI-15587902; CC Q92673; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-1171329, EBI-742054; CC Q92673; P20042: EIF2S2; NbExp=3; IntAct=EBI-1171329, EBI-711977; CC Q92673; PRO_0000034005 [P39905]: GDNF; NbExp=6; IntAct=EBI-1171329, EBI-25397146; CC Q92673; P56159-2: GFRA1; NbExp=3; IntAct=EBI-1171329, EBI-15854635; CC Q92673; Q9UJY5: GGA1; NbExp=5; IntAct=EBI-1171329, EBI-447141; CC Q92673; Q9UJY4: GGA2; NbExp=6; IntAct=EBI-1171329, EBI-447646; CC Q92673; O43301: HSPA12A; NbExp=5; IntAct=EBI-1171329, EBI-296980; CC Q92673; P05231: IL6; NbExp=4; IntAct=EBI-1171329, EBI-720533; CC Q92673; P08887: IL6R; NbExp=7; IntAct=EBI-1171329, EBI-299383; CC Q92673; Q92993: KAT5; NbExp=3; IntAct=EBI-1171329, EBI-399080; CC Q92673; P30533: LRPAP1; NbExp=5; IntAct=EBI-1171329, EBI-715927; CC Q92673; P19404: NDUFV2; NbExp=3; IntAct=EBI-1171329, EBI-713665; CC Q92673; P00491: PNP; NbExp=3; IntAct=EBI-1171329, EBI-712238; CC Q92673; P78424: POU6F2; NbExp=3; IntAct=EBI-1171329, EBI-12029004; CC Q92673; Q15669: RHOH; NbExp=3; IntAct=EBI-1171329, EBI-1244971; CC Q92673; PRO_0000033164 [Q92673]: SORL1; NbExp=9; IntAct=EBI-1171329, EBI-25298876; CC Q92673; Q8N0S8: VPS29; NbExp=3; IntAct=EBI-1171329, EBI-25892084; CC Q92673; Q62997: Gfra1; Xeno; NbExp=5; IntAct=EBI-1171329, EBI-25397991; CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane CC {ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:21994944}; Single-pass type I membrane protein CC {ECO:0000305}. Golgi apparatus, trans-Golgi network membrane CC {ECO:0000269|PubMed:17646382, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:23333276}; Single-pass type I membrane protein CC {ECO:0000305}. Endosome membrane {ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:23333276}; Single-pass type I membrane protein CC {ECO:0000305}. Early endosome membrane {ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:17646382, ECO:0000269|PubMed:21385844, CC ECO:0000269|PubMed:31138794}; Single-pass type I membrane protein CC {ECO:0000305}. Recycling endosome membrane CC {ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:31138794}; Single-pass CC type I membrane protein {ECO:0000305}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:21385844}; Single-pass CC type I membrane protein {ECO:0000305}. Endosome, multivesicular body CC membrane {ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:23333276}; CC Single-pass type I membrane protein {ECO:0000305}. Cell membrane CC {ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:14764453, CC ECO:0000269|PubMed:15053742, ECO:0000269|PubMed:17855360, CC ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:21994944, CC ECO:0000269|PubMed:31138794}; Single-pass type I membrane protein CC {ECO:0000305}. Cytoplasmic vesicle, secretory vesicle membrane CC {ECO:0000269|PubMed:21994944}; Single-pass type I membrane protein CC {ECO:0000305}. Secreted {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:15053742, CC ECO:0000269|PubMed:16393139, ECO:0000269|PubMed:16531402}. Note=Mostly CC intracellular, predominantly in the trans-Golgi network (TGN) and in CC endosome, as well as in endosome-to-TGN retrograde vesicles; found at CC low levels on the plasma membrane (PubMed:11294867, PubMed:15053742, CC PubMed:17855360, PubMed:21385844, PubMed:21994944, PubMed:31138794). At CC the cell surface, partially subjected to proteolytic shedding that CC releases the ectodomain (also called soluble SORLA, solLR11 or sLR11) CC in the extracellular milieu (PubMed:11082041, PubMed:16393139, CC PubMed:16531402). The shedding may be catalyzed by ADAM17/TACE CC (PubMed:16393139). Following shedding, PSEN1/presenilin-1 cleaves the CC remaining transmembrane fragment and catalyzes the release of a C- CC terminal fragment in the cytosol and of a soluble N-terminal beta CC fragment in the extracellular milieu. The C-terminal cytosolic fragment CC localizes to the nucleus (PubMed:16531402). At the cell surface, the CC full-length protein undergoes partial clathrin-dependent endocytosis CC guided by clathrin adapter protein 2 (AP-2) (PubMed:11294867, CC PubMed:15053742, PubMed:17646382). {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:15053742, CC ECO:0000269|PubMed:16393139, ECO:0000269|PubMed:16531402, CC ECO:0000269|PubMed:17646382, ECO:0000269|PubMed:17855360, CC ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:21994944, CC ECO:0000269|PubMed:31138794}. CC -!- TISSUE SPECIFICITY: Highly expressed in brain (at protein level) CC (PubMed:16174740, PubMed:21147781, PubMed:9157966). Most abundant in CC the cerebellum, cerebral cortex and occipital pole; low levels in the CC putamen and thalamus (PubMed:16174740, PubMed:9157966). Expression is CC significantly reduced in the frontal cortex of patients suffering from CC Alzheimer disease (PubMed:16174740). Also expressed in spinal cord, CC spleen, testis, prostate, ovary, thyroid and lymph nodes CC (PubMed:8940146, PubMed:9157966). {ECO:0000269|PubMed:16174740, CC ECO:0000269|PubMed:21147781, ECO:0000269|PubMed:8940146, CC ECO:0000269|PubMed:9157966}. CC -!- INDUCTION: Up-regulated by morphogenetic neuropeptide, also called head CC activator or HA (PubMed:11082041). Up-regulated under hypoxic CC conditions in hematopoietic stem and progenitor cells, a physiological CC condition encountered by these cells in the endosteum. This up- CC regulation may be mediated by HIF1A-induced transcription CC (PubMed:23486467). {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:23486467}. CC -!- PTM: Within the Golgi apparatus, the propeptide may be cleaved off by CC FURIN or a furin-like protease (Probable). After cleavage, the CC propeptide interacts with the mature protein N-terminus, preventing the CC association with other ligands (PubMed:11294867). At the cell surface, CC partially subjected to proteolytic shedding that releases the CC ectodomain in the extracellular milieu (PubMed:11082041, CC PubMed:16393139, PubMed:16531402, PubMed:28265003). The shedding may be CC catalyzed by ADAM17/TACE (PubMed:16393139, PubMed:16531402). Following CC shedding, PSEN1/presenilin-1 cleaves the remaining transmembrane CC fragment and catalyzes the release of a C-terminal fragment in the CC cytosol and of a soluble N-terminal beta fragment in the extracellular CC milieu. The C-terminal cytosolic fragment localizes to the nucleus CC (PubMed:16531402). {ECO:0000269|PubMed:11082041, CC ECO:0000269|PubMed:11294867, ECO:0000269|PubMed:16393139, CC ECO:0000269|PubMed:16531402, ECO:0000269|PubMed:28265003, CC ECO:0000305|PubMed:11082041, ECO:0000305|PubMed:11294867}. CC -!- PTM: Phosphorylation at Ser-2206 facilitates the interaction with GGA1. CC {ECO:0000269|PubMed:20015111}. CC -!- DISEASE: Alzheimer disease (AD) [MIM:104300]: Alzheimer disease is a CC neurodegenerative disorder characterized by progressive dementia, loss CC of cognitive abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:21220680, ECO:0000269|PubMed:22472873, CC ECO:0000269|PubMed:23565137, ECO:0000269|PubMed:24523320}. Note=The CC gene represented in this entry may be involved in disease pathogenesis. CC -!- MISCELLANEOUS: There may be a positive correlation of body mass index CC with levels of SORL1 transcript and SORLA protein in visceral adipose CC tissue. {ECO:0000269|PubMed:27322061}. CC -!- SIMILARITY: Belongs to the VPS10-related sortilin family. SORL1 CC subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y08110; CAA69325.1; -; mRNA. DR EMBL; U60975; AAC50891.2; -; mRNA. DR EMBL; AP000664; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP000977; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471065; EAW67525.1; -; Genomic_DNA. DR EMBL; BC137171; AAI37172.1; -; mRNA. DR CCDS; CCDS8436.1; -. DR RefSeq; NP_003096.2; NM_003105.6. DR PDB; 2DM4; NMR; -; A=1651-1745. DR PDB; 3G2S; X-ray; 1.70 A; C/D=2202-2214. DR PDB; 3G2T; X-ray; 2.00 A; C/D=2202-2214. DR PDB; 3WSX; X-ray; 2.35 A; A=29-753. DR PDB; 3WSY; X-ray; 3.11 A; A=86-753, C=42-56. DR PDB; 3WSZ; X-ray; 3.20 A; A=86-753. DR PDB; 7VT0; EM; 3.40 A; A/B=89-752. DR PDBsum; 2DM4; -. DR PDBsum; 3G2S; -. DR PDBsum; 3G2T; -. DR PDBsum; 3WSX; -. DR PDBsum; 3WSY; -. DR PDBsum; 3WSZ; -. DR PDBsum; 7VT0; -. DR AlphaFoldDB; Q92673; -. DR BMRB; Q92673; -. DR EMDB; EMD-32117; -. DR SMR; Q92673; -. DR BioGRID; 112536; 163. DR CORUM; Q92673; -. DR DIP; DIP-41229N; -. DR FunCoup; Q92673; 1351. DR IntAct; Q92673; 141. DR MINT; Q92673; -. DR STRING; 9606.ENSP00000260197; -. DR TCDB; 9.B.87.1.17; the selenoprotein p receptor (selp-receptor) family. DR GlyConnect; 1766; 17 N-Linked glycans (11 sites). DR GlyCosmos; Q92673; 35 sites, 18 glycans. DR GlyGen; Q92673; 45 sites, 94 N-linked glycans (19 sites), 5 O-linked glycans (10 sites). DR iPTMnet; Q92673; -. DR PhosphoSitePlus; Q92673; -. DR SwissPalm; Q92673; -. DR BioMuta; SORL1; -. DR DMDM; 296452912; -. DR jPOST; Q92673; -. DR MassIVE; Q92673; -. DR PaxDb; 9606-ENSP00000260197; -. DR PeptideAtlas; Q92673; -. DR ProteomicsDB; 75402; -. DR Pumba; Q92673; -. DR ABCD; Q92673; 1 sequenced antibody. DR Antibodypedia; 32786; 274 antibodies from 39 providers. DR DNASU; 6653; -. DR Ensembl; ENST00000260197.12; ENSP00000260197.6; ENSG00000137642.14. DR GeneID; 6653; -. DR KEGG; hsa:6653; -. DR MANE-Select; ENST00000260197.12; ENSP00000260197.6; NM_003105.6; NP_003096.2. DR UCSC; uc001pxx.4; human. DR AGR; HGNC:11185; -. DR ClinPGx; PA36022; -. DR CTD; 6653; -. DR DisGeNET; 6653; -. DR GeneCards; SORL1; -. DR HGNC; HGNC:11185; SORL1. DR HPA; ENSG00000137642; Low tissue specificity. DR MalaCards; SORL1; -. DR MIM; 104300; phenotype. DR MIM; 602005; gene. DR NIAGADS; ENSG00000137642; -. DR OpenTargets; ENSG00000137642; -. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR VEuPathDB; HostDB:ENSG00000137642; -. DR eggNOG; KOG1215; Eukaryota. DR eggNOG; KOG3511; Eukaryota. DR GeneTree; ENSGT01030000234563; -. DR HOGENOM; CLU_001389_0_0_1; -. DR InParanoid; Q92673; -. DR OMA; LCPDGME; -. DR OrthoDB; 443634at2759; -. DR PAN-GO; Q92673; 5 GO annotations based on evolutionary models. DR PhylomeDB; Q92673; -. DR PathwayCommons; Q92673; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; Q92673; -. DR SIGNOR; Q92673; -. DR Agora; ENSG00000137642; -. DR BioGRID-ORCS; 6653; 18 hits in 1151 CRISPR screens. DR ChiTaRS; SORL1; human. DR EvolutionaryTrace; Q92673; -. DR GenomeRNAi; 6653; -. DR Pharos; Q92673; Tbio. DR PRO; PR:Q92673; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q92673; protein. DR Bgee; ENSG00000137642; Expressed in frontal pole and 206 other cell types or tissues. DR ExpressionAtlas; Q92673; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IEA:GOC. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProt. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0031985; C:Golgi cisterna; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005771; C:multivesicular body; IDA:UniProtKB. DR GO; GO:0032585; C:multivesicular body membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005641; C:nuclear envelope lumen; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0097356; C:perinucleolar compartment; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IMP:Alzheimers_University_of_Toronto. DR GO; GO:0055038; C:recycling endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005802; C:trans-Golgi network; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030658; C:transport vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0001540; F:amyloid-beta binding; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030169; F:low-density lipoprotein particle binding; IPI:BHF-UCL. DR GO; GO:0005041; F:low-density lipoprotein particle receptor activity; TAS:ARUK-UCL. DR GO; GO:0042923; F:neuropeptide binding; IPI:UniProtKB. DR GO; GO:0140318; F:protein transporter activity; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0031267; F:small GTPase binding; IPI:Alzheimers_University_of_Toronto. DR GO; GO:0004888; F:transmembrane signaling receptor activity; IDA:UniProtKB. DR GO; GO:1990845; P:adaptive thermogenesis; ISS:UniProtKB. DR GO; GO:0016477; P:cell migration; IEA:Ensembl. DR GO; GO:0002024; P:diet induced thermogenesis; ISS:UniProtKB. DR GO; GO:0099638; P:endosome to plasma membrane protein transport; IEA:Ensembl. DR GO; GO:0038020; P:insulin receptor recycling; IDA:UniProtKB. DR GO; GO:1902992; P:negative regulation of amyloid precursor protein catabolic process; IDA:Alzheimers_University_of_Toronto. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; ISS:UniProtKB. DR GO; GO:1902997; P:negative regulation of neurofibrillary tangle assembly; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IMP:Alzheimers_University_of_Toronto. DR GO; GO:0010897; P:negative regulation of triglyceride catabolic process; ISS:UniProtKB. DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB. DR GO; GO:1904179; P:positive regulation of adipose tissue development; IDA:UniProtKB. DR GO; GO:1902955; P:positive regulation of early endosome to recycling endosome transport; IMP:Alzheimers_University_of_Toronto. DR GO; GO:2001137; P:positive regulation of endocytic recycling; IMP:Alzheimers_University_of_Toronto. DR GO; GO:1902953; P:positive regulation of ER to Golgi vesicle-mediated transport; IMP:Alzheimers_University_of_Toronto. DR GO; GO:1900168; P:positive regulation of glial cell-derived neurotrophic factor production; IDA:UniProtKB. DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0070863; P:positive regulation of protein exit from endoplasmic reticulum; IMP:Alzheimers_University_of_Toronto. DR GO; GO:1902966; P:positive regulation of protein localization to early endosome; IMP:Alzheimers_University_of_Toronto. DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0034067; P:protein localization to Golgi apparatus; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0045053; P:protein retention in Golgi apparatus; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0006605; P:protein targeting; IDA:UniProtKB. DR GO; GO:0006622; P:protein targeting to lysosome; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0006898; P:receptor-mediated endocytosis; IDA:UniProtKB. DR GO; GO:0014910; P:regulation of smooth muscle cell migration; IDA:UniProtKB. DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; IDA:UniProt. DR CDD; cd00063; FN3; 5. DR CDD; cd00112; LDLa; 11. DR FunFam; 4.10.400.10:FF:000006; Putative low-density lipoprotein receptor; 1. DR FunFam; 2.130.10.10:FF:000303; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:000404; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:000416; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:000461; Sortilin related receptor 1; 1. DR FunFam; 2.60.40.10:FF:001616; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000027; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000030; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000036; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000037; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000039; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000041; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000048; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000052; Sortilin related receptor 1; 1. DR FunFam; 4.10.400.10:FF:000060; Sortilin related receptor 1; 1. DR FunFam; 2.10.70.80:FF:000002; Sortilin-related receptor isoform A; 1. DR FunFam; 2.120.10.30:FF:000021; Sortilin-related receptor isoform A; 1. DR FunFam; 3.30.60.270:FF:000002; Sortilin-related receptor isoform A; 1. DR FunFam; 4.10.400.10:FF:000033; Sortilin-related receptor isoform A; 1. DR Gene3D; 2.10.70.80; -; 1. DR Gene3D; 3.30.60.270; -; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 3. DR Gene3D; 4.10.400.10; Low-density Lipoprotein Receptor; 11. DR Gene3D; 2.120.10.30; TolB, C-terminal domain; 1. DR Gene3D; 2.130.10.10; YVTN repeat-like/Quinoprotein amine dehydrogenase; 1. DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR057841; FN3_SORL1. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR036055; LDL_receptor-like_sf. DR InterPro; IPR023415; LDLR_class-A_CS. DR InterPro; IPR000033; LDLR_classB_rpt. DR InterPro; IPR002172; LDrepeatLR_classA_rpt. DR InterPro; IPR031777; Sortilin_C. DR InterPro; IPR031778; Sortilin_N. DR InterPro; IPR006581; VPS10. DR InterPro; IPR050310; VPS10-sortilin. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR PANTHER; PTHR12106; SORTILIN RELATED; 1. DR PANTHER; PTHR12106:SF27; SORTILIN-RELATED RECEPTOR; 1. DR Pfam; PF00041; fn3; 3. DR Pfam; PF25814; fn3_SORL1; 1. DR Pfam; PF00057; Ldl_recept_a; 10. DR Pfam; PF00058; Ldl_recept_b; 2. DR Pfam; PF15902; Sortilin-Vps10; 1. DR Pfam; PF15901; Sortilin_C; 1. DR PRINTS; PR00261; LDLRECEPTOR. DR SMART; SM00060; FN3; 6. DR SMART; SM00192; LDLa; 11. DR SMART; SM00135; LY; 5. DR SMART; SM00602; VPS10; 1. DR SUPFAM; SSF49265; Fibronectin type III; 3. DR SUPFAM; SSF57424; LDL receptor-like module; 11. DR SUPFAM; SSF110296; Oligoxyloglucan reducing end-specific cellobiohydrolase; 2. DR SUPFAM; SSF63825; YWTD domain; 1. DR PROSITE; PS01186; EGF_2; 1. DR PROSITE; PS50853; FN3; 4. DR PROSITE; PS01209; LDLRA_1; 10. DR PROSITE; PS50068; LDLRA_2; 11. DR PROSITE; PS51120; LDLRB; 5. DR PROSITE; PS52072; VPS10P; 1. PE 1: Evidence at protein level; KW 3D-structure; Alzheimer disease; Amyloidosis; Cell membrane; KW Cleavage on pair of basic residues; Cytoplasmic vesicle; KW Direct protein sequencing; Disease variant; Disulfide bond; KW EGF-like domain; Endocytosis; Endoplasmic reticulum; Endosome; KW Glycoprotein; Golgi apparatus; Membrane; Neurodegeneration; Phosphoprotein; KW Protein transport; Proteomics identification; Receptor; Reference proteome; KW Repeat; Secreted; Signal; Transmembrane; Transmembrane helix; Transport. FT SIGNAL 1..28 FT /evidence="ECO:0000255" FT PROPEP 29..81 FT /note="Removed in mature form" FT /evidence="ECO:0000269|PubMed:8940146" FT /id="PRO_0000033164" FT CHAIN 82..2214 FT /note="Sortilin-related receptor" FT /id="PRO_0000033165" FT TOPO_DOM 82..2137 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 2138..2158 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 2159..2214 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 91..754 FT /note="Vps10p" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REPEAT 136..147 FT /note="BNR 1" FT REPEAT 232..243 FT /note="BNR 2" FT REPEAT 441..452 FT /note="BNR 3" FT REPEAT 521..532 FT /note="BNR 4" FT REPEAT 562..573 FT /note="BNR 5" FT REPEAT 800..843 FT /note="LDL-receptor class B 1" FT REPEAT 844..887 FT /note="LDL-receptor class B 2" FT REPEAT 888..932 FT /note="LDL-receptor class B 3" FT REPEAT 933..970 FT /note="LDL-receptor class B 4" FT REPEAT 971..1013 FT /note="LDL-receptor class B 5" FT DOMAIN 1026..1072 FT /note="EGF-like" FT DOMAIN 1076..1114 FT /note="LDL-receptor class A 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1115..1155 FT /note="LDL-receptor class A 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1156..1194 FT /note="LDL-receptor class A 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1198..1236 FT /note="LDL-receptor class A 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1238..1272 FT /note="LDL-receptor class A 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1273..1317 FT /note="LDL-receptor class A 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1323..1361 FT /note="LDL-receptor class A 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1366..1405 FT /note="LDL-receptor class A 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1417..1455 FT /note="LDL-receptor class A 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1469..1508 FT /note="LDL-receptor class A 10" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1512..1551 FT /note="LDL-receptor class A 11" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DOMAIN 1557..1649 FT /note="Fibronectin type-III 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1653..1745 FT /note="Fibronectin type-III 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1749..1844 FT /note="Fibronectin type-III 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1843..1927 FT /note="Fibronectin type-III 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 1934..2029 FT /note="Fibronectin type-III 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 2030..2118 FT /note="Fibronectin type-III 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT REGION 91..617 FT /note="10-bladed beta-propeller" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REGION 625..675 FT /note="10CCa cysteine-knot" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REGION 677..754 FT /note="10CCb cysteine-knot" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT REGION 2190..2214 FT /note="Required for efficient Golgi apparatus - endosome FT sorting" FT /evidence="ECO:0000269|PubMed:17646382" FT REGION 2201..2214 FT /note="Required for interaction with GGA1 and GGA2" FT /evidence="ECO:0000269|PubMed:11821067" FT MOTIF 63..65 FT /note="Cell attachment site" FT /evidence="ECO:0000255" FT MOTIF 2161..2164 FT /note="Potential nuclear localization signal for the C- FT terminal fragment generated by PSEN1" FT /evidence="ECO:0000305|PubMed:16531402" FT MOTIF 2172..2177 FT /note="Endocytosis signal" FT /evidence="ECO:0000255" FT MOTIF 2208..2212 FT /note="DXXLL motif involved in the interaction with GGA1" FT /evidence="ECO:0000269|PubMed:20015111" FT MOD_RES 114 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 2206 FT /note="Phosphoserine; by ROCK2" FT /evidence="ECO:0000269|PubMed:21147781" FT CARBOHYD 99 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 158 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 368 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 430 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 616 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 674 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 818 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 871 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1035 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1068 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1164 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1191 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1246 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1367 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1458 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1608 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1706 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1733 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 1809 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1854 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1894 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1986 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 2010 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 2054 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 2069 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 2076 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 2092 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT DISULFID 467..473 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 625..660 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 643..675 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 677..736 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 684..699 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 716..752 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01417" FT DISULFID 1078..1090 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1085..1103 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1097..1112 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1117..1131 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1125..1144 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1138..1153 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1158..1170 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1165..1183 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1177..1192 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1199..1211 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1206..1224 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1218..1235 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1239..1249 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1244..1262 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1256..1271 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1275..1289 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1283..1302 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1296..1315 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1325..1337 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1332..1350 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1344..1359 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1368..1381 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1376..1394 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1388..1403 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1419..1431 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1426..1444 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1438..1453 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1471..1484 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1478..1497 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1491..1506 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1514..1527 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1521..1540 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT DISULFID 1534..1549 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124" FT VARIANT 120 FT /note="L -> S (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036371" FT VARIANT 141 FT /note="Y -> C (in AD; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070012" FT VARIANT 511 FT /note="G -> R (in AD; uncertain significance; loss of FT interaction with APP amyloid-beta peptides, hence reduced FT turnover of APP amyloid-beta peptides in cells)" FT /evidence="ECO:0000269|PubMed:22472873, FT ECO:0000269|PubMed:24523320" FT /id="VAR_070013" FT VARIANT 528 FT /note="A -> T (in dbSNP:rs2298813)" FT /evidence="ECO:0000269|PubMed:18407551" FT /id="VAR_020360" FT VARIANT 924 FT /note="N -> S (in AD; uncertain significance; FT dbSNP:rs377498269)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070014" FT VARIANT 1074 FT /note="Q -> E (in dbSNP:rs1699107)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:8940146, ECO:0000269|PubMed:9157966, FT ECO:0000269|Ref.4" FT /id="VAR_034508" FT VARIANT 1358 FT /note="N -> S (in AD; uncertain significance; FT dbSNP:rs747306346)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070015" FT VARIANT 1581 FT /note="M -> L (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036372" FT VARIANT 1681 FT /note="G -> D (in AD; uncertain significance; FT dbSNP:rs1565352546)" FT /evidence="ECO:0000269|PubMed:22472873" FT /id="VAR_070016" FT VARIANT 1967 FT /note="V -> I (in dbSNP:rs1792120)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:8940146, ECO:0000269|PubMed:9157966, FT ECO:0000269|Ref.4" FT /id="VAR_034509" FT VARIANT 1972 FT /note="L -> V (in a colorectal cancer sample; somatic FT mutation; dbSNP:rs766895956)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036373" FT MUTAGEN 78..81 FT /note="RRKR->GRKG: Loss of propeptide cleavage." FT /evidence="ECO:0000269|PubMed:11294867" FT MUTAGEN 2163..2164 FT /note="RR->AA: Affects the nuclear location of the C- FT terminal fragment generated by PSEN1." FT /evidence="ECO:0000269|PubMed:16531402" FT MUTAGEN 2172..2177 FT /note="FANSHY->AAASHA: No effect on endocytosis." FT /evidence="ECO:0000269|PubMed:17646382" FT MUTAGEN 2190..2214 FT /note="Missing: Strong reduction in Golgi apparatus FT - endosome sorting. Loss of interaction with AP-1 complex." FT /evidence="ECO:0000269|PubMed:17646382" FT MUTAGEN 2190..2198 FT /note="DDLGEDDED->AALGAAAAA: Loss of interaction with GGA1 FT and PACS1. No effect on interaction with APP. Affects FT subcellular location, increasing localization at the cell FT surface, possibly due to drastically decreased endocytosis. FT Impaired Golgi apparatus - endosome sorting. Increased FT amyloidogenic APP processing by beta-secretase, resulting FT in increased levels of soluble APP-beta and amyloid-beta FT protein 40 and 42. Loss of APOA5 internalization." FT /evidence="ECO:0000269|PubMed:17646382, FT ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:18603531" FT MUTAGEN 2190..2191 FT /note="DD->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2194..2198 FT /note="EDDED->AAAAA: Strong decrease in interaction with FT HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2201..2202 FT /note="MI->AA: No effect on endocytosis. Decreased Golgi FT apparatus - endosome sorting." FT /evidence="ECO:0000269|PubMed:17646382" FT MUTAGEN 2203..2204 FT /note="TG->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2205..2206 FT /note="FS->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2207..2208 FT /note="DD->AA: Strong decrease in interaction with FT HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2208..2211 FT /note="DVPM->AVPA: Loss of interaction with GGA1 and PACS1. FT No effect on interaction with APP. Affects subcellular FT location, by causing increased localization to recycling FT endosomes. Increased APP processing by alpha-secretase, FT resulting in increased levels of soluble APP-alpha and C83 FT APP fragments. Decreased APP processing by beta-secretase, FT resulting in reduced levels of C99 APP fragment." FT /evidence="ECO:0000269|PubMed:17855360" FT MUTAGEN 2209..2210 FT /note="VP->AA: No effect on the interaction with HSPA12A." FT /evidence="ECO:0000269|PubMed:30679749" FT MUTAGEN 2211..2214 FT /note="Missing: No effect on endocytosis. Affects LPL FT sorting to endosomes." FT /evidence="ECO:0000269|PubMed:17646382, FT ECO:0000269|PubMed:21385844" FT STRAND 48..51 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 91..98 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 103..109 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 117..122 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 125..128 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 133..140 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 145..147 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 149..151 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 164..169 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 177..192 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 198..201 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 207..211 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 219..223 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 230..236 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 242..253 FT /evidence="ECO:0007829|PDB:3WSX" FT TURN 256..258 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 264..268 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 271..273 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 275..282 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 287..289 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 290..298 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 300..303 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 306..313 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 318..320 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 323..330 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 333..337 FT /evidence="ECO:0007829|PDB:3WSZ" FT STRAND 349..353 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 355..358 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 360..363 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 366..368 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 369..374 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 377..379 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 383..391 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 394..396 FT /evidence="ECO:0007829|PDB:3WSY" FT TURN 397..400 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 402..405 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 407..409 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 411..416 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 420..422 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 424..428 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 431..434 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 435..437 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 439..445 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 451..453 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 460..462 FT /evidence="ECO:0007829|PDB:3WSY" FT HELIX 469..471 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 473..479 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 480..485 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 488..490 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 492..495 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 498..500 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 504..510 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 512..514 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 519..525 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 528..530 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 531..536 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 538..543 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 544..546 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 548..553 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 560..566 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 572..575 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 577..579 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 581..588 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 590..592 FT /evidence="ECO:0007829|PDB:7VT0" FT STRAND 596..602 FT /evidence="ECO:0007829|PDB:3WSX" FT TURN 604..607 FT /evidence="ECO:0007829|PDB:3WSZ" FT STRAND 610..616 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 618..621 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 627..629 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 630..633 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 635..637 FT /evidence="ECO:0007829|PDB:3WSY" FT TURN 638..641 FT /evidence="ECO:0007829|PDB:3WSY" FT STRAND 647..654 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 670..674 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 679..681 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 682..684 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 688..690 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 694..696 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 699..701 FT /evidence="ECO:0007829|PDB:3WSX" FT HELIX 703..705 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 722..724 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 727..730 FT /evidence="ECO:0007829|PDB:3WSX" FT TURN 740..745 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 748..750 FT /evidence="ECO:0007829|PDB:3WSX" FT STRAND 1655..1660 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1669..1674 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1683..1692 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1699..1710 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1718..1729 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1731..1734 FT /evidence="ECO:0007829|PDB:2DM4" FT STRAND 1738..1741 FT /evidence="ECO:0007829|PDB:2DM4" SQ SEQUENCE 2214 AA; 248426 MW; 4C215BB33E65C0B2 CRC64; MATRSSRRES RLPFLFTLVA LLPPGALCEV WTQRLHGGSA PLPQDRGFLV VQGDPRELRL WARGDARGAS RADEKPLRRK RSAALQPEPI KVYGQVSLND SHNQMVVHWA GEKSNVIVAL ARDSLALARP KSSDVYVSYD YGKSFKKISD KLNFGLGNRS EAVIAQFYHS PADNKRYIFA DAYAQYLWIT FDFCNTLQGF SIPFRAADLL LHSKASNLLL GFDRSHPNKQ LWKSDDFGQT WIMIQEHVKS FSWGIDPYDK PNTIYIERHE PSGYSTVFRS TDFFQSRENQ EVILEEVRDF QLRDKYMFAT KVVHLLGSEQ QSSVQLWVSF GRKPMRAAQF VTRHPINEYY IADASEDQVF VCVSHSNNRT NLYISEAEGL KFSLSLENVL YYSPGGAGSD TLVRYFANEP FADFHRVEGL QGVYIATLIN GSMNEENMRS VITFDKGGTW EFLQAPAFTG YGEKINCELS QGCSLHLAQR LSQLLNLQLR RMPILSKESA PGLIIATGSV GKNLASKTNV YISSSAGARW REALPGPHYY TWGDHGGIIT AIAQGMETNE LKYSTNEGET WKTFIFSEKP VFVYGLLTEP GEKSTVFTIF GSNKENVHSW LILQVNATDA LGVPCTENDY KLWSPSDERG NECLLGHKTV FKRRTPHATC FNGEDFDRPV VVSNCSCTRE DYECDFGFKM SEDLSLEVCV PDPEFSGKSY SPPVPCPVGS TYRRTRGYRK ISGDTCSGGD VEARLEGELV PCPLAEENEF ILYAVRKSIY RYDLASGATE QLPLTGLRAA VALDFDYEHN CLYWSDLALD VIQRLCLNGS TGQEVIINSG LETVEALAFE PLSQLLYWVD AGFKKIEVAN PDGDFRLTIV NSSVLDRPRA LVLVPQEGVM FWTDWGDLKP GIYRSNMDGS AAYHLVSEDV KWPNGISVDD QWIYWTDAYL ECIERITFSG QQRSVILDNL PHPYAIAVFK NEIYWDDWSQ LSIFRASKYS GSQMEILANQ LTGLMDMKIF YKGKNTGSNA CVPRPCSLLC LPKANNSRSC RCPEDVSSSV LPSGDLMCDC PQGYQLKNNT CVKQENTCLR NQYRCSNGNC INSIWWCDFD NDCGDMSDER NCPTTICDLD TQFRCQESGT CIPLSYKCDL EDDCGDNSDE SHCEMHQCRS DEYNCSSGMC IRSSWVCDGD NDCRDWSDEA NCTAIYHTCE ASNFQCRNGH CIPQRWACDG DTDCQDGSDE DPVNCEKKCN GFRCPNGTCI PSSKHCDGLR DCSDGSDEQH CEPLCTHFMD FVCKNRQQCL FHSMVCDGII QCRDGSDEDA AFAGCSQDPE FHKVCDEFGF QCQNGVCISL IWKCDGMDDC GDYSDEANCE NPTEAPNCSR YFQFRCENGH CIPNRWKCDR ENDCGDWSDE KDCGDSHILP FSTPGPSTCL PNYYRCSSGT CVMDTWVCDG YRDCADGSDE EACPLLANVT AASTPTQLGR CDRFEFECHQ PKTCIPNWKR CDGHQDCQDG RDEANCPTHS TLTCMSREFQ CEDGEACIVL SERCDGFLDC SDESDEKACS DELTVYKVQN LQWTADFSGD VTLTWMRPKK MPSASCVYNV YYRVVGESIW KTLETHSNKT NTVLKVLKPD TTYQVKVQVQ CLSKAHNTND FVTLRTPEGL PDAPRNLQLS LPREAEGVIV GHWAPPIHTH GLIREYIVEY SRSGSKMWAS QRAASNFTEI KNLLVNTLYT VRVAAVTSRG IGNWSDSKSI TTIKGKVIPP PDIHIDSYGE NYLSFTLTME SDIKVNGYVV NLFWAFDTHK QERRTLNFRG SILSHKVGNL TAHTSYEISA WAKTDLGDSP LAFEHVMTRG VRPPAPSLKA KAINQTAVEC TWTGPRNVVY GIFYATSFLD LYRNPKSLTT SLHNKTVIVS KDEQYLFLVR VVVPYQGPSS DYVVVKMIPD SRLPPRHLHV VHTGKTSVVI KWESPYDSPD QDLLYAVAVK DLIRKTDRSY KVKSRNSTVE YTLNKLEPGG KYHIIVQLGN MSKDSSIKIT TVSLSAPDAL KIITENDHVL LFWKSLALKE KHFNESRGYE IHMFDSAMNI TAYLGNTTDN FFKISNLKMG HNYTFTVQAR CLFGNQICGE PAILLYDELG SGADASATQA ARSTDVAAVV VPILFLILLS LGVGFAILYT KHRRLQSSFT AFANSHYSSR LGSAIFSSGD DLGEDDEDAP MITGFSDDVP MVIA // ID SPTC1_HUMAN Reviewed; 473 AA. AC O15269; A8K681; Q5VWB4; Q96IX6; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 28-JAN-2026, entry version 218. DE RecName: Full=Serine palmitoyltransferase 1; DE EC=2.3.1.50 {ECO:0000269|PubMed:19416851}; DE AltName: Full=Long chain base biosynthesis protein 1; DE Short=LCB 1; DE AltName: Full=Serine-palmitoyl-CoA transferase 1; DE Short=SPT 1; DE Short=SPT1; GN Name=SPTLC1; Synonyms=LCB1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Kidney; RX PubMed=9363775; DOI=10.1111/j.1432-1033.1997.00239.x; RA Weiss B., Stoffel W.; RT "Human and murine serine-palmitoyl-CoA transferase. Cloning, expression and RT characterization of the key enzyme in sphingolipid synthesis."; RL Eur. J. Biochem. 249:239-247(1997). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANTS HSAN1A RP TRP-133; TYR-133 AND ASP-144. RX PubMed=11242114; DOI=10.1038/85879; RA Dawkins J.L., Hulme D.J., Brahmbhatt S.B., Auer-Grumbach M., RA Nicholson G.A.; RT "Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base RT subunit-1, cause hereditary sensory neuropathy type I."; RL Nat. Genet. 27:309-312(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP TISSUE SPECIFICITY. RX PubMed=17023427; DOI=10.1074/jbc.m608066200; RA Hornemann T., Richard S., Ruetti M.F., Wei Y., von Eckardstein A.; RT "Cloning and initial characterization of a new subunit for mammalian RT serine-palmitoyltransferase."; RL J. Biol. Chem. 281:37275-37281(2006). RN [8] RP FUNCTION. RX PubMed=19648650; DOI=10.1074/jbc.m109.023192; RA Hornemann T., Penno A., Ruetti M.F., Ernst D., Kivrak-Pfiffner F., RA Rohrer L., von Eckardstein A.; RT "The SPTLC3 subunit of serine palmitoyltransferase generates short chain RT sphingoid bases."; RL J. Biol. Chem. 284:26322-26330(2009). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE SPT COMPLEX, AND RP INTERACTION WITH SPTSSA AND SPTSSB. RX PubMed=19416851; DOI=10.1073/pnas.0811269106; RA Han G., Gupta S.D., Gable K., Niranjanakumari S., Moitra P., Eichler F., RA Brown R.H. Jr., Harmon J.M., Dunn T.M.; RT "Identification of small subunits of mammalian serine palmitoyltransferase RT that confer distinct acyl-CoA substrate specificities."; RL Proc. Natl. Acad. Sci. U.S.A. 106:8186-8191(2009). RN [10] RP BIOPHYSICOCHEMICAL PROPERTIES, AND CHARACTERIZATION OF VARIANT HSAN1A RP TRP-133. RX PubMed=20504773; DOI=10.1074/jbc.m110.122259; RA Gable K., Gupta S.D., Han G., Niranjanakumari S., Harmon J.M., Dunn T.M.; RT "A disease-causing mutation in the active site of serine RT palmitoyltransferase causes catalytic promiscuity."; RL J. Biol. Chem. 285:22846-22852(2010). RN [11] RP INTERACTION WITH ORMDL3. RX PubMed=20182505; DOI=10.1038/nature08787; RA Breslow D.K., Collins S.R., Bodenmiller B., Aebersold R., Simons K., RA Shevchenko A., Ejsing C.S., Weissman J.S.; RT "Orm family proteins mediate sphingolipid homeostasis."; RL Nature 463:1048-1053(2010). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] RP INDUCTION IN ALZHEIMER DISEASE. RX PubMed=21994399; DOI=10.1523/jneurosci.3883-11.2011; RA Geekiyanage H., Chan C.; RT "MicroRNA-137/181c regulates serine palmitoyltransferase and in turn RT amyloid beta, novel targets in sporadic Alzheimer's disease."; RL J. Neurosci. 31:14820-14830(2011). RN [14] RP PHOSPHORYLATION AT TYR-164, AND MUTAGENESIS OF TYR-164. RX PubMed=23629659; DOI=10.1074/jbc.m112.409185; RA Taouji S., Higa A., Delom F., Palcy S., Mahon F.X., Pasquet J.M., Bosse R., RA Segui B., Chevet E.; RT "Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on RT tyrosine 164 inhibits its activity and promotes cell survival."; RL J. Biol. Chem. 288:17190-17201(2013). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP REGULATION OF SPT COMPLEX ACTIVITY BY ORMDL PROTEINS IN THE PRESENCE OF RP CERAMIDES. RX PubMed=30700557; DOI=10.1074/jbc.ra118.007291; RA Davis D.L., Gable K., Suemitsu J., Dunn T.M., Wattenberg B.W.; RT "The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly RT regulated by ceramide: Reconstitution of SPT regulation in isolated RT membranes."; RL J. Biol. Chem. 294:5146-5156(2019). RN [17] RP FUNCTION. RX PubMed=36170811; DOI=10.1016/j.celrep.2022.111415; RA Spears M.E., Lee N., Hwang S., Park S.J., Carlisle A.E., Li R., Doshi M.B., RA Armando A.M., Gao J., Simin K., Zhu L.J., Greer P.L., Quehenberger O., RA Torres E.M., Kim D.; RT "De novo sphingolipid biosynthesis necessitates detoxification in cancer RT cells."; RL Cell Rep. 40:111415-111415(2022). RN [18] {ECO:0007744|PDB:7K0I, ECO:0007744|PDB:7K0J, ECO:0007744|PDB:7K0K, ECO:0007744|PDB:7K0L, ECO:0007744|PDB:7K0M, ECO:0007744|PDB:7K0N, ECO:0007744|PDB:7K0O, ECO:0007744|PDB:7K0P, ECO:0007744|PDB:7K0Q} RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=33558761; DOI=10.1038/s41594-020-00551-9; RA Wang Y., Niu Y., Zhang Z., Gable K., Gupta S.D., Somashekarappa N., Han G., RA Zhao H., Myasnikov A.G., Kalathur R.C., Dunn T.M., Lee C.H.; RT "Structural insights into the regulation of human serine RT palmitoyltransferase complexes."; RL Nat. Struct. Mol. Biol. 28:240-248(2021). RN [19] {ECO:0007744|PDB:6M4N, ECO:0007744|PDB:6M4O, ECO:0007744|PDB:7CQI, ECO:0007744|PDB:7CQK} RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, FUNCTION, AND MUTAGENESIS OF PHE-138; PHE-337 AND RP SER-338. RX PubMed=33558762; DOI=10.1038/s41594-020-00553-7; RA Li S., Xie T., Liu P., Wang L., Gong X.; RT "Structural insights into the assembly and substrate selectivity of human RT SPT-ORMDL3 complex."; RL Nat. Struct. Mol. Biol. 28:249-257(2021). RN [20] {ECO:0007744|PDB:7YIU, ECO:0007744|PDB:7YIY, ECO:0007744|PDB:7YJ1, ECO:0007744|PDB:7YJ2} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) IN COMPLEX WITH SPTLC2; RP SPTSSA AND ORMDL3, CHARACTERIZATION OF VARIANTS ALS27 PHE-23; LEU-39 DEL RP AND 40-PHE-SER-41 DEL, AND ACTIVITY REGULATION. RX PubMed=37308477; DOI=10.1038/s41467-023-39274-y; RA Xie T., Liu P., Wu X., Dong F., Zhang Z., Yue J., Mahawar U., Farooq F., RA Vohra H., Fang Q., Liu W., Wattenberg B.W., Gong X.; RT "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid RT homeostasis."; RL Nat. Commun. 14:3475-3475(2023). RN [21] RP VARIANT ALA-387. RX PubMed=15037712; DOI=10.1212/01.wnl.0000115388.10828.5c; RA Verhoeven K., Coen K., De Vriendt E., Jacobs A., Van Gerwen V., Smouts I., RA Pou-Serradell A., Martin J.-J., Timmerman V., De Jonghe P.; RT "SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type RT I."; RL Neurology 62:1001-1002(2004). RN [22] RP VARIANT LEU-151. RX PubMed=17060578; DOI=10.1212/01.wnl.0000240068.21499.f5; RA Meggouh F., Bienfait H.M.E., Weterman M.A.J., de Visser M., Baas F.; RT "Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene."; RL Neurology 67:1476-1478(2006). RN [23] RP VARIANT [LARGE SCALE ANALYSIS] TRP-239. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [24] RP VARIANTS HSAN1A PHE-331 AND VAL-352, AND VARIANT ALA-387. RX PubMed=19651702; DOI=10.1093/brain/awp198; RA Rotthier A., Baets J., De Vriendt E., Jacobs A., Auer-Grumbach M., Levy N., RA Bonello-Palot N., Kilic S.S., Weis J., Nascimento A., Swinkels M., RA Kruyt M.C., Jordanova A., De Jonghe P., Timmerman V.; RT "Genes for hereditary sensory and autonomic neuropathies: a genotype- RT phenotype correlation."; RL Brain 132:2699-2711(2009). RN [25] RP CHARACTERIZATION OF VARIANTS HSAN1A TYR-133; TRP-133 AND ASP-144, RP CHARACTERIZATION OF VARIANT ALA-387, LACK OF ASSOCIATION OF VARIANT ALA-387 RP WITH HSAN1A, AND INTERACTION WITH SPTLC2. RX PubMed=19132419; DOI=10.1007/s10048-008-0168-7; RA Hornemann T., Penno A., Richard S., Nicholson G., van Dijk F.S., RA Rotthier A., Timmerman V., von Eckardstein A.; RT "A systematic comparison of all mutations in hereditary sensory neuropathy RT type I (HSAN I) reveals that the G387A mutation is not disease RT associated."; RL Neurogenetics 10:135-143(2009). RN [26] RP VARIANT HSAN1A PHE-331, CHARACTERIZATION OF VARIANTS HSAN1A TRP-133; RP PHE-331 AND VAL-352, AND SUBCELLULAR LOCATION. RX PubMed=21618344; DOI=10.1002/humu.21481; RA Rotthier A., Penno A., Rautenstrauss B., Auer-Grumbach M., Stettner G.M., RA Asselbergh B., Van Hoof K., Sticht H., Levy N., Timmerman V., Hornemann T., RA Janssens K.; RT "Characterization of two mutations in the SPTLC1 subunit of serine RT palmitoyltransferase associated with hereditary sensory and autonomic RT neuropathy type I."; RL Hum. Mutat. 32:E2211-E2225(2011). RN [27] RP VARIANT HSAN1A TRP-133, AND VARIANT GLY-310. RX PubMed=22302274; DOI=10.1007/s00415-011-6397-y; RA Davidson G.L., Murphy S.M., Polke J.M., Laura M., Salih M.A., Muntoni F., RA Blake J., Brandner S., Davies N., Horvath R., Price S., Donaghy M., RA Roberts M., Foulds N., Ramdharry G., Soler D., Lunn M.P., Manji H., RA Davis M.B., Houlden H., Reilly M.M.; RT "Frequency of mutations in the genes associated with hereditary sensory and RT autonomic neuropathy in a UK cohort."; RL J. Neurol. 259:1673-1685(2012). RN [28] RP INVOLVEMENT IN HSAN1A, VARIANT HSAN1A TYR-331, AND CHARACTERIZATION OF RP VARIANT HSAN1A TYR-331. RX PubMed=23454272; DOI=10.1016/j.ejmg.2013.02.002; RA Auer-Grumbach M., Bode H., Pieber T.R., Schabhuettl M., Fischer D., RA Seidl R., Graf E., Wieland T., Schuh R., Vacariu G., Grill F., RA Timmerman V., Strom T.M., Hornemann T.; RT "Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a RT distinct syndromic phenotype."; RL Eur. J. Med. Genet. 56:266-269(2013). RN [29] RP VARIANT HSAN1A PHE-331. RX PubMed=24247255; DOI=10.3892/mmr.2013.1808; RA Suh B.C., Hong Y.B., Nakhro K., Nam S.H., Chung K.W., Choi B.O.; RT "Early-onset severe hereditary sensory and autonomic neuropathy type 1 with RT S331F SPTLC1 mutation."; RL Mol. Med. Report. 9:481-486(2014). RN [30] RP VARIANT HSAN1A ASP-144. RX PubMed=30420926; DOI=10.1155/2018/1898151; RA Ho K.W.D., Jerath N.U.; RT "V144D Mutation of SPTLC1 Can Present with Both Painful and Painless RT Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I."; RL Case Rep. Genet. 2018:1898151-1898151(2018). RN [31] RP INVOLVEMENT IN ALS27, AND VARIANTS ALS27 SER-20; LEU-39 DEL AND TYR-331. RX PubMed=34459874; DOI=10.1001/jamaneurol.2021.2598; RG FALS Sequencing Consortium; RG American Genome Center; RG International ALS Genomics Consortium; RG and ITALSGEN Consortium; RA Johnson J.O., Chia R., Miller D.E., Li R., Kumaran R., Abramzon Y., RA Alahmady N., Renton A.E., Topp S.D., Gibbs J.R., Cookson M.R., Sabir M.S., RA Dalgard C.L., Troakes C., Jones A.R., Shatunov A., Iacoangeli A., RA Al Khleifat A., Ticozzi N., Silani V., Gellera C., Blair I.P., RA Dobson-Stone C., Kwok J.B., Bonkowski E.S., Palvadeau R., Tienari P.J., RA Morrison K.E., Shaw P.J., Al-Chalabi A., Brown R.H. Jr., Calvo A., Mora G., RA Al-Saif H., Gotkine M., Leigh F., Chang I.J., Perlman S.J., Glass I., RA Scott A.I., Shaw C.E., Basak A.N., Landers J.E., Chio A., Crawford T.O., RA Smith B.N., Traynor B.J., Smith B.N., Ticozzi N., Fallini C., Gkazi A.S., RA Topp S.D., Scotter E.L., Kenna K.P., Keagle P., Tiloca C., Vance C., RA Troakes C., Colombrita C., King A., Pensato V., Castellotti B., Baas F., RA Ten Asbroek A.L.M.A., McKenna-Yasek D., McLaughlin R.L., Polak M., RA Asress S., Esteban-Perez J., Stevic Z., D'Alfonso S., Mazzini L., RA Comi G.P., Del Bo R., Ceroni M., Gagliardi S., Querin G., Bertolin C., RA van Rheenen W., Rademakers R., van Blitterswijk M., Lauria G., Duga S., RA Corti S., Cereda C., Corrado L., Soraru G., Williams K.L., Nicholson G.A., RA Blair I.P., Leblond-Manry C., Rouleau G.A., Hardiman O., Morrison K.E., RA Veldink J.H., van den Berg L.H., Al-Chalabi A., Pall H., Shaw P.J., RA Turner M.R., Talbot K., Taroni F., Garcia-Redondo A., Wu Z., Glass J.D., RA Gellera C., Ratti A., Brown R.H. Jr., Silani V., Shaw C.E., Landers J.E., RA Dalgard C.L., Adeleye A., Soltis A.R., Alba C., Viollet C., Bacikova D., RA Hupalo D.N., Sukumar G., Pollard H.B., Wilkerson M.D., Martinez E.M., RA Abramzon Y., Ahmed S., Arepalli S., Baloh R.H., Bowser R., Brady C.B., RA Brice A., Broach J., Campbell R.H., Camu W., Chia R., Cooper-Knock J., RA Ding J., Drepper C., Drory V.E., Dunckley T.L., Eicher J.D., England B.K., RA Faghri F., Feldman E., Floeter M.K., Fratta P., Geiger J.T., Gerhard G., RA Gibbs J.R., Gibson S.B., Glass J.D., Hardy J., Harms M.B., RA Heiman-Patterson T.D., Hernandez D.G., Jansson L., Kirby J., Kowall N.W., RA Laaksovirta H., Landeck N., Landi F., Le Ber I., Lumbroso S., RA MacGowan D.J.L., Maragakis N.J., Mora G., Mouzat K., Murphy N.A., RA Myllykangas L., Nalls M.A., Orrell R.W., Ostrow L.W., Pamphlett R., RA Pickering-Brown S., Pioro E.P., Pletnikova O., Pliner H.A., Pulst S.M., RA Ravits J.M., Renton A.E., Rivera A., Robberecht W., Rogaeva E., RA Rollinson S., Rothstein J.D., Scholz S.W., Sendtner M., Shaw P.J., RA Sidle K.C., Simmons Z., Singleton A.B., Smith N., Stone D.J., Tienari P.J., RA Troncoso J.C., Valori M., Van Damme P., Van Deerlin V.M., Van Den Bosch L., RA Zinman L., Landers J.E., Chio A., Traynor B.J., Angelocola S.M., RA Ausiello F.P., Barberis M., Bartolomei I., Battistini S., Bersano E., RA Bisogni G., Borghero G., Brunetti M., Cabona C., Calvo A., Canale F., RA Canosa A., Cantisani T.A., Capasso M., Caponnetto C., Cardinali P., RA Carrera P., Casale F., Chio A., Colletti T., Conforti F.L., Conte A., RA Conti E., Corbo M., Cuccu S., Dalla Bella E., D'Errico E., DeMarco G., RA Dubbioso R., Ferrarese C., Ferraro P.M., Filippi M., Fini N., Floris G., RA Fuda G., Gallone S., Gianferrari G., Giannini F., Grassano M., Greco L., RA Iazzolino B., Introna A., La Bella V., Lattante S., Lauria G., Liguori R., RA Logroscino G., Logullo F.O., Lunetta C., Mandich P., Mandrioli J., RA Manera U., Manganelli F., Marangi G., Marinou K., Marrosu M.G., RA Martinelli I., Messina S., Moglia C., Mora G., Mosca L., Murru M.R., RA Origone P., Passaniti C., Petrelli C., Petrucci A., Pozzi S., Pugliatti M., RA Quattrini A., Ricci C., Riolo G., Riva N., Russo M., Sabatelli M., RA Salamone P., Salivetto M., Salvi F., Santarelli M., Sbaiz L., Sideri R., RA Simone I., Simonini C., Spataro R., Tanel R., Tedeschi G., Ticca A., RA Torriello A., Tranquilli S., Tremolizzo L., Trojsi F., Vasta R., RA Vacchiano V., Vita G., Volanti P., Zollino M., Zucchi E.; RT "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic RT Lateral Sclerosis."; RL JAMA Neurol. 78:1236-1248(2021). RN [32] RP INVOLVEMENT IN ALS27, VARIANTS ALS27 SER-20; PHE-23; LEU-39 DEL AND RP 40-PHE-SER-41 DEL, CHARACTERIZATION OF VARIANTS ALS27 SER-20; PHE-23; RP LEU-39 DEL AND 40-PHE-SER-41 DEL, AND HOMEOSTATIC REGULATION BY ORMDL3 IN RP THE PRESENCE OF CERAMIDES. RX PubMed=34059824; DOI=10.1038/s41591-021-01346-1; RA Mohassel P., Donkervoort S., Lone M.A., Nalls M., Gable K., Gupta S.D., RA Foley A.R., Hu Y., Saute J.A.M., Moreira A.L., Kok F., Introna A., RA Logroscino G., Grunseich C., Nickolls A.R., Pourshafie N., Neuhaus S.B., RA Saade D., Gangfuss A., Koelbel H., Piccus Z., Le Pichon C.E., Fiorillo C., RA Ly C.V., Toepf A., Brady L., Specht S., Zidell A., Pedro H., Mittelmann E., RA Thomas F.P., Chao K.R., Konersman C.G., Cho M.T., Brandt T., Straub V., RA Connolly A.M., Schara U., Roos A., Tarnopolsky M., Hoeke A., Brown R.H., RA Lee C.H., Hornemann T., Dunn T.M., Boennemann C.G.; RT "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid RT synthesis."; RL Nat. Med. 27:1197-1204(2021). RN [33] RP INVOLVEMENT IN ALS27, AND VARIANT ALS27 ARG-38. RX PubMed=36204986; DOI=10.1080/21678421.2022.2096409; RA Liu X., He J., Yu W., Fan D.; RT "A de novo c.113 T > C: p.L38R mutation of SPTLC1: case report of a girl RT with sporadic juvenile amyotrophic lateral sclerosis."; RL Amyotroph. Lateral Scler. Frontotemporal Degener. 23:634-637(2022). CC -!- FUNCTION: Component of the serine palmitoyltransferase multisubunit CC enzyme (SPT) that catalyzes the initial and rate-limiting step in CC sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA CC (most commonly palmitoyl-CoA) to form long-chain bases. The SPT complex CC is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this CC complex, the heterodimer with SPTLC2 or SPTLC3 forms the catalytic core CC (PubMed:19416851, PubMed:33558762, PubMed:36170811). The composition of CC the serine palmitoyltransferase (SPT) complex determines the substrate CC preference (PubMed:19416851, PubMed:33558762). The SPTLC1-SPTLC2-SPTSSA CC complex shows a strong preference for C16-CoA substrate, while the CC SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as CC substrates, with a slight preference for C14-CoA (PubMed:19416851, CC PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong CC preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB CC isozyme displays an ability to use a broader range of acyl-CoAs, CC without apparent preference (PubMed:19416851, PubMed:19648650, CC PubMed:33558761, PubMed:33558762). Required for adipocyte cell CC viability and metabolic homeostasis (By similarity). CC {ECO:0000250|UniProtKB:O35704, ECO:0000269|PubMed:19416851, CC ECO:0000269|PubMed:19648650, ECO:0000269|PubMed:33558761, CC ECO:0000269|PubMed:33558762, ECO:0000269|PubMed:36170811}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-serine + hexadecanoyl-CoA + H(+) = 3-oxosphinganine + CO2 + CC CoA; Xref=Rhea:RHEA:14761, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, CC ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379, CC ChEBI:CHEBI:58299; EC=2.3.1.50; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14762; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=octadecanoyl-CoA + L-serine + H(+) = 3-oxoeicosasphinganine + CC CO2 + CoA; Xref=Rhea:RHEA:33683, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57394, ChEBI:CHEBI:65073; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33684; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=tetradecanoyl-CoA + L-serine + H(+) = 3-oxohexadecasphinganine CC + CO2 + CoA; Xref=Rhea:RHEA:35675, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57385, ChEBI:CHEBI:71007; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35676; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- CATALYTIC ACTIVITY: CC Reaction=dodecanoyl-CoA + L-serine + H(+) = 3-oxotetradecasphinganine + CC CO2 + CoA; Xref=Rhea:RHEA:35679, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:16526, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287, CC ChEBI:CHEBI:57375, ChEBI:CHEBI:71008; CC Evidence={ECO:0000269|PubMed:19416851}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35680; CC Evidence={ECO:0000269|PubMed:19416851}; CC -!- COFACTOR: CC Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326; CC Evidence={ECO:0000250}; CC -!- ACTIVITY REGULATION: SPT complex catalytic activity is negatively CC regulated by ORMDL proteins, including ORMDL3, in the presence of CC ceramides (PubMed:37308477). This mechanism allows to maintain ceramide CC levels at sufficient concentrations for the production of complex CC sphingolipids, but which prevents the accumulation of ceramides to CC levels that trigger apoptosis (Probable). {ECO:0000269|PubMed:37308477, CC ECO:0000305}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.75 mM for L-serine {ECO:0000269|PubMed:20504773}; CC KM=0.3 mM for L-serine {ECO:0000269|PubMed:33558761}; CC Vmax=1350 pmol/min/mg enzyme {ECO:0000269|PubMed:20504773}; CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism. CC {ECO:0000269|PubMed:19416851}. CC -!- SUBUNIT: Component of the serine palmitoyltransferase (SPT) complex, CC which is also composed of SPTLC2 or SPTLC3 and SPTSSA or SPTSSB CC (PubMed:19132419, PubMed:19416851, PubMed:33558761, PubMed:33558762, CC PubMed:37308477). The heterodimer consisting of SPTLC1 and CC SPTLC2/SPTLC3 forms the catalytic core of the enzyme, while SPTSSA or CC SPTSSB subunits determine substrate specificity (PubMed:33558762, CC PubMed:37308477). SPT also interacts with ORMDL proteins, especially CC ORMDL3, which negatively regulate SPT activity in the presence of CC ceramides (PubMed:20182505, PubMed:30700557, PubMed:33558762, CC PubMed:34059824, PubMed:37308477). Forms dimers of heterodimers with CC SPTLC2 (PubMed:33558761, PubMed:33558762). Interacts with RTN4 (isoform CC B) (By similarity). {ECO:0000250|UniProtKB:O35704, CC ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19416851, CC ECO:0000269|PubMed:20182505, ECO:0000269|PubMed:30700557, CC ECO:0000269|PubMed:33558761, ECO:0000269|PubMed:33558762, CC ECO:0000269|PubMed:34059824, ECO:0000269|PubMed:37308477}. CC -!- INTERACTION: CC O15269; Q8N138: ORMDL3; NbExp=6; IntAct=EBI-1044323, EBI-721750; CC O15269; O15270: SPTLC2; NbExp=5; IntAct=EBI-1044323, EBI-766136; CC O15269; Q9NUV7: SPTLC3; NbExp=3; IntAct=EBI-1044323, EBI-11614219; CC O15269; Q969W0: SPTSSA; NbExp=3; IntAct=EBI-1044323, EBI-723396; CC O15269-2; Q86SG2: ANKRD23; NbExp=3; IntAct=EBI-25912901, EBI-5661893; CC O15269-2; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-25912901, EBI-12891828; CC O15269-2; Q8IYM2: SLFN12; NbExp=3; IntAct=EBI-25912901, EBI-2822550; CC O15269-2; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-25912901, EBI-3942425; CC O15269-2; Q9UNE7: STUB1; NbExp=3; IntAct=EBI-25912901, EBI-357085; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:21618344}; Single-pass membrane protein CC {ECO:0000250|UniProtKB:O35704}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O15269-1; Sequence=Displayed; CC Name=2; CC IsoId=O15269-2; Sequence=VSP_043127, VSP_043128; CC -!- TISSUE SPECIFICITY: Widely expressed. Not detected in small intestine. CC {ECO:0000269|PubMed:17023427}. CC -!- INDUCTION: Expression at protein level is highly increased in brains of CC patients with Alzheimer disease. No changes are observed at mRNA level. CC {ECO:0000269|PubMed:21994399}. CC -!- DOMAIN: The transmembrane domain is involved in the interaction with CC ORMDL3. {ECO:0000269|PubMed:33558762}. CC -!- PTM: Phosphorylation at Tyr-164 inhibits activity and promotes cell CC survival. {ECO:0000269|PubMed:23629659}. CC -!- DISEASE: Amyotrophic lateral sclerosis 27, juvenile (ALS27) CC [MIM:620285]: A form of amyotrophic lateral sclerosis, a CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. ALS27 is an autosomal CC dominant form manifesting as toe walking and gait abnormalities in CC early childhood. {ECO:0000269|PubMed:34059824, CC ECO:0000269|PubMed:34459874, ECO:0000269|PubMed:36204986, CC ECO:0000269|PubMed:37308477}. Note=The disease is caused by variants CC affecting the gene represented in this entry. Variants associated with CC ALS27 tend to disrupt the normal homeostatic regulation of serine CC palmitoyltransferase (SPT) by ORMDL proteins, resulting in up-regulated CC SPT activity and elevated levels of canonical SPT products. CC {ECO:0000269|PubMed:34059824}. CC -!- DISEASE: Neuropathy, hereditary sensory and autonomic, 1A (HSAN1A) CC [MIM:162400]: A form of hereditary sensory and autonomic neuropathy, a CC genetically and clinically heterogeneous group of disorders CC characterized by degeneration of dorsal root and autonomic ganglion CC cells, and by prominent sensory abnormalities with a variable degree of CC motor and autonomic dysfunction. The neurological phenotype is often CC complicated by severe infections, osteomyelitis, and amputations. CC HSAN1A is an autosomal dominant axonal form with onset in the second or CC third decades. Initial symptoms are loss of pain, touch, heat, and cold CC sensation over the feet, followed by distal muscle wasting and CC weakness. Loss of pain sensation leads to chronic skin ulcers and CC distal amputations. {ECO:0000269|PubMed:11242114, CC ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702, CC ECO:0000269|PubMed:20504773, ECO:0000269|PubMed:21618344, CC ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:23454272, CC ECO:0000269|PubMed:24247255, ECO:0000269|PubMed:30420926}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. Variants associated with HSAN1A tend to increase serine CC palmitoyltransferase (SPT) usage of alanine or glycine rather than CC serine, resulting in deoxysphingolipid synthesis. Deoxysphingolipids CC cannot be efficiently degraded by the cell machinery and cause cell CC toxicity. {ECO:0000305|PubMed:34059824}. CC -!- SIMILARITY: Belongs to the class-II pyridoxal-phosphate-dependent CC aminotransferase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y08685; CAA69941.1; -; mRNA. DR EMBL; AF286717; AAK29328.1; -; Genomic_DNA. DR EMBL; AF286703; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286704; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286705; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286706; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286707; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286708; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286709; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286710; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286711; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286712; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286713; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286714; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286715; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AF286716; AAK29328.1; JOINED; Genomic_DNA. DR EMBL; AK291546; BAF84235.1; -; mRNA. DR EMBL; AL391219; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL354751; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471089; EAW62804.1; -; Genomic_DNA. DR EMBL; BC007085; AAH07085.1; -; mRNA. DR CCDS; CCDS6692.1; -. [O15269-1] DR CCDS; CCDS6693.1; -. [O15269-2] DR RefSeq; NP_001268232.1; NM_001281303.1. DR RefSeq; NP_006406.1; NM_006415.4. [O15269-1] DR RefSeq; NP_847894.1; NM_178324.3. [O15269-2] DR PDB; 6M4N; EM; 3.80 A; A/E=1-473. DR PDB; 6M4O; EM; 3.40 A; B/S=1-473. DR PDB; 7CQI; EM; 3.20 A; C/S=1-473. DR PDB; 7CQK; EM; 3.30 A; C/S=1-473. DR PDB; 7K0I; EM; 3.30 A; A/D=1-473. DR PDB; 7K0J; EM; 3.10 A; A=1-473. DR PDB; 7K0K; EM; 2.60 A; A=1-473. DR PDB; 7K0L; EM; 3.40 A; A=1-473. DR PDB; 7K0M; EM; 2.90 A; A/E=1-473. DR PDB; 7K0N; EM; 3.10 A; A/E=1-473. DR PDB; 7K0O; EM; 3.10 A; A/E=1-473. DR PDB; 7K0P; EM; 3.10 A; A/E=1-473. DR PDB; 7K0Q; EM; 3.30 A; A=1-473. DR PDB; 7YIU; EM; 2.90 A; A/E=1-473. DR PDB; 7YIY; EM; 2.70 A; A/E=1-473. DR PDB; 7YJ1; EM; 3.10 A; A/E=1-473. DR PDB; 7YJ2; EM; 2.90 A; A/E=1-473. DR PDBsum; 6M4N; -. DR PDBsum; 6M4O; -. DR PDBsum; 7CQI; -. DR PDBsum; 7CQK; -. DR PDBsum; 7K0I; -. DR PDBsum; 7K0J; -. DR PDBsum; 7K0K; -. DR PDBsum; 7K0L; -. DR PDBsum; 7K0M; -. DR PDBsum; 7K0N; -. DR PDBsum; 7K0O; -. DR PDBsum; 7K0P; -. DR PDBsum; 7K0Q; -. DR PDBsum; 7YIU; -. DR PDBsum; 7YIY; -. DR PDBsum; 7YJ1; -. DR PDBsum; 7YJ2; -. DR AlphaFoldDB; O15269; -. DR EMDB; EMD-22598; -. DR EMDB; EMD-22599; -. DR EMDB; EMD-22600; -. DR EMDB; EMD-22601; -. DR EMDB; EMD-22602; -. DR EMDB; EMD-22604; -. DR EMDB; EMD-22605; -. DR EMDB; EMD-22606; -. DR EMDB; EMD-22608; -. DR EMDB; EMD-30079; -. DR EMDB; EMD-30080; -. DR EMDB; EMD-30081; -. DR EMDB; EMD-30082; -. DR EMDB; EMD-30441; -. DR EMDB; EMD-30442; -. DR EMDB; EMD-33864; -. DR EMDB; EMD-33866; -. DR EMDB; EMD-33868; -. DR EMDB; EMD-33869; -. DR SMR; O15269; -. DR BioGRID; 115809; 198. DR ComplexPortal; CPX-6663; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSA variant. DR ComplexPortal; CPX-6664; Serine palmitoyltransferase complex, SPTLC1-SPTLC2-SPTSSB variant. DR ComplexPortal; CPX-6665; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSA variant. DR ComplexPortal; CPX-6681; Serine palmitoyltransferase complex, SPTLC1-SPTLC3-SPTSSB variant. DR CORUM; O15269; -. DR DIP; DIP-45626N; -. DR FunCoup; O15269; 3163. DR IntAct; O15269; 137. DR MINT; O15269; -. DR STRING; 9606.ENSP00000262554; -. DR BindingDB; O15269; -. DR ChEMBL; CHEMBL1250343; -. DR DrugBank; DB00114; Pyridoxal phosphate. DR DrugBank; DB00133; Serine. DR GlyGen; O15269; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O15269; -. DR MetOSite; O15269; -. DR PhosphoSitePlus; O15269; -. DR SwissPalm; O15269; -. DR BioMuta; SPTLC1; -. DR jPOST; O15269; -. DR MassIVE; O15269; -. DR PaxDb; 9606-ENSP00000262554; -. DR PeptideAtlas; O15269; -. DR ProteomicsDB; 48557; -. [O15269-1] DR ProteomicsDB; 48558; -. [O15269-2] DR Pumba; O15269; -. DR Antibodypedia; 2269; 395 antibodies from 37 providers. DR DNASU; 10558; -. DR Ensembl; ENST00000262554.7; ENSP00000262554.2; ENSG00000090054.17. [O15269-1] DR Ensembl; ENST00000337841.4; ENSP00000337635.4; ENSG00000090054.17. [O15269-2] DR Ensembl; ENST00000690139.1; ENSP00000510483.1; ENSG00000090054.17. [O15269-2] DR GeneID; 10558; -. DR KEGG; hsa:10558; -. DR MANE-Select; ENST00000262554.7; ENSP00000262554.2; NM_006415.4; NP_006406.1. DR UCSC; uc004arl.3; human. [O15269-1] DR AGR; HGNC:11277; -. DR ClinPGx; PA36106; -. DR CTD; 10558; -. DR DisGeNET; 10558; -. DR GeneCards; SPTLC1; -. DR GeneReviews; SPTLC1; -. DR HGNC; HGNC:11277; SPTLC1. DR HPA; ENSG00000090054; Low tissue specificity. DR MalaCards; SPTLC1; -. DR MIM; 162400; phenotype. DR MIM; 605712; gene. DR MIM; 620285; phenotype. DR OpenTargets; ENSG00000090054; -. DR Orphanet; 36386; Hereditary sensory and autonomic neuropathy type 1. DR Orphanet; 300605; Juvenile amyotrophic lateral sclerosis. DR VEuPathDB; HostDB:ENSG00000090054; -. DR eggNOG; KOG1358; Eukaryota. DR GeneTree; ENSGT00550000074872; -. DR HOGENOM; CLU_015846_0_1_1; -. DR InParanoid; O15269; -. DR OMA; LTKYGCG; -. DR OrthoDB; 3168162at2759; -. DR PAN-GO; O15269; 4 GO annotations based on evolutionary models. DR PhylomeDB; O15269; -. DR BioCyc; MetaCyc:HS01673-MONOMER; -. DR BRENDA; 2.3.1.50; 2681. DR PathwayCommons; O15269; -. DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis. DR SABIO-RK; O15269; -. DR SignaLink; O15269; -. DR SIGNOR; O15269; -. DR UniPathway; UPA00222; -. DR Agora; ENSG00000090054; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 10558; 265 hits in 1179 CRISPR screens. DR ChiTaRS; SPTLC1; human. DR GeneWiki; SPTLC1; -. DR GenomeRNAi; 10558; -. DR Pharos; O15269; Tchem. DR PRO; PR:O15269; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; O15269; protein. DR Bgee; ENSG00000090054; Expressed in esophagus squamous epithelium and 210 other cell types or tissues. DR ExpressionAtlas; O15269; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0017059; C:serine palmitoyltransferase complex; IDA:UniProtKB. DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro. DR GO; GO:0004758; F:serine C-palmitoyltransferase activity; IDA:UniProtKB. DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:MGI. DR GO; GO:1904504; P:positive regulation of lipophagy; IDA:MGI. DR GO; GO:1904649; P:regulation of fat cell apoptotic process; ISS:UniProtKB. DR GO; GO:0046511; P:sphinganine biosynthetic process; IEA:Ensembl. DR GO; GO:0030148; P:sphingolipid biosynthetic process; IDA:MGI. DR GO; GO:0006665; P:sphingolipid metabolic process; TAS:ProtInc. DR GO; GO:0006686; P:sphingomyelin biosynthetic process; IEA:Ensembl. DR GO; GO:0046512; P:sphingosine biosynthetic process; IDA:ComplexPortal. DR FunFam; 3.40.640.10:FF:000049; serine palmitoyltransferase 1 isoform X1; 1. DR Gene3D; 3.90.1150.10; Aspartate Aminotransferase, domain 1; 1. DR Gene3D; 3.40.640.10; Type I PLP-dependent aspartate aminotransferase-like (Major domain); 1. DR InterPro; IPR004839; Aminotransferase_I/II_large. DR InterPro; IPR050087; AON_synthase_class-II. DR InterPro; IPR015424; PyrdxlP-dep_Trfase. DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major. DR InterPro; IPR015422; PyrdxlP-dep_Trfase_small. DR PANTHER; PTHR13693; CLASS II AMINOTRANSFERASE/8-AMINO-7-OXONONANOATE SYNTHASE; 1. DR PANTHER; PTHR13693:SF2; SERINE PALMITOYLTRANSFERASE 1; 1. DR Pfam; PF00155; Aminotran_1_2; 1. DR SUPFAM; SSF53383; PLP-dependent transferases; 1. PE 1: Evidence at protein level; KW 3D-structure; Acyltransferase; Alternative splicing; KW Amyotrophic lateral sclerosis; Disease variant; Endoplasmic reticulum; KW Lipid metabolism; Membrane; Neurodegeneration; Neuropathy; Phosphoprotein; KW Proteomics identification; Pyridoxal phosphate; Reference proteome; KW Sphingolipid metabolism; Transferase; Transmembrane; Transmembrane helix. FT CHAIN 1..473 FT /note="Serine palmitoyltransferase 1" FT /id="PRO_0000163853" FT TOPO_DOM 1..15 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 16..36 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 37..473 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 1..66 FT /note="Interaction with SPTLC2" FT /evidence="ECO:0000269|PubMed:33558762" FT MOD_RES 164 FT /note="Phosphotyrosine; by ABL" FT /evidence="ECO:0000269|PubMed:23629659" FT VAR_SEQ 143 FT /note="D -> E (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043127" FT VAR_SEQ 144..473 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043128" FT VARIANT 20 FT /note="A -> S (in ALS27; the underlying nucleotide FT substitution predominantly results in exon 2 skipping; in FT patient's whole blood sample, only exon 2 deletion was FT observed, but not the missense variant per se; when exon 2 FT deletion variant is expressed in induced pluripotent stem FT cells (iPSC) differentiated into motor neuron-like cells, FT increased production of sphinganine and ceramides is FT observed; when exon 2 deletion variant is transfected into FT HEK293 cells, decreased response to inhibition mediated by FT ORMDL3 or ceramide is observed; dbSNP:rs879254294)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:34459874" FT /id="VAR_088446" FT VARIANT 23 FT /note="Y -> F (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3; dbSNP:rs1554716504)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:37308477" FT /id="VAR_088447" FT VARIANT 38 FT /note="L -> R (in ALS27; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36204986" FT /id="VAR_088448" FT VARIANT 39 FT /note="Missing (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3; dbSNP:rs1197928094)" FT /evidence="ECO:0000269|PubMed:34059824, FT ECO:0000269|PubMed:34459874" FT /id="VAR_088449" FT VARIANT 40..41 FT /note="Missing (in ALS27; increased production of FT sphinganine and ceramides, when expressed in induced FT pluripotent stem cells (iPSC) differentiated into motor FT neuron-like cells; decreased response to inhibition FT mediated by ORMDL3 and ceramide; no effect on the FT interaction with ORMDL3)" FT /evidence="ECO:0000269|PubMed:34059824" FT /id="VAR_088450" FT VARIANT 133 FT /note="C -> W (in HSAN1A; inactive in the heterodimeric SPT FT complex; largely reduced canonical activity towards serine; FT contrary to wild-type, uses alanine as substrate leading to FT the formation of 1-deoxysphinganine (1-deoxySa); does not FT affect the interaction with SPTLC2; dbSNP:rs119482082)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:20504773, FT ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:22302274" FT /id="VAR_011392" FT VARIANT 133 FT /note="C -> Y (in HSAN1A; reduced canonical activity FT towards serine; does not affect the interaction with FT SPTLC2; dbSNP:rs119482081)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419" FT /id="VAR_011393" FT VARIANT 144 FT /note="V -> D (in HSAN1A; reduced canonical activity FT towards serine; does not affect the interaction with FT SPTLC2; dbSNP:rs119482083)" FT /evidence="ECO:0000269|PubMed:11242114, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:30420926" FT /id="VAR_011394" FT VARIANT 151 FT /note="R -> L (in dbSNP:rs45461899)" FT /evidence="ECO:0000269|PubMed:17060578" FT /id="VAR_037889" FT VARIANT 239 FT /note="R -> W (in a breast cancer sample; somatic mutation; FT dbSNP:rs542876370)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036610" FT VARIANT 310 FT /note="A -> G (found in a patient with HSAN1A; uncertain FT significance; dbSNP:rs768841574)" FT /evidence="ECO:0000269|PubMed:22302274" FT /id="VAR_068476" FT VARIANT 331 FT /note="S -> F (in HSAN1A; severe form with early onset; FT reduced canonical activity towards serine and increased FT production of deoxysphingolipids; no effect on subcellular FT location at the endoplasmic reticulum; dbSNP:rs267607087)" FT /evidence="ECO:0000269|PubMed:19651702, FT ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:24247255" FT /id="VAR_066245" FT VARIANT 331 FT /note="S -> Y (in ALS27 and HSAN1A; reduced canonical FT activity towards serine and increased production of FT deoxysphingolipids; dbSNP:rs267607087)" FT /evidence="ECO:0000269|PubMed:23454272, FT ECO:0000269|PubMed:34459874" FT /id="VAR_073294" FT VARIANT 352 FT /note="A -> V (in HSAN1A; reduced canonical activity FT towards serine and increased production of FT deoxysphingolipids; no effect on subcellular location at FT the endoplasmic reticulum; dbSNP:rs267607088)" FT /evidence="ECO:0000269|PubMed:19651702, FT ECO:0000269|PubMed:21618344" FT /id="VAR_066246" FT VARIANT 387 FT /note="G -> A (does not affect catalytic activity towards FT serine; does not affect the interaction with SPTLC2; FT dbSNP:rs119482084)" FT /evidence="ECO:0000269|PubMed:15037712, FT ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702" FT /id="VAR_037890" FT MUTAGEN 138 FT /note="F->A: Decreased catalytic activity with L-serine and FT palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT MUTAGEN 164 FT /note="Y->F: Increased serine palmitoyltransferase activity FT and sphingolipid content." FT /evidence="ECO:0000269|PubMed:23629659" FT MUTAGEN 337 FT /note="F->A: Strongly decreased catalytic activity with L- FT serine and palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT MUTAGEN 338 FT /note="S->A: Decreased catalytic activity with L-serine and FT palmitoyl-CoA as substrates." FT /evidence="ECO:0000269|PubMed:33558762" FT HELIX 11..18 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 22..39 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 54..63 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 78..80 FT /evidence="ECO:0007829|PDB:7K0J" FT STRAND 85..87 FT /evidence="ECO:0007829|PDB:7YJ2" FT STRAND 90..97 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 99..103 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 108..110 FT /evidence="ECO:0007829|PDB:7K0J" FT HELIX 115..128 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 136..139 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 143..156 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 159..166 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 169..178 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 184..188 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 193..201 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 205..209 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 214..229 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 232..235 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 240..247 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 249..251 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 258..267 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 270..274 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 276..281 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 282..286 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 289..293 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 297..299 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 303..306 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 309..311 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 316..320 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 322..325 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 326..331 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 333..336 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 343..358 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 362..376 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 377..379 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 383..387 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 395..400 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 405..419 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 420..422 FT /evidence="ECO:0007829|PDB:7YIY" FT HELIX 433..435 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 436..438 FT /evidence="ECO:0007829|PDB:6M4O" FT STRAND 443..445 FT /evidence="ECO:0007829|PDB:7YIY" FT STRAND 450..452 FT /evidence="ECO:0007829|PDB:7YIU" FT HELIX 454..468 FT /evidence="ECO:0007829|PDB:7YIY" FT TURN 469..471 FT /evidence="ECO:0007829|PDB:7YIY" SQ SEQUENCE 473 AA; 52744 MW; BA9E056A869D2EA2 CRC64; MATATEQWVL VEMVQALYEA PAYHLILEGI LILWIIRLLF SKTYKLQERS DLTVKEKEEL IEEWQPEPLV PPVPKDHPAL NYNIVSGPPS HKTVVNGKEC INFASFNFLG LLDNPRVKAA ALASLKKYGV GTCGPRGFYG TFDVHLDLED RLAKFMKTEE AIIYSYGFAT IASAIPAYSK RGDIVFVDRA ACFAIQKGLQ ASRSDIKLFK HNDMADLERL LKEQEIEDQK NPRKARVTRR FIVVEGLYMN TGTICPLPEL VKLKYKYKAR IFLEESLSFG VLGEHGRGVT EHYGINIDDI DLISANMENA LASIGGFCCG RSFVIDHQRL SGQGYCFSAS LPPLLAAAAI EALNIMEENP GIFAVLKEKC GQIHKALQGI SGLKVVGESL SPAFHLQLEE STGSREQDVR LLQEIVDQCM NRSIALTQAR YLEKEEKCLP PPSIRVVVTV EQTEEELERA ASTIKEVAQA VLL // ID SYUA_HUMAN Reviewed; 140 AA. AC P37840; A8K2A4; Q13701; Q4JHI3; Q6IAU6; DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1994, sequence version 1. DT 28-JAN-2026, entry version 259. DE RecName: Full=Alpha-synuclein; DE AltName: Full=Non-A beta component of AD amyloid; DE AltName: Full=Non-A4 component of amyloid precursor; DE Short=NACP; GN Name=SNCA; Synonyms=NACP, PARK1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 61-95. RC TISSUE=Brain; RX PubMed=8248242; DOI=10.1073/pnas.90.23.11282; RA Ueda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M., RA Otero D.A., Kondo J., Ihara Y., Saitoh T.; RT "Molecular cloning of cDNA encoding an unrecognized component of amyloid in RT Alzheimer disease."; RL Proc. Natl. Acad. Sci. U.S.A. 90:11282-11286(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2-4 AND 2-5). RX PubMed=7601450; DOI=10.1016/0888-7543(95)80208-4; RA Campion D., Martin C., Heilig R., Charbonnier F., Moreau V., Flaman J.-M., RA Petit J.-L., Hannequin D., Brice A., Frebourg T.; RT "The NACP/synuclein gene: chromosomal assignment and screening for RT alterations in Alzheimer disease."; RL Genomics 26:254-257(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2-4). RC TISSUE=Brain; RX PubMed=7802671; DOI=10.1006/bbrc.1994.2816; RA Ueda K., Saitoh T., Mori H.; RT "Tissue-dependent alternative splicing of mRNA for NACP, the precursor of RT non-A beta component of Alzheimer's disease amyloid."; RL Biochem. Biophys. Res. Commun. 205:1366-1372(1994). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Xia Y., Silva R.D., Chen X.H., Saitoh T.; RL Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2-4). RX PubMed=11156617; DOI=10.1101/gr.165801; RA Touchman J.W., Dehejia A., Chiba-Falek O., Cabin D.E., Schwartz J.R., RA Orrison B.M., Polymeropoulos M.H., Nussbaum R.L.; RT "Human and mouse alpha-synuclein genes: comparative genomic sequence RT analysis and identification of a novel gene regulatory element."; RL Genome Res. 11:78-86(2001). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Hu X., Xu Y., Peng X., Yuan J., Qiang B.; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [12] RP PROTEIN SEQUENCE OF 59-96, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Fetal brain cortex; RA Lubec G., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [13] RP TISSUE SPECIFICITY. RX PubMed=8194594; DOI=10.1016/0014-5793(94)00395-5; RA Jakes R., Spillantini M.G., Goedert M.; RT "Identification of two distinct synucleins from human brain."; RL FEBS Lett. 345:27-32(1994). RN [14] RP PHOSPHORYLATION AT SER-87 AND SER-129 BY CK1 AND CK2. RX PubMed=10617630; DOI=10.1074/jbc.275.1.390; RA Okochi M., Walter J., Koyama A., Nakajo S., Baba M., Iwatsubo T., RA Meijer L., Kahle P.J., Haass C.; RT "Constitutive phosphorylation of the Parkinson's disease associated alpha- RT synuclein."; RL J. Biol. Chem. 275:390-397(2000). RN [15] RP PHOSPHORYLATION BY G-PROTEIN COUPLED RECEPTOR KINASE. RX PubMed=10852916; DOI=10.1074/jbc.m003542200; RA Pronin A.N., Morris A.J., Surguchov A., Benovic J.L.; RT "Synucleins are a novel class of substrates for G protein-coupled receptor RT kinases."; RL J. Biol. Chem. 275:26515-26522(2000). RN [16] RP PHOSPHORYLATION AT TYR-125 BY FYN. RX PubMed=11162638; DOI=10.1006/bbrc.2000.4253; RA Nakamura T., Yamashita H., Takahashi T., Nakamura S.; RT "Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125."; RL Biochem. Biophys. Res. Commun. 280:1085-1092(2001). RN [17] RP INTERACTION WITH PHOSPHOLIPASE D. RX PubMed=11821392; DOI=10.1074/jbc.m110414200; RA Ahn B.H., Rhim H., Kim S.Y., Sung Y.M., Lee M.Y., Choi J.Y., Wolozin B., RA Chang J.S., Lee Y.H., Kwon T.K., Chung K.C., Yoon S.H., Hahn S.J., RA Kim M.S., Jo Y.H., Min do S.; RT "Alpha-synuclein interacts with phospholipase D isozymes and inhibits RT pervanadate-induced phospholipase D activation in human embryonic kidney- RT 293 cells."; RL J. Biol. Chem. 277:12334-12342(2002). RN [18] RP PHOSPHORYLATION AT SER-129. RX PubMed=11813001; DOI=10.1038/ncb748; RA Fujiwara H., Hasegawa M., Dohmae N., Kawashima A., Masliah E., RA Goldberg M.S., Shen J., Takio K., Iwatsubo T.; RT "alpha-Synuclein is phosphorylated in synucleinopathy lesions."; RL Nat. Cell Biol. 4:160-164(2002). RN [19] RP INTERACTION WITH HISTONES, AND SUBCELLULAR LOCATION. RX PubMed=12859192; DOI=10.1021/bi0341152; RA Goers J., Manning-Bog A.B., McCormack A.L., Millett I.S., Doniach S., RA Di Monte D.A., Uversky V.N., Fink A.L.; RT "Nuclear localization of alpha-synuclein and its interaction with RT histones."; RL Biochemistry 42:8465-8471(2003). RN [20] RP ROLE OF THE C-TERMINUS IN FIBRILLOGENESIS. RX PubMed=12859200; DOI=10.1021/bi027363r; RA Murray I.V., Giasson B.I., Quinn S.M., Koppaka V., Axelsen P.H., RA Ischiropoulos H., Trojanowski J.Q., Lee V.M.; RT "Role of alpha-synuclein carboxy-terminus on fibril formation in vitro."; RL Biochemistry 42:8530-8540(2003). RN [21] RP REVIEW. RX PubMed=12558071; DOI=10.2174/1566524033361690; RA Alves da Costa C.; RT "Recent advances on alpha-synuclein cell biology: functions and RT dysfunctions."; RL Curr. Mol. Med. 3:17-24(2003). RN [22] RP MUTAGENESIS OF TYR-39; TYR-125; TYR-133 AND TYR-136, CHARACTERIZATION OF RP VARIANT THR-53, AND PHOSPHORYLATION AT TYR-125. RX PubMed=12893833; DOI=10.1074/jbc.m213217200; RA Takahashi T., Yamashita H., Nagano Y., Nakamura T., Ohmori H., Avraham H., RA Avraham S., Yasuda M., Matsumoto M.; RT "Identification and characterization of a novel Pyk2/related adhesion focal RT tyrosine kinase-associated protein that inhibits alpha-synuclein RT phosphorylation."; RL J. Biol. Chem. 278:42225-42233(2003). RN [23] RP INTERACTION WITH RPH3A AND RAB3A. RX PubMed=15207266; DOI=10.1016/j.nbd.2004.01.001; RA Dalfo E., Barrachina M., Rosa J.L., Ambrosio S., Ferrer I.; RT "Abnormal alpha-synuclein interactions with rab3a and rabphilin in diffuse RT Lewy body disease."; RL Neurobiol. Dis. 16:92-97(2004). RN [24] RP SUBCELLULAR LOCATION. RX PubMed=15282274; DOI=10.1523/jneurosci.1594-04.2004; RA Fortin D.L., Troyer M.D., Nakamura K., Kubo S., Anthony M.D., Edwards R.H.; RT "Lipid rafts mediate the synaptic localization of alpha-synuclein."; RL J. Neurosci. 24:6715-6723(2004). RN [25] RP FIBRILS FORMATION, DOMAIN NAC, AND MUTAGENESIS OF 67-GLY--VAL-71; RP 71-VAL--VAL-82; 76-ALA-VAL-77; VAL-77; ALA-78 AND 85-ALA--PHE-94. RX PubMed=19722699; DOI=10.1021/bi900539p; RA Waxman E.A., Mazzulli J.R., Giasson B.I.; RT "Characterization of hydrophobic residue requirements for alpha-synuclein RT fibrillization."; RL Biochemistry 48:9427-9436(2009). RN [26] RP FUNCTION, AND INTERACTION WITH VAMP2 AND SNAP25. RX PubMed=20798282; DOI=10.1126/science.1195227; RA Burre J., Sharma M., Tsetsenis T., Buchman V., Etherton M.R., Suedhof T.C.; RT "Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro."; RL Science 329:1663-1667(2010). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [28] RP COPPER-BINDING, AND MUTAGENESIS OF ASP-2 AND HIS-50. RX PubMed=21319811; DOI=10.1021/bi101912q; RA Dudzik C.G., Walter E.D., Millhauser G.L.; RT "Coordination features and affinity of the Cu(2)+ site in the alpha- RT synuclein protein of Parkinson's disease."; RL Biochemistry 50:1771-1777(2011). RN [29] RP SUBUNIT. RX PubMed=21841800; DOI=10.1038/nature10324; RA Bartels T., Choi J.G., Selkoe D.J.; RT "alpha-Synuclein occurs physiologically as a helically folded tetramer that RT resists aggregation."; RL Nature 477:107-110(2011). RN [30] RP INTERACTION WITH SERF1A. RX PubMed=22854022; DOI=10.1016/j.celrep.2012.06.012; RA Falsone S.F., Meyer N.H., Schrank E., Leitinger G., Pham C.L., RA Fodero-Tavoletti M.T., Holmberg M., Dulle M., Scicluna B., Gesslbauer B., RA Rueckert H.M., Wagner G.E., Merle D.A., Nollen E.A., Kungl A.J., Hill A.F., RA Cappai R., Zangger K.; RT "SERF protein is a direct modifier of amyloid fiber assembly."; RL Cell Rep. 2:358-371(2012). RN [31] RP ACETYLATION AT MET-1. RX PubMed=22407793; DOI=10.1002/pro.2056; RA Trexler A.J., Rhoades E.; RT "N-Terminal acetylation is critical for forming alpha-helical oligomer of RT alpha-synuclein."; RL Protein Sci. 21:601-605(2012). RN [32] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SLC6A3. RX PubMed=26442590; DOI=10.1074/jbc.m115.691592; RA Butler B., Saha K., Rana T., Becker J.P., Sambo D., Davari P., RA Goodwin J.S., Khoshbouei H.; RT "Dopamine Transporter Activity Is Modulated by alpha-Synuclein."; RL J. Biol. Chem. 290:29542-29554(2015). RN [33] RP INTERACTION WITH STXBP1, AND SUBCELLULAR LOCATION. RX PubMed=27597756; DOI=10.1083/jcb.201512016; RA Chai Y.J., Sierecki E., Tomatis V.M., Gormal R.S., Giles N., Morrow I.C., RA Xia D., Goetz J., Parton R.G., Collins B.M., Gambin Y., Meunier F.A.; RT "Munc18-1 is a molecular chaperone for alpha-synuclein, controlling its RT self-replicating aggregation."; RL J. Cell Biol. 214:705-718(2016). RN [34] RP FUNCTION. RX PubMed=28288128; DOI=10.1038/nn.4529; RA Logan T., Bendor J., Toupin C., Thorn K., Edwards R.H.; RT "alpha-Synuclein promotes dilation of the exocytotic fusion pore."; RL Nat. Neurosci. 20:681-689(2017). RN [35] RP FUNCTION. RX PubMed=30404828; DOI=10.1242/jcs.213017; RA Huang C.C., Chiu T.Y., Lee T.Y., Hsieh H.J., Lin C.C., Kao L.S.; RT "Soluble alpha-synuclein facilitates priming and fusion by releasing Ca2+ RT from the thapsigargin-sensitive Ca2+ pool in PC12 cells."; RL J. Cell Sci. 131:0-0(2018). RN [36] RP INTERACTION WITH DDX10, AND SUBCELLULAR LOCATION. RX PubMed=33657088; DOI=10.1371/journal.pgen.1009407; RA Popova B., Wang D., Paetz C., Akkermann D., Lazaro D.F., Galka D., RA Kolog Gulko M., Bohnsack M.T., Moebius W., Bohnsack K.E., Outeiro T.F., RA Braus G.H.; RT "DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of alpha-synuclein RT toxicity and oligomerization."; RL PLoS Genet. 17:e1009407-e1009407(2021). RN [37] RP INTERACTION WITH SERF1A, AND SUBCELLULAR LOCATION. RX PubMed=31034892; DOI=10.1016/j.jmb.2019.04.031; RA Merle D.A., Witternigg A., Tam-Amersdorfer C., Hartlmueller C., RA Spreitzer E., Schrank E., Wagner-Lichtenegger S., Werzer O., Zangger K., RA Kungl A.J., Madl T., Meyer N.H., Falsone S.F.; RT "Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered RT Protein Complex."; RL J. Mol. Biol. 431:2581-2598(2019). RN [38] RP STRUCTURE BY NMR IN COMPLEX WITH DETERGENT MICELLES. RX PubMed=15615727; DOI=10.1074/jbc.m411805200; RA Ulmer T.S., Bax A., Cole N.B., Nussbaum R.L.; RT "Structure and dynamics of micelle-bound human alpha-synuclein."; RL J. Biol. Chem. 280:9595-9603(2005). RN [39] RP STRUCTURE BY NMR OF 1-12, INTERACTION WITH SNCAIP, AND SUBCELLULAR RP LOCATION. RX PubMed=19762560; DOI=10.1096/fj.09-133082; RA Xie Y.Y., Zhou C.J., Zhou Z.R., Hong J., Che M.X., Fu Q.S., Song A.X., RA Lin D.H., Hu H.Y.; RT "Interaction with synphilin-1 promotes inclusion formation of alpha- RT synuclein: mechanistic insights and pathological implication."; RL FASEB J. 24:196-205(2010). RN [40] RP X-RAY CRYSTALLOGRAPHY (1.30 ANGSTROMS) OF 1-57 AND 58-79. RX PubMed=21462277; DOI=10.1002/pro.630; RA Zhao M., Cascio D., Sawaya M.R., Eisenberg D.; RT "Structures of segments of alpha-synuclein fused to maltose-binding protein RT suggest intermediate states during amyloid formation."; RL Protein Sci. 20:996-1004(2011). RN [41] RP STRUCTURE BY NMR OF 1-19, AND INTERACTION WITH CALM1. RX PubMed=23607618; DOI=10.1021/bi400199p; RA Gruschus J.M., Yap T.L., Pistolesi S., Maltsev A.S., Lee J.C.; RT "NMR structure of calmodulin complexed to an N-terminally acetylated alpha- RT synuclein peptide."; RL Biochemistry 52:3436-3445(2013). RN [42] RP STRUCTURE BY ELECTRON MICROSCOPY (1.41 ANGSTROMS) OF 47-56 AND 68-78. RX PubMed=26352473; DOI=10.1038/nature15368; RA Rodriguez J.A., Ivanova M.I., Sawaya M.R., Cascio D., Reyes F.E., Shi D., RA Sangwan S., Guenther E.L., Johnson L.M., Zhang M., Jiang L., Arbing M.A., RA Nannenga B.L., Hattne J., Whitelegge J., Brewster A.S., Messerschmidt M., RA Boutet S., Sauter N.K., Gonen T., Eisenberg D.S.; RT "Structure of the toxic core of alpha-synuclein from invisible crystals."; RL Nature 525:486-490(2015). RN [43] RP STRUCTURE BY NMR. RX PubMed=27018801; DOI=10.1038/nsmb.3194; RA Tuttle M.D., Comellas G., Nieuwkoop A.J., Covell D.J., Berthold D.A., RA Kloepper K.D., Courtney J.M., Kim J.K., Barclay A.M., Kendall A., Wan W., RA Stubbs G., Schwieters C.D., Lee V.M., George J.M., Rienstra C.M.; RT "Solid-state NMR structure of a pathogenic fibril of full-length human RT alpha-synuclein."; RL Nat. Struct. Mol. Biol. 23:409-415(2016). RN [44] RP STRUCTURE BY ELECTRON MICROSCOPY (3.50 ANGSTROMS). RX PubMed=30190461; DOI=10.1038/s41467-018-05971-2; RA Li B., Ge P., Murray K.A., Sheth P., Zhang M., Nair G., Sawaya M.R., RA Shin W.S., Boyer D.R., Ye S., Eisenberg D.S., Zhou Z.H., Jiang L.; RT "Cryo-EM of full-length alpha-synuclein reveals fibril polymorphs with a RT common structural kernel."; RL Nat. Commun. 9:3609-3609(2018). RN [45] RP VARIANT PARK1 THR-53. RX PubMed=9197268; DOI=10.1126/science.276.5321.2045; RA Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A., Dutra A., RA Pike B., Root H., Rubenstein J., Boyer R., Stenroos E.S., RA Chandrasekharappa S., Athanassiadou A., Papapetropoulos T., Johnson W.G., RA Lazzarini A.M., Duvoisin R.C., di Iorio G., Golbe L.I., Nussbaum R.L.; RT "Mutation in the alpha-synuclein gene identified in families with RT Parkinson's disease."; RL Science 276:2045-2047(1997). RN [46] RP VARIANT PARK1 PRO-30. RX PubMed=9462735; DOI=10.1038/ng0298-106; RA Krueger R., Kuhn W., Mueller T., Woitalla D., Graeber M., Koesel S., RA Przuntek H., Epplen J.T., Schoels L., Riess O.; RT "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's RT disease."; RL Nat. Genet. 18:106-108(1998). RN [47] RP VARIANT PARK1/DLB LYS-46. RX PubMed=14755719; DOI=10.1002/ana.10795; RA Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R., RA Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B., Llorens V., RA Gomez Tortosa E., del Ser T., Munoz D.G., de Yebenes J.G.; RT "The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body RT dementia."; RL Ann. Neurol. 55:164-173(2004). RN [48] RP CHARACTERIZATION OF VARIANT LYS-46. RX PubMed=15498564; DOI=10.1016/j.febslet.2004.09.038; RA Choi W., Zibaee S., Jakes R., Serpell L.C., Davletov B., Crowther R.A., RA Goedert M.; RT "Mutation E46K increases phospholipid binding and assembly into filaments RT of human alpha-synuclein."; RL FEBS Lett. 576:363-368(2004). RN [49] RP VARIANT PARK1 GLN-50. RX PubMed=23457019; DOI=10.1002/mds.25421; RA Appel-Cresswell S., Vilarino-Guell C., Encarnacion M., Sherman H., Yu I., RA Shah B., Weir D., Thompson C., Szu-Tu C., Trinh J., Aasly J.O., Rajput A., RA Rajput A.H., Jon Stoessl A., Farrer M.J.; RT "Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's RT disease."; RL Mov. Disord. 28:811-813(2013). RN [50] RP VARIANT PARK1 GLN-50, AND CHARACTERIZATION OF VARIANT PARK1 GLN-50. RX PubMed=23427326; DOI=10.1212/wnl.0b013e31828727ba; RA Proukakis C., Dudzik C.G., Brier T., MacKay D.S., Cooper J.M., RA Millhauser G.L., Houlden H., Schapira A.H.; RT "A novel alpha-synuclein missense mutation in Parkinson disease."; RL Neurology 80:1062-1064(2013). RN [51] RP CHARACTERIZATION OF VARIANT PARK1 GLN-50, SUBCELLULAR LOCATION, SUBUNIT, RP AND PHOSPHORYLATION AT SER-129. RX PubMed=24936070; DOI=10.1074/jbc.m114.553297; RA Khalaf O., Fauvet B., Oueslati A., Dikiy I., Mahul-Mellier A.L., RA Ruggeri F.S., Mbefo M.K., Vercruysse F., Dietler G., Lee S.J., Eliezer D., RA Lashuel H.A.; RT "The H50Q mutation enhances alpha-synuclein aggregation, secretion, and RT toxicity."; RL J. Biol. Chem. 289:21856-21876(2014). RN [52] RP CHARACTERIZATION OF VARIANTS PARK1 PRO-30; LYS-46; GLN-50 AND THR-53, RP MUTAGENESIS OF GLU-35 AND GLU-57, SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=25561023; DOI=10.1021/cn500332w; RA Tsigelny I.F., Sharikov Y., Kouznetsova V.L., Greenberg J.P., Wrasidlo W., RA Overk C., Gonzalez T., Trejo M., Spencer B., Kosberg K., Masliah E.; RT "Molecular determinants of alpha-synuclein mutants' oligomerization and RT membrane interactions."; RL ACS Chem. Neurosci. 6:403-416(2015). CC -!- FUNCTION: Neuronal protein that plays several roles in synaptic CC activity such as regulation of synaptic vesicle trafficking and CC subsequent neurotransmitter release (PubMed:20798282, PubMed:26442590, CC PubMed:28288128, PubMed:30404828). Participates as a monomer in CC synaptic vesicle exocytosis by enhancing vesicle priming, fusion and CC dilation of exocytotic fusion pores (PubMed:28288128, PubMed:30404828). CC Mechanistically, acts by increasing local Ca(2+) release from CC microdomains which is essential for the enhancement of ATP-induced CC exocytosis (PubMed:30404828). Also acts as a molecular chaperone in its CC multimeric membrane-bound state, assisting in the folding of synaptic CC fusion components called SNAREs (Soluble NSF Attachment Protein CC REceptors) at presynaptic plasma membrane in conjunction with cysteine CC string protein-alpha/DNAJC5 (PubMed:20798282). This chaperone activity CC is important to sustain normal SNARE-complex assembly during aging CC (PubMed:20798282). Also plays a role in the regulation of the dopamine CC neurotransmission by associating with the dopamine transporter (DAT1) CC and thereby modulating its activity (PubMed:26442590). CC {ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:26442590, CC ECO:0000269|PubMed:28288128, ECO:0000269|PubMed:30404828}. CC -!- SUBUNIT: Soluble monomer. Homotetramer (PubMed:21841800). A dynamic CC intracellular population of tetramers and monomers coexists normally CC and the tetramer plays an essential role in maintaining homeostasis CC (PubMed:21841800). Interacts with UCHL1 (By similarity). Interacts with CC phospholipase D and histones. Interacts (via N-terminus) with CC synphilin-1/SNCAIP; this interaction promotes formation of SNCA CC inclusions in the cytoplasm (PubMed:19762560). Interacts with CALM1 CC (PubMed:23607618). Interacts with STXBP1; this interaction controls CC SNCA self-replicating aggregation (PubMed:27597756). Interacts with CC SNARE components VAMP2 and SNAP25; these interactions allows SNARE CC complex assembly and integrity (PubMed:20798282). Interacts with RPH3A CC and RAB3A (PubMed:15207266). Interacts with SERF1A; this interaction CC promotes the aggregation of SNCA (PubMed:22854022, PubMed:31034892). CC Interacts with SEPTIN4 (By similarity). Interacts with DDX10; this CC interaction causes DDX10 mislocalization to the nucleoplasm and CC cytoplasmic inclusions (PubMed:33657088). CC {ECO:0000250|UniProtKB:O55042, ECO:0000250|UniProtKB:P37377, CC ECO:0000269|PubMed:15207266, ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:20798282, ECO:0000269|PubMed:21841800, CC ECO:0000269|PubMed:22854022, ECO:0000269|PubMed:23607618, CC ECO:0000269|PubMed:27597756, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. CC -!- INTERACTION: CC P37840; Q6PCB6: ABHD17C; NbExp=3; IntAct=EBI-985879, EBI-22011868; CC P37840; P00519: ABL1; NbExp=3; IntAct=EBI-985879, EBI-375543; CC P37840; P00519-1: ABL1; NbExp=6; IntAct=EBI-985879, EBI-5278159; CC P37840; P00519-2: ABL1; NbExp=5; IntAct=EBI-985879, EBI-9254597; CC P37840; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-985879, EBI-25840993; CC P37840; P63010-2: AP2B1; NbExp=3; IntAct=EBI-985879, EBI-11529439; CC P37840; O00203: AP3B1; NbExp=3; IntAct=EBI-985879, EBI-1044383; CC P37840; P02647: APOA1; NbExp=3; IntAct=EBI-985879, EBI-701692; CC P37840; P02649: APOE; NbExp=11; IntAct=EBI-985879, EBI-1222467; CC P37840; P05067: APP; NbExp=6; IntAct=EBI-985879, EBI-77613; CC P37840; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-985879, EBI-10694449; CC P37840; Q9NP61: ARFGAP3; NbExp=3; IntAct=EBI-985879, EBI-2875816; CC P37840; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-985879, EBI-10186132; CC P37840; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-985879, EBI-707573; CC P37840; P18847: ATF3; NbExp=3; IntAct=EBI-985879, EBI-712767; CC P37840; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-985879, EBI-1048913; CC P37840; P46379-2: BAG6; NbExp=3; IntAct=EBI-985879, EBI-10988864; CC P37840; Q07812: BAX; NbExp=4; IntAct=EBI-985879, EBI-516580; CC P37840; Q07817: BCL2L1; NbExp=3; IntAct=EBI-985879, EBI-78035; CC P37840; O15392: BIRC5; NbExp=3; IntAct=EBI-985879, EBI-518823; CC P37840; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-985879, EBI-2837444; CC P37840; Q5SZD1: C6orf141; NbExp=3; IntAct=EBI-985879, EBI-10697767; CC P37840; P62158: CALM3; NbExp=3; IntAct=EBI-985879, EBI-397435; CC P37840; Q8N5S9-2: CAMKK1; NbExp=3; IntAct=EBI-985879, EBI-25850646; CC P37840; P55212: CASP6; NbExp=3; IntAct=EBI-985879, EBI-718729; CC P37840; Q7Z7K6: CENPV; NbExp=4; IntAct=EBI-985879, EBI-1210604; CC P37840; Q9HD42: CHMP1A; NbExp=3; IntAct=EBI-985879, EBI-1057156; CC P37840; Q16740: CLPP; NbExp=3; IntAct=EBI-985879, EBI-1056029; CC P37840; P10909: CLU; NbExp=4; IntAct=EBI-985879, EBI-1104674; CC P37840; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-985879, EBI-350590; CC P37840; Q8IUI8: CRLF3; NbExp=3; IntAct=EBI-985879, EBI-2872414; CC P37840; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-985879, EBI-9087876; CC P37840; P99999: CYCS; NbExp=3; IntAct=EBI-985879, EBI-446479; CC P37840; O75398: DEAF1; NbExp=3; IntAct=EBI-985879, EBI-718185; CC P37840; Q8NDP9: DKFZp547K2416; NbExp=3; IntAct=EBI-985879, EBI-25842538; CC P37840; O60479: DLX3; NbExp=3; IntAct=EBI-985879, EBI-3908248; CC P37840; A0AVK6: E2F8; NbExp=3; IntAct=EBI-985879, EBI-7779316; CC P37840; O75530-2: EED; NbExp=3; IntAct=EBI-985879, EBI-11132357; CC P37840; O00472: ELL2; NbExp=3; IntAct=EBI-985879, EBI-395274; CC P37840; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-985879, EBI-9246952; CC P37840; O00471: EXOC5; NbExp=3; IntAct=EBI-985879, EBI-949824; CC P37840; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-985879, EBI-396453; CC P37840; Q0VDC6: FKBP1A; NbExp=3; IntAct=EBI-985879, EBI-10226858; CC P37840; Q6PIV2: FOXR1; NbExp=3; IntAct=EBI-985879, EBI-10253815; CC P37840; P02792: FTL; NbExp=3; IntAct=EBI-985879, EBI-713279; CC P37840; P06241: FYN; NbExp=3; IntAct=EBI-985879, EBI-515315; CC P37840; P06241-3: FYN; NbExp=3; IntAct=EBI-985879, EBI-10691738; CC P37840; P62879: GNB2; NbExp=3; IntAct=EBI-985879, EBI-356942; CC P37840; P49841: GSK3B; NbExp=2; IntAct=EBI-985879, EBI-373586; CC P37840; P68431: H3C12; NbExp=3; IntAct=EBI-985879, EBI-79722; CC P37840; Q71DI3: H3C15; NbExp=3; IntAct=EBI-985879, EBI-750650; CC P37840; Q969S8: HDAC10; NbExp=3; IntAct=EBI-985879, EBI-301762; CC P37840; Q9HCC6: HES4; NbExp=3; IntAct=EBI-985879, EBI-2680288; CC P37840; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-985879, EBI-25845242; CC P37840; P09017: HOXC4; NbExp=3; IntAct=EBI-985879, EBI-3923226; CC P37840; P08107: HSPA1B; NbExp=7; IntAct=EBI-985879, EBI-629985; CC P37840; P42858: HTT; NbExp=4; IntAct=EBI-985879, EBI-466029; CC P37840; P80217-2: IFI35; NbExp=3; IntAct=EBI-985879, EBI-12823003; CC P37840; Q16352: INA; NbExp=3; IntAct=EBI-985879, EBI-366258; CC P37840; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-985879, EBI-21911304; CC P37840; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-985879, EBI-2127319; CC P37840; Q9UIH9: KLF15; NbExp=3; IntAct=EBI-985879, EBI-2796400; CC P37840; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-985879, EBI-714379; CC P37840; Q92876: KLK6; NbExp=3; IntAct=EBI-985879, EBI-2432309; CC P37840; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-985879, EBI-1044640; CC P37840; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-985879, EBI-11985629; CC P37840; P13473-2: LAMP2; NbExp=3; IntAct=EBI-985879, EBI-21591415; CC P37840; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-985879, EBI-1108377; CC P37840; Q9H2C1: LHX5; NbExp=3; IntAct=EBI-985879, EBI-25835523; CC P37840; Q9UPM6: LHX6; NbExp=3; IntAct=EBI-985879, EBI-10258746; CC P37840; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-985879, EBI-739832; CC P37840; Q8N448: LNX2; NbExp=3; IntAct=EBI-985879, EBI-2340947; CC P37840; A2RU56: LOC401296; NbExp=3; IntAct=EBI-985879, EBI-9088215; CC P37840; Q5S007: LRRK2; NbExp=6; IntAct=EBI-985879, EBI-5323863; CC P37840; O95777: LSM8; NbExp=3; IntAct=EBI-985879, EBI-347779; CC P37840; P07948: LYN; NbExp=3; IntAct=EBI-985879, EBI-79452; CC P37840; Q8TD91-2: MAGEC3; NbExp=3; IntAct=EBI-985879, EBI-10694180; CC P37840; P10636-6: MAPT; NbExp=3; IntAct=EBI-985879, EBI-7796455; CC P37840; P10636-8: MAPT; NbExp=12; IntAct=EBI-985879, EBI-366233; CC P37840; Q8N6F8: METTL27; NbExp=3; IntAct=EBI-985879, EBI-8487781; CC P37840; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-985879, EBI-4397720; CC P37840; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-985879, EBI-21250407; CC P37840; Q8N594: MPND; NbExp=3; IntAct=EBI-985879, EBI-2512452; CC P37840; Q9Y3D2: MSRB2; NbExp=3; IntAct=EBI-985879, EBI-9092052; CC P37840; P00414: MT-CO3; NbExp=3; IntAct=EBI-985879, EBI-3932264; CC P37840; P02795: MT2A; NbExp=3; IntAct=EBI-985879, EBI-996616; CC P37840; Q9Y483-4: MTF2; NbExp=3; IntAct=EBI-985879, EBI-10698053; CC P37840; O00746: NME4; NbExp=3; IntAct=EBI-985879, EBI-744871; CC P37840; O15381-5: NVL; NbExp=3; IntAct=EBI-985879, EBI-18577082; CC P37840; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-985879, EBI-25888682; CC P37840; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-985879, EBI-1058491; CC P37840; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-985879, EBI-25830200; CC P37840; Q6VY07: PACS1; NbExp=3; IntAct=EBI-985879, EBI-2555014; CC P37840; O96013-2: PAK4; NbExp=3; IntAct=EBI-985879, EBI-21659863; CC P37840; Q9NR21-5: PARP11; NbExp=3; IntAct=EBI-985879, EBI-17159452; CC P37840; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-985879, EBI-6309018; CC P37840; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-985879, EBI-716063; CC P37840; O75925: PIAS1; NbExp=3; IntAct=EBI-985879, EBI-629434; CC P37840; Q6ZR37: PLEKHG7; NbExp=3; IntAct=EBI-985879, EBI-12891828; CC P37840; P17252: PRKCA; NbExp=3; IntAct=EBI-985879, EBI-1383528; CC P37840; Q02156: PRKCE; NbExp=3; IntAct=EBI-985879, EBI-706254; CC P37840; O60260-5: PRKN; NbExp=8; IntAct=EBI-985879, EBI-21251460; CC P37840; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-985879, EBI-5280197; CC P37840; P62191: PSMC1; NbExp=3; IntAct=EBI-985879, EBI-357598; CC P37840; P17980: PSMC3; NbExp=6; IntAct=EBI-985879, EBI-359720; CC P37840; Q9UI14: RABAC1; NbExp=4; IntAct=EBI-985879, EBI-712367; CC P37840; Q9UJ41-4: RABGEF1; NbExp=3; IntAct=EBI-985879, EBI-14093916; CC P37840; P62826: RAN; NbExp=3; IntAct=EBI-985879, EBI-286642; CC P37840; Q13702-2: RAPSN; NbExp=3; IntAct=EBI-985879, EBI-22012855; CC P37840; P57052: RBM11; NbExp=3; IntAct=EBI-985879, EBI-741332; CC P37840; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-985879, EBI-714023; CC P37840; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-985879, EBI-21535400; CC P37840; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-985879, EBI-25829984; CC P37840; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-985879, EBI-749039; CC P37840; Q8IYW5: RNF168; NbExp=3; IntAct=EBI-985879, EBI-914207; CC P37840; Q96D59: RNF183; NbExp=3; IntAct=EBI-985879, EBI-743938; CC P37840; Q8N488: RYBP; NbExp=3; IntAct=EBI-985879, EBI-752324; CC P37840; O75446: SAP30; NbExp=3; IntAct=EBI-985879, EBI-632609; CC P37840; O00560: SDCBP; NbExp=3; IntAct=EBI-985879, EBI-727004; CC P37840; O43236: SEPTIN4; NbExp=3; IntAct=EBI-985879, EBI-1047513; CC P37840; O75920-2: SERF1B; NbExp=4; IntAct=EBI-985879, EBI-21283682; CC P37840; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-985879, EBI-10182463; CC P37840; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-985879, EBI-358545; CC P37840; Q01959: SLC6A3; NbExp=3; IntAct=EBI-985879, EBI-6661445; CC P37840; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-985879, EBI-9845742; CC P37840; P37840: SNCA; NbExp=51; IntAct=EBI-985879, EBI-985879; CC P37840; Q9Y6H5: SNCAIP; NbExp=22; IntAct=EBI-985879, EBI-717182; CC P37840; Q9Y6H5-2: SNCAIP; NbExp=2; IntAct=EBI-985879, EBI-15577909; CC P37840; Q16143: SNCB; NbExp=3; IntAct=EBI-985879, EBI-727106; CC P37840; P00441: SOD1; NbExp=9; IntAct=EBI-985879, EBI-990792; CC P37840; P23497-2: SP100; NbExp=3; IntAct=EBI-985879, EBI-6589365; CC P37840; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-985879, EBI-11959123; CC P37840; Q8NHS9: SPATA22; NbExp=3; IntAct=EBI-985879, EBI-7067260; CC P37840; Q8TCT7-2: SPPL2B; NbExp=3; IntAct=EBI-985879, EBI-8345366; CC P37840; Q13501: SQSTM1; NbExp=3; IntAct=EBI-985879, EBI-307104; CC P37840; O75886: STAM2; NbExp=3; IntAct=EBI-985879, EBI-373258; CC P37840; Q16623: STX1A; NbExp=2; IntAct=EBI-985879, EBI-712466; CC P37840; Q9BR01-2: SULT4A1; NbExp=3; IntAct=EBI-985879, EBI-25831443; CC P37840; Q92797-2: SYMPK; NbExp=3; IntAct=EBI-985879, EBI-21560407; CC P37840; Q16650: TBR1; NbExp=3; IntAct=EBI-985879, EBI-1047158; CC P37840; Q13569: TDG; NbExp=3; IntAct=EBI-985879, EBI-348333; CC P37840; P28347-2: TEAD1; NbExp=3; IntAct=EBI-985879, EBI-12151837; CC P37840; Q15554-4: TERF2; NbExp=3; IntAct=EBI-985879, EBI-25840535; CC P37840; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-985879, EBI-74615; CC P37840; O94811: TPPP; NbExp=8; IntAct=EBI-985879, EBI-3927802; CC P37840; P19474: TRIM21; NbExp=3; IntAct=EBI-985879, EBI-81290; CC P37840; P68363: TUBA1B; NbExp=3; IntAct=EBI-985879, EBI-487083; CC P37840; P07437: TUBB; NbExp=3; IntAct=EBI-985879, EBI-350864; CC P37840; Q8WVJ9: TWIST2; NbExp=3; IntAct=EBI-985879, EBI-1797313; CC P37840; P62987: UBA52; NbExp=3; IntAct=EBI-985879, EBI-357304; CC P37840; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-985879, EBI-749370; CC P37840; O15205: UBD; NbExp=3; IntAct=EBI-985879, EBI-6657186; CC P37840; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-985879, EBI-11530712; CC P37840; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-985879, EBI-17761788; CC P37840; O75604-3: USP2; NbExp=3; IntAct=EBI-985879, EBI-10696113; CC P37840; P63027: VAMP2; NbExp=5; IntAct=EBI-985879, EBI-520113; CC P37840; P40337-2: VHL; NbExp=3; IntAct=EBI-985879, EBI-12157263; CC P37840; Q9UBQ0-2: VPS29; NbExp=3; IntAct=EBI-985879, EBI-11141397; CC P37840; O00308: WWP2; NbExp=3; IntAct=EBI-985879, EBI-743923; CC P37840; Q04917: YWHAH; NbExp=4; IntAct=EBI-985879, EBI-306940; CC P37840; O43167-2: ZBTB24; NbExp=3; IntAct=EBI-985879, EBI-25842419; CC P37840; Q96NC0: ZMAT2; NbExp=3; IntAct=EBI-985879, EBI-2682299; CC P37840; Q8WUU4: ZNF296; NbExp=3; IntAct=EBI-985879, EBI-8834821; CC P37840; Q8N895: ZNF366; NbExp=3; IntAct=EBI-985879, EBI-2813661; CC P37840; Q8N988-2: ZNF557; NbExp=3; IntAct=EBI-985879, EBI-10699005; CC P37840; Q68EA5: ZNF57; NbExp=3; IntAct=EBI-985879, EBI-8490788; CC P37840; Q8NBB4-2: ZSCAN1; NbExp=3; IntAct=EBI-985879, EBI-12021938; CC P37840; A8K878; NbExp=3; IntAct=EBI-985879, EBI-25831303; CC P37840; P0DTC9: N; Xeno; NbExp=2; IntAct=EBI-985879, EBI-25475856; CC P37840; Q61327: Slc6a3; Xeno; NbExp=5; IntAct=EBI-985879, EBI-7839708; CC P37840-1; P37840-1: SNCA; NbExp=21; IntAct=EBI-9684465, EBI-9684465; CC P37840-1; Q04917: YWHAH; NbExp=9; IntAct=EBI-9684465, EBI-306940; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19762560, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:26442590, ECO:0000269|PubMed:31034892, CC ECO:0000269|PubMed:33657088}. Membrane {ECO:0000269|PubMed:24936070}. CC Nucleus {ECO:0000269|PubMed:12859192, ECO:0000269|PubMed:24936070}. CC Synapse {ECO:0000269|PubMed:15282274}. Secreted CC {ECO:0000269|PubMed:24936070}. Cell projection, axon CC {ECO:0000250|UniProtKB:O55042}. Note=Membrane-bound in dopaminergic CC neurons (PubMed:15282274). Expressed and colocalized with SEPTIN4 in CC dopaminergic axon terminals, especially at the varicosities (By CC similarity). {ECO:0000250|UniProtKB:O55042, CC ECO:0000269|PubMed:15282274}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=NACP140; CC IsoId=P37840-1; Sequence=Displayed; CC Name=2-4; Synonyms=NACP112; CC IsoId=P37840-2; Sequence=VSP_006364; CC Name=2-5; CC IsoId=P37840-3; Sequence=VSP_006363; CC -!- TISSUE SPECIFICITY: Highly expressed in presynaptic terminals in the CC central nervous system. Expressed principally in brain. CC {ECO:0000269|PubMed:8194594}. CC -!- DOMAIN: The 'non A-beta component of Alzheimer disease amyloid plaque' CC domain (NAC domain) is involved in fibrils formation. The middle CC hydrophobic region forms the core of the filaments. The C-terminus may CC regulate aggregation and determine the diameter of the filaments. CC {ECO:0000269|PubMed:19722699}. CC -!- PTM: Phosphorylated, predominantly on serine residues. Phosphorylation CC by CK1 appears to occur on residues distinct from the residue CC phosphorylated by other kinases. Phosphorylation of Ser-129 is CC selective and extensive in synucleinopathy lesions. In vitro, CC phosphorylation at Ser-129 promoted insoluble fibril formation. CC Phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic CC stress. {ECO:0000269|PubMed:10617630, ECO:0000269|PubMed:10852916, CC ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11813001, CC ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:24936070}. CC -!- PTM: Hallmark lesions of neurodegenerative synucleinopathies contain CC alpha-synuclein that is modified by nitration of tyrosine residues and CC possibly by dityrosine cross-linking to generated stable oligomers. CC -!- PTM: Ubiquitinated. The predominant conjugate is the diubiquitinated CC form. {ECO:0000250|UniProtKB:P37377}. CC -!- PTM: Acetylation at Met-1 seems to be important for proper folding and CC native oligomeric structure. {ECO:0000269|PubMed:22407793}. CC -!- DISEASE: Note=Genetic alterations of SNCA resulting in aberrant CC polymerization into fibrils, are associated with several CC neurodegenerative diseases (synucleinopathies). SNCA fibrillar CC aggregates represent the major non A-beta component of Alzheimer CC disease amyloid plaque, and a major component of Lewy body inclusions. CC They are also found within Lewy body (LB)-like intraneuronal CC inclusions, glial inclusions and axonal spheroids in neurodegeneration CC with brain iron accumulation type 1. CC -!- DISEASE: Parkinson disease 1, autosomal dominant (PARK1) [MIM:168601]: CC A complex neurodegenerative disorder characterized by bradykinesia, CC resting tremor, muscular rigidity and postural instability. Additional CC features are characteristic postural abnormalities, dysautonomia, CC dystonic cramps, and dementia. The pathology of Parkinson disease CC involves the loss of dopaminergic neurons in the substantia nigra and CC the presence of Lewy bodies (intraneuronal accumulations of aggregated CC proteins), in surviving neurons in various areas of the brain. The CC disease is progressive and usually manifests after the age of 50 years, CC although early-onset cases (before 50 years) are known. The majority of CC the cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:14755719, CC ECO:0000269|PubMed:23427326, ECO:0000269|PubMed:23457019, CC ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, CC ECO:0000269|PubMed:9197268, ECO:0000269|PubMed:9462735}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinson disease 4, autosomal dominant (PARK4) [MIM:605543]: CC A complex neurodegenerative disorder with manifestations ranging from CC typical Parkinson disease to dementia with Lewy bodies. Clinical CC features include parkinsonian symptoms (resting tremor, rigidity, CC postural instability and bradykinesia), dementia, diffuse Lewy body CC pathology, autonomic dysfunction, hallucinations and paranoia. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Dementia, Lewy body (DLB) [MIM:127750]: A neurodegenerative CC disorder characterized by mental impairment leading to dementia, CC parkinsonism, fluctuating cognitive function, visual hallucinations, CC falls, syncopal episodes, and sensitivity to neuroleptic medication. CC Brainstem or cortical intraneuronal accumulations of aggregated CC proteins (Lewy bodies) are the only essential pathologic features. CC Patients may also have hippocampal and neocortical senile plaques, CC sometimes in sufficient number to fulfill the diagnostic criteria for CC Alzheimer disease. {ECO:0000269|PubMed:14755719}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the synuclein family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L08850; AAA16117.1; -; mRNA. DR EMBL; L36674; AAA98493.1; -; mRNA. DR EMBL; L36675; AAA98487.1; -; mRNA. DR EMBL; D31839; BAA06625.1; -; mRNA. DR EMBL; U46901; AAC02114.1; -; Genomic_DNA. DR EMBL; U46897; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46898; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; U46899; AAC02114.1; JOINED; Genomic_DNA. DR EMBL; AF163864; AAG30302.1; -; Genomic_DNA. DR EMBL; AF163864; AAG30303.1; -; Genomic_DNA. DR EMBL; AY049786; AAL15443.1; -; mRNA. DR EMBL; AK290169; BAF82858.1; -; mRNA. DR EMBL; CR457058; CAG33339.1; -; mRNA. DR EMBL; DQ088379; AAY88735.1; -; Genomic_DNA. DR EMBL; CH471057; EAX06036.1; -; Genomic_DNA. DR EMBL; BC013293; AAH13293.1; -; mRNA. DR EMBL; BC108275; AAI08276.1; -; mRNA. DR CCDS; CCDS3634.1; -. [P37840-1] DR CCDS; CCDS43252.1; -. [P37840-2] DR PIR; A49669; A49669. DR PIR; S56746; S56746. DR RefSeq; NP_000336.1; NM_000345.4. [P37840-1] DR RefSeq; NP_001139526.1; NM_001146054.2. [P37840-1] DR RefSeq; NP_001139527.1; NM_001146055.2. [P37840-1] DR RefSeq; NP_001362214.1; NM_001375285.1. [P37840-1] DR RefSeq; NP_001362215.1; NM_001375286.1. [P37840-1] DR RefSeq; NP_001362216.1; NM_001375287.1. [P37840-1] DR RefSeq; NP_001362217.1; NM_001375288.1. [P37840-1] DR RefSeq; NP_009292.1; NM_007308.3. [P37840-2] DR PDB; 1XQ8; NMR; -; A=1-140. DR PDB; 2JN5; NMR; -; A=1-12. DR PDB; 2KKW; NMR; -; A=1-140. DR PDB; 2M55; NMR; -; B=1-19. DR PDB; 2N0A; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 2X6M; X-ray; 1.62 A; B=132-140. DR PDB; 3Q25; X-ray; 1.90 A; A=1-19. DR PDB; 3Q26; X-ray; 1.54 A; A=10-42. DR PDB; 3Q27; X-ray; 1.30 A; A=32-57. DR PDB; 3Q28; X-ray; 1.60 A; A=58-79. DR PDB; 3Q29; X-ray; 2.30 A; A/C=1-19. DR PDB; 4BXL; NMR; -; C=35-56. DR PDB; 4R0U; X-ray; 1.38 A; A=72-78. DR PDB; 4R0W; X-ray; 1.50 A; A=70-76. DR PDB; 4RIK; X-ray; 1.85 A; A=69-77. DR PDB; 4RIL; EM; 1.43 A; A=68-78. DR PDB; 4ZNN; EM; 1.41 A; A=47-56. DR PDB; 5CRW; X-ray; 1.60 A; B=31-41. DR PDB; 6A6B; EM; 3.07 A; A/B/C/D/E/F/G/H/I/J/K/L=37-99. DR PDB; 6CT7; X-ray; 1.90 A; S/T=1-10. DR PDB; 6CU7; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6CU8; EM; 3.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6H6B; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-121. DR PDB; 6I42; X-ray; 1.38 A; B=48-60. DR PDB; 6L1T; EM; 3.22 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6L1U; EM; 3.37 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O=1-140. DR PDB; 6L4S; EM; 3.37 A; A/B/C/D/E/F=45-99. DR PDB; 6LRQ; EM; 3.49 A; A/B/C/D/E/F=1-140. DR PDB; 6OSJ; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSL; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6OSM; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6PEO; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 6PES; EM; 3.60 A; A/B/C/D/E/V/W/X/Y/Z=1-140. DR PDB; 6RT0; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6RTB; EM; 3.46 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SST; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6SSX; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6UFR; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYO; EM; 2.60 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYP; EM; 3.29 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 6XYQ; EM; 3.09 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7C1D; EM; 3.80 A; A/B/C/D/E/F=1-140. DR PDB; 7E0F; EM; 3.02 A; A/B/C/D/E/F=1-140. DR PDB; 7L7H; EM; 4.00 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7LC9; EM; 3.20 A; A/B/C/D/E/F/G/H/I/J/K/L=41-140. DR PDB; 7NCA; EM; 3.47 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCG; EM; 3.43 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCH; EM; 3.84 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCI; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCJ; EM; 4.23 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7NCK; EM; 3.18 A; A/B/C/D/E/F=1-140. DR PDB; 7OZG; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7OZH; EM; 3.02 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 7STX; EM; 3.14 A; C=1-5. DR PDB; 7UAK; EM; 3.38 A; A/B/C/D/E/F=1-140. DR PDB; 7V47; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7V48; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7V49; EM; 3.40 A; A/B/C=1-140. DR PDB; 7V4A; EM; 3.20 A; A/B/C=1-140. DR PDB; 7V4B; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7V4C; EM; 3.30 A; A/B/F=1-140. DR PDB; 7V4D; EM; 3.50 A; A/B/C/D/E/F=1-140. DR PDB; 7WMM; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7WNZ; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=36-100. DR PDB; 7WO0; EM; 2.70 A; A/B/C/D/E/F/G/O/P/Q/R/S/T/U=35-99. DR PDB; 7XJX; EM; 2.70 A; A/B/C/D/E/F=1-140. DR PDB; 7XO0; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO1; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7XO2; EM; 3.00 A; A/B/C/D/E/I=1-140. DR PDB; 7XO3; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 7YK2; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YK8; EM; 2.80 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 7YNF; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 7YNG; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 7YNL; EM; 2.60 A; A/B/C/D/E/F/G/H=1-140. DR PDB; 7YNM; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNN; EM; 2.90 A; A/B/C/D/G/H/I/J=1-140. DR PDB; 7YNO; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNP; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNQ; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 7YNR; EM; 2.90 A; A/B/C/D/E/F=1-140. DR PDB; 7YNS; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 7YNT; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8A4L; EM; 2.68 A; A/B/C/D/E/F/G/H/I/J/K/L/M/O/P=1-140. DR PDB; 8A9L; EM; 2.16 A; A=1-140. DR PDB; 8ADS; EM; 3.05 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADU; EM; 3.24 A; A/B/C/D/E=1-140. DR PDB; 8ADV; EM; 2.98 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8ADW; EM; 2.95 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8AEX; EM; 2.76 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8B9V; X-ray; 2.16 A; A=110-119. DR PDB; 8BQV; EM; 2.00 A; A=1-140. DR PDB; 8BQW; EM; 2.30 A; A/C=1-140. DR PDB; 8CE7; EM; 2.70 A; A/C=1-140. DR PDB; 8CEB; EM; 2.70 A; A/C=1-140. DR PDB; 8CYR; EM; 4.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYS; EM; 3.10 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYT; EM; 3.00 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8CYV; EM; 3.50 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYW; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CYX; EM; 3.00 A; A/B/C/D/E/I/J/K/L/M=1-140. DR PDB; 8CYY; EM; 3.10 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ0; EM; 2.90 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ1; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ2; EM; 3.00 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ3; EM; 3.20 A; A/B/C/D/E/F/I/J/K/L/M/N=1-140. DR PDB; 8CZ6; EM; 3.20 A; A/B/C/D/E/F/G/I/J/K/L/M/N/O=1-140. DR PDB; 8FPT; NMR; -; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8G0L; EM; 3.39 A; C=1-5. DR PDB; 8GF7; EM; 4.80 A; A/B/C/D/E/F=7-96. DR PDB; 8H03; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8H04; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8H05; EM; 3.40 A; A/B/C=1-140. DR PDB; 8HZB; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZC; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8HZS; EM; 3.30 A; A/B/C/D/E/F=1-140. DR PDB; 8JEX; EM; 3.10 A; A/B/G/H/K/P=1-140. DR PDB; 8JEY; EM; 2.60 A; A/B/C/D/E/F=1-140. DR PDB; 8JJV; X-ray; 1.23 A; B=43-56. DR PDB; 8JLY; X-ray; 1.29 A; B=43-56. DR PDB; 8OG0; X-ray; 1.71 A; P=136-140. DR PDB; 8OJR; NMR; -; A=1-25. DR PDB; 8OL8; NMR; -; A=2-12. DR PDB; 8OQI; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PIX; EM; 3.41 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PJO; EM; 2.31 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8PK2; EM; 3.26 A; A/B/C/D/E=1-140. DR PDB; 8PK4; EM; 3.30 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8QPZ; EM; 2.50 A; A/B/C/D/E/F/G/H/I/J/K/L=8-140. DR PDB; 8RI9; EM; 3.30 A; A/B/C/D/E=1-140. DR PDB; 8RQM; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8RRR; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8UKA; EM; 3.90 A; A/B/C/D/E/a/b/c/d/e=1-140. DR PDB; 8X7B; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7L; EM; 3.40 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7M; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7O; EM; 3.50 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7P; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7Q; EM; 2.70 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8X7R; EM; 3.00 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 8XWD; EM; 3.10 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2P; EM; 3.20 A; A/B/C/D/E/F=1-140. DR PDB; 8Y2Q; EM; 2.80 A; A/B/C/D/E/F=1-140. DR PDB; 8ZLI; EM; 3.40 A; A/B/C/D/E/F/I/J/K/L=45-99. DR PDB; 8ZLO; EM; 3.10 A; A/B/C/D/E/F/G/H/I/J/O/T=45-99. DR PDB; 8ZLP; EM; 3.50 A; A/B/C/F/G/H=1-98. DR PDB; 8ZMY; EM; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=1-98. DR PDB; 8ZVY; X-ray; 1.72 A; C/D=121-140. DR PDB; 8ZWH; EM; 2.50 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWI; EM; 3.00 A; A/B/C/D/E/F=1-140. DR PDB; 8ZWJ; EM; 3.10 A; A/B/C/D/E/G=1-140. DR PDB; 8ZWK; EM; 3.40 A; A/B/C/D/E/F=1-140. DR PDB; 9C5R; EM; 2.61 A; A/B/C/D/E/F/G/H/I/J=1-140. DR PDB; 9CD9; EM; 3.20 A; E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z=1-140. DR PDB; 9CDA; EM; 3.30 A; K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b=1-140. DR PDB; 9CK3; EM; 2.04 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDB; 9CX6; EM; 3.20 A; G/H=1-140. DR PDB; 9D5C; EM; 4.80 A; A/B/C/F/G/H=1-96. DR PDB; 9EUU; EM; 1.93 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9FYP; EM; 2.23 A; I/J/K/L/M/N/O/P/Q/R=1-140. DR PDB; 9HGR; EM; 2.70 A; A/B=1-140. DR PDB; 9HGS; EM; 3.00 A; C=1-140. DR PDB; 9HXA; EM; 3.70 A; A/C=1-140. DR PDB; 9IJP; EM; 3.10 A; B/C/E/G/I/L=1-140. DR PDB; 9O4B; EM; 2.59 A; A/B/C/D/E/F/G/H/I/J/K/L=1-140. DR PDBsum; 1XQ8; -. DR PDBsum; 2JN5; -. DR PDBsum; 2KKW; -. DR PDBsum; 2M55; -. DR PDBsum; 2N0A; -. DR PDBsum; 2X6M; -. DR PDBsum; 3Q25; -. DR PDBsum; 3Q26; -. DR PDBsum; 3Q27; -. DR PDBsum; 3Q28; -. DR PDBsum; 3Q29; -. DR PDBsum; 4BXL; -. DR PDBsum; 4R0U; -. DR PDBsum; 4R0W; -. DR PDBsum; 4RIK; -. DR PDBsum; 4RIL; -. DR PDBsum; 4ZNN; -. DR PDBsum; 5CRW; -. DR PDBsum; 6A6B; -. DR PDBsum; 6CT7; -. DR PDBsum; 6CU7; -. DR PDBsum; 6CU8; -. DR PDBsum; 6H6B; -. DR PDBsum; 6I42; -. DR PDBsum; 6L1T; -. DR PDBsum; 6L1U; -. DR PDBsum; 6L4S; -. DR PDBsum; 6LRQ; -. DR PDBsum; 6OSJ; -. DR PDBsum; 6OSL; -. DR PDBsum; 6OSM; -. DR PDBsum; 6PEO; -. DR PDBsum; 6PES; -. DR PDBsum; 6RT0; -. DR PDBsum; 6RTB; -. DR PDBsum; 6SST; -. DR PDBsum; 6SSX; -. DR PDBsum; 6UFR; -. DR PDBsum; 6XYO; -. DR PDBsum; 6XYP; -. DR PDBsum; 6XYQ; -. DR PDBsum; 7C1D; -. DR PDBsum; 7E0F; -. DR PDBsum; 7L7H; -. DR PDBsum; 7LC9; -. DR PDBsum; 7NCA; -. DR PDBsum; 7NCG; -. DR PDBsum; 7NCH; -. DR PDBsum; 7NCI; -. DR PDBsum; 7NCJ; -. DR PDBsum; 7NCK; -. DR PDBsum; 7OZG; -. DR PDBsum; 7OZH; -. DR PDBsum; 7STX; -. DR PDBsum; 7UAK; -. DR PDBsum; 7V47; -. DR PDBsum; 7V48; -. DR PDBsum; 7V49; -. DR PDBsum; 7V4A; -. DR PDBsum; 7V4B; -. DR PDBsum; 7V4C; -. DR PDBsum; 7V4D; -. DR PDBsum; 7WMM; -. DR PDBsum; 7WNZ; -. DR PDBsum; 7WO0; -. DR PDBsum; 7XJX; -. DR PDBsum; 7XO0; -. DR PDBsum; 7XO1; -. DR PDBsum; 7XO2; -. DR PDBsum; 7XO3; -. DR PDBsum; 7YK2; -. DR PDBsum; 7YK8; -. DR PDBsum; 7YNF; -. DR PDBsum; 7YNG; -. DR PDBsum; 7YNL; -. DR PDBsum; 7YNM; -. DR PDBsum; 7YNN; -. DR PDBsum; 7YNO; -. DR PDBsum; 7YNP; -. DR PDBsum; 7YNQ; -. DR PDBsum; 7YNR; -. DR PDBsum; 7YNS; -. DR PDBsum; 7YNT; -. DR PDBsum; 8A4L; -. DR PDBsum; 8A9L; -. DR PDBsum; 8ADS; -. DR PDBsum; 8ADU; -. DR PDBsum; 8ADV; -. DR PDBsum; 8ADW; -. DR PDBsum; 8AEX; -. DR PDBsum; 8B9V; -. DR PDBsum; 8BQV; -. DR PDBsum; 8BQW; -. DR PDBsum; 8CE7; -. DR PDBsum; 8CEB; -. DR PDBsum; 8CYR; -. DR PDBsum; 8CYS; -. DR PDBsum; 8CYT; -. DR PDBsum; 8CYV; -. DR PDBsum; 8CYW; -. DR PDBsum; 8CYX; -. DR PDBsum; 8CYY; -. DR PDBsum; 8CZ0; -. DR PDBsum; 8CZ1; -. DR PDBsum; 8CZ2; -. DR PDBsum; 8CZ3; -. DR PDBsum; 8CZ6; -. DR PDBsum; 8FPT; -. DR PDBsum; 8G0L; -. DR PDBsum; 8GF7; -. DR PDBsum; 8H03; -. DR PDBsum; 8H04; -. DR PDBsum; 8H05; -. DR PDBsum; 8HZB; -. DR PDBsum; 8HZC; -. DR PDBsum; 8HZS; -. DR PDBsum; 8JEX; -. DR PDBsum; 8JEY; -. DR PDBsum; 8JJV; -. DR PDBsum; 8JLY; -. DR PDBsum; 8OG0; -. DR PDBsum; 8OJR; -. DR PDBsum; 8OL8; -. DR PDBsum; 8OQI; -. DR PDBsum; 8PIX; -. DR PDBsum; 8PJO; -. DR PDBsum; 8PK2; -. DR PDBsum; 8PK4; -. DR PDBsum; 8QPZ; -. DR PDBsum; 8RI9; -. DR PDBsum; 8RQM; -. DR PDBsum; 8RRR; -. DR PDBsum; 8UKA; -. DR PDBsum; 8X7B; -. DR PDBsum; 8X7L; -. DR PDBsum; 8X7M; -. DR PDBsum; 8X7O; -. DR PDBsum; 8X7P; -. DR PDBsum; 8X7Q; -. DR PDBsum; 8X7R; -. DR PDBsum; 8XWD; -. DR PDBsum; 8Y2P; -. DR PDBsum; 8Y2Q; -. DR PDBsum; 8ZLI; -. DR PDBsum; 8ZLO; -. DR PDBsum; 8ZLP; -. DR PDBsum; 8ZMY; -. DR PDBsum; 8ZVY; -. DR PDBsum; 8ZWH; -. DR PDBsum; 8ZWI; -. DR PDBsum; 8ZWJ; -. DR PDBsum; 8ZWK; -. DR PDBsum; 9C5R; -. DR PDBsum; 9CD9; -. DR PDBsum; 9CDA; -. DR PDBsum; 9CK3; -. DR PDBsum; 9CX6; -. DR PDBsum; 9D5C; -. DR PDBsum; 9EUU; -. DR PDBsum; 9FYP; -. DR PDBsum; 9HGR; -. DR PDBsum; 9HGS; -. DR PDBsum; 9HXA; -. DR PDBsum; 9IJP; -. DR PDBsum; 9O4B; -. DR AlphaFoldDB; P37840; -. DR BMRB; P37840; -. DR EMDB; EMD-0148; -. DR EMDB; EMD-0801; -. DR EMDB; EMD-0803; -. DR EMDB; EMD-0833; -. DR EMDB; EMD-0958; -. DR EMDB; EMD-10305; -. DR EMDB; EMD-10307; -. DR EMDB; EMD-10650; -. DR EMDB; EMD-10651; -. DR EMDB; EMD-10652; -. DR EMDB; EMD-12264; -. DR EMDB; EMD-12265; -. DR EMDB; EMD-12266; -. DR EMDB; EMD-12267; -. DR EMDB; EMD-12268; -. DR EMDB; EMD-12269; -. DR EMDB; EMD-13123; -. DR EMDB; EMD-13124; -. DR EMDB; EMD-15148; -. DR EMDB; EMD-15285; -. DR EMDB; EMD-15369; -. DR EMDB; EMD-15370; -. DR EMDB; EMD-15371; -. DR EMDB; EMD-15372; -. DR EMDB; EMD-15388; -. DR EMDB; EMD-16188; -. DR EMDB; EMD-16189; -. DR EMDB; EMD-16600; -. DR EMDB; EMD-16603; -. DR EMDB; EMD-17111; -. DR EMDB; EMD-17693; -. DR EMDB; EMD-17714; -. DR EMDB; EMD-17723; -. DR EMDB; EMD-17726; -. DR EMDB; EMD-18570; -. DR EMDB; EMD-19184; -. DR EMDB; EMD-19446; -. DR EMDB; EMD-19462; -. DR EMDB; EMD-19986; -. DR EMDB; EMD-20183; -. DR EMDB; EMD-20185; -. DR EMDB; EMD-20186; -. DR EMDB; EMD-20328; -. DR EMDB; EMD-20331; -. DR EMDB; EMD-20759; -. DR EMDB; EMD-23212; -. DR EMDB; EMD-23270; -. DR EMDB; EMD-25438; -. DR EMDB; EMD-26427; -. DR EMDB; EMD-27082; -. DR EMDB; EMD-27083; -. DR EMDB; EMD-27084; -. DR EMDB; EMD-27085; -. DR EMDB; EMD-27086; -. DR EMDB; EMD-27087; -. DR EMDB; EMD-27088; -. DR EMDB; EMD-27089; -. DR EMDB; EMD-27090; -. DR EMDB; EMD-27091; -. DR EMDB; EMD-27092; -. DR EMDB; EMD-27093; -. DR EMDB; EMD-29657; -. DR EMDB; EMD-29980; -. DR EMDB; EMD-30269; -. DR EMDB; EMD-30931; -. DR EMDB; EMD-3094; -. DR EMDB; EMD-3095; -. DR EMDB; EMD-31702; -. DR EMDB; EMD-31703; -. DR EMDB; EMD-31704; -. DR EMDB; EMD-31705; -. DR EMDB; EMD-31706; -. DR EMDB; EMD-31707; -. DR EMDB; EMD-31708; -. DR EMDB; EMD-32615; -. DR EMDB; EMD-32636; -. DR EMDB; EMD-32637; -. DR EMDB; EMD-33236; -. DR EMDB; EMD-33332; -. DR EMDB; EMD-33333; -. DR EMDB; EMD-33334; -. DR EMDB; EMD-33335; -. DR EMDB; EMD-33884; -. DR EMDB; EMD-33890; -. DR EMDB; EMD-33960; -. DR EMDB; EMD-33961; -. DR EMDB; EMD-33965; -. DR EMDB; EMD-33966; -. DR EMDB; EMD-33967; -. DR EMDB; EMD-33968; -. DR EMDB; EMD-33969; -. DR EMDB; EMD-33970; -. DR EMDB; EMD-33971; -. DR EMDB; EMD-35087; -. DR EMDB; EMD-35088; -. DR EMDB; EMD-35090; -. DR EMDB; EMD-36202; -. DR EMDB; EMD-36203; -. DR EMDB; EMD-38097; -. DR EMDB; EMD-38103; -. DR EMDB; EMD-38104; -. DR EMDB; EMD-38105; -. DR EMDB; EMD-38106; -. DR EMDB; EMD-38107; -. DR EMDB; EMD-38108; -. DR EMDB; EMD-38733; -. DR EMDB; EMD-38862; -. DR EMDB; EMD-38863; -. DR EMDB; EMD-42350; -. DR EMDB; EMD-45221; -. DR EMDB; EMD-45464; -. DR EMDB; EMD-45465; -. DR EMDB; EMD-45639; -. DR EMDB; EMD-45650; -. DR EMDB; EMD-45651; -. DR EMDB; EMD-45979; -. DR EMDB; EMD-47820; -. DR EMDB; EMD-4994; -. DR EMDB; EMD-4996; -. DR EMDB; EMD-50077; -. DR EMDB; EMD-50860; -. DR EMDB; EMD-50888; -. DR EMDB; EMD-52165; -. DR EMDB; EMD-52166; -. DR EMDB; EMD-52458; -. DR EMDB; EMD-54402; -. DR EMDB; EMD-60226; -. DR EMDB; EMD-60231; -. DR EMDB; EMD-60232; -. DR EMDB; EMD-60262; -. DR EMDB; EMD-60527; -. DR EMDB; EMD-60528; -. DR EMDB; EMD-60529; -. DR EMDB; EMD-60530; -. DR EMDB; EMD-60637; -. DR EMDB; EMD-61330; -. DR EMDB; EMD-61355; -. DR EMDB; EMD-61356; -. DR EMDB; EMD-61357; -. DR EMDB; EMD-61383; -. DR EMDB; EMD-61384; -. DR EMDB; EMD-61394; -. DR EMDB; EMD-6482; -. DR EMDB; EMD-6988; -. DR EMDB; EMD-70093; -. DR EMDB; EMD-70295; -. DR EMDB; EMD-7618; -. DR EMDB; EMD-7619; -. DR PCDDB; P37840; -. DR SMR; P37840; -. DR BioGRID; 112506; 1553. DR CORUM; P37840; -. DR DIP; DIP-35354N; -. DR FunCoup; P37840; 336. DR IntAct; P37840; 474. DR MINT; P37840; -. DR STRING; 9606.ENSP00000500990; -. DR BindingDB; P37840; -. DR ChEMBL; CHEMBL6152; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB04209; Dequalinium. DR DrugBank; DB02709; Resveratrol. DR DrugCentral; P37840; -. DR GuidetoPHARMACOLOGY; 3285; -. DR TCDB; 1.C.77.1.1; the synuclein (synuclein) family. DR GlyConnect; 2893; 1 O-GlcNAc glycan (1 site). DR GlyCosmos; P37840; 5 sites, 1 glycan. DR GlyGen; P37840; 7 sites, 2 O-linked glycans (7 sites). DR iPTMnet; P37840; -. DR MetOSite; P37840; -. DR PhosphoSitePlus; P37840; -. DR SwissPalm; P37840; -. DR BioMuta; SNCA; -. DR DMDM; 586067; -. DR jPOST; P37840; -. DR MassIVE; P37840; -. DR PaxDb; 9606-ENSP00000338345; -. DR PeptideAtlas; P37840; -. DR ProteomicsDB; 55279; -. [P37840-1] DR ProteomicsDB; 55280; -. [P37840-2] DR ProteomicsDB; 55281; -. [P37840-3] DR Pumba; P37840; -. DR TopDownProteomics; P37840-1; -. [P37840-1] DR ABCD; P37840; 22 sequenced antibodies. DR Antibodypedia; 14688; 3097 antibodies from 56 providers. DR DNASU; 6622; -. DR Ensembl; ENST00000336904.7; ENSP00000338345.3; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000345009.8; ENSP00000343683.4; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000394986.5; ENSP00000378437.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000394989.6; ENSP00000378440.2; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000394991.8; ENSP00000378442.4; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000420646.6; ENSP00000396241.2; ENSG00000145335.18. [P37840-2] DR Ensembl; ENST00000505199.5; ENSP00000421485.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000506244.5; ENSP00000422238.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000508895.5; ENSP00000426955.1; ENSG00000145335.18. [P37840-1] DR Ensembl; ENST00000618500.4; ENSP00000484044.1; ENSG00000145335.18. [P37840-3] DR Ensembl; ENST00000673718.1; ENSP00000500990.1; ENSG00000145335.18. [P37840-1] DR GeneID; 6622; -. DR KEGG; hsa:6622; -. DR MANE-Select; ENST00000394991.8; ENSP00000378442.4; NM_000345.4; NP_000336.1. DR UCSC; uc003hso.3; human. [P37840-1] DR AGR; HGNC:11138; -. DR ClinPGx; PA35986; -. DR CTD; 6622; -. DR DisGeNET; 6622; -. DR GeneCards; SNCA; -. DR GeneReviews; SNCA; -. DR HGNC; HGNC:11138; SNCA. DR HPA; ENSG00000145335; Group enriched (bone marrow, brain). DR MalaCards; SNCA; -. DR MIM; 127750; phenotype. DR MIM; 163890; gene. DR MIM; 168600; phenotype. DR MIM; 168601; phenotype. DR MIM; 605543; phenotype. DR OpenTargets; ENSG00000145335; -. DR Orphanet; 411602; Hereditary late-onset Parkinson disease. DR Orphanet; 171695; Parkinsonian-pyramidal syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000145335; -. DR eggNOG; ENOG502S0Q7; Eukaryota. DR GeneTree; ENSGT00950000183175; -. DR HOGENOM; CLU_129378_1_0_1; -. DR InParanoid; P37840; -. DR OMA; LPQEGMM; -. DR OrthoDB; 9900372at2759; -. DR PAN-GO; P37840; 8 GO annotations based on evolutionary models. DR PhylomeDB; P37840; -. DR PathwayCommons; P37840; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; P37840; -. DR SIGNOR; P37840; -. DR Agora; ENSG00000145335; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 6622; 12 hits in 1150 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SNCA; human. DR EvolutionaryTrace; P37840; -. DR GeneWiki; Alpha-synuclein; -. DR GenomeRNAi; 6622; -. DR Pharos; P37840; Tchem. DR PRO; PR:P37840; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P37840; protein. DR Bgee; ENSG00000145335; Expressed in trabecular bone tissue and 205 other cell types or tissues. DR ExpressionAtlas; P37840; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:UniProtKB. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0043679; C:axon terminus; IBA:GO_Central. DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:ParkinsonsUK-UCL. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB. DR GO; GO:0097413; C:Lewy body; IDA:MGI. DR GO; GO:0005764; C:lysosome; TAS:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005759; C:mitochondrial matrix; IEA:Ensembl. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; TAS:ParkinsonsUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central. DR GO; GO:0005640; C:nuclear outer membrane; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0032991; C:protein-containing complex; IMP:UniProtKB. DR GO; GO:0005840; C:ribosome; IEA:Ensembl. DR GO; GO:0099512; C:supramolecular fiber; IDA:UniProtKB. DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; IPI:ARUK-UCL. DR GO; GO:0043014; F:alpha-tubulin binding; IPI:UniProtKB. DR GO; GO:0048487; F:beta-tubulin binding; IEA:Ensembl. DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:1903136; F:cuprous ion binding; IMP:CAFA. DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IDA:UniProtKB. DR GO; GO:0070840; F:dynein complex binding; IPI:UniProtKB. DR GO; GO:0008047; F:enzyme activator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:BHF-UCL. DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB. DR GO; GO:0042393; F:histone binding; IDA:UniProtKB. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0019894; F:kinesin binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; EXP:DisProt. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IEA:Ensembl. DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB. DR GO; GO:0043274; F:phospholipase binding; IEA:Ensembl. DR GO; GO:0005543; F:phospholipid binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0051219; F:phosphoprotein binding; IDA:BHF-UCL. DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl. DR GO; GO:0004860; F:protein kinase inhibitor activity; TAS:ARUK-UCL. DR GO; GO:0140311; F:protein sequestering activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0000149; F:SNARE binding; IDA:UniProtKB. DR GO; GO:0048156; F:tau protein binding; IDA:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; TAS:ParkinsonsUK-UCL. DR GO; GO:0141108; F:transporter regulator activity; IGI:ARUK-UCL. DR GO; GO:0015631; F:tubulin binding; EXP:DisProt. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl. DR GO; GO:1990000; P:amyloid fibril formation; EXP:DisProt. DR GO; GO:0048148; P:behavioral response to cocaine; IEA:Ensembl. DR GO; GO:0071280; P:cellular response to copper ion; IDA:UniProtKB. DR GO; GO:0071872; P:cellular response to epinephrine stimulus; TAS:UniProtKB. DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; IEA:Ensembl. DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0042416; P:dopamine biosynthetic process; TAS:UniProtKB. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; TAS:UniProtKB. DR GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:0006631; P:fatty acid metabolic process; IEA:Ensembl. DR GO; GO:0006749; P:glutathione metabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; TAS:ParkinsonsUK-UCL. DR GO; GO:0042775; P:mitochondrial ATP synthesis coupled electron transport; IEA:Ensembl. DR GO; GO:0007006; P:mitochondrial membrane organization; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:1904715; P:negative regulation of chaperone-mediated autophagy; IMP:ParkinsonsUK-UCL. DR GO; GO:0045963; P:negative regulation of dopamine metabolic process; IEA:Ensembl. DR GO; GO:0051585; P:negative regulation of dopamine uptake involved in synaptic transmission; IDA:UniProtKB. DR GO; GO:0045920; P:negative regulation of exocytosis; IMP:UniProtKB. DR GO; GO:0031115; P:negative regulation of microtubule polymerization; IDA:BHF-UCL. DR GO; GO:1902957; P:negative regulation of mitochondrial electron transport, NADH to ubiquinone; TAS:ParkinsonsUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051622; P:negative regulation of norepinephrine uptake; IDA:UniProtKB. DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0051612; P:negative regulation of serotonin uptake; IDA:UniProtKB. DR GO; GO:0070495; P:negative regulation of thrombin-activated receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:ParkinsonsUK-UCL. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0006638; P:neutral lipid metabolic process; IEA:Ensembl. DR GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:UniProtKB. DR GO; GO:0045921; P:positive regulation of exocytosis; IMP:UniProtKB. DR GO; GO:1903285; P:positive regulation of hydrogen peroxide catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:ParkinsonsUK-UCL. DR GO; GO:0060732; P:positive regulation of inositol phosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0001956; P:positive regulation of neurotransmitter secretion; IEA:Ensembl. DR GO; GO:1904377; P:positive regulation of protein localization to cell periphery; IGI:ParkinsonsUK-UCL. DR GO; GO:0001921; P:positive regulation of receptor recycling; IDA:UniProtKB. DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:UniProtKB. DR GO; GO:0035543; P:positive regulation of SNARE complex assembly; IDA:CACAO. DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB. DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB. DR GO; GO:0031623; P:receptor internalization; IDA:UniProtKB. DR GO; GO:0050812; P:regulation of acyl-CoA biosynthetic process; IEA:Ensembl. DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:UniProtKB. DR GO; GO:0014048; P:regulation of glutamate secretion; IEA:Ensembl. DR GO; GO:0040012; P:regulation of locomotion; IEA:Ensembl. DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl. DR GO; GO:0043030; P:regulation of macrophage activation; IEA:Ensembl. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:BHF-UCL. DR GO; GO:0051621; P:regulation of norepinephrine uptake; IGI:ARUK-UCL. DR GO; GO:1905606; P:regulation of presynapse assembly; IGI:ARUK-UCL. DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; TAS:ParkinsonsUK-UCL. DR GO; GO:1903421; P:regulation of synaptic vesicle recycling; TAS:ParkinsonsUK-UCL. DR GO; GO:1904307; P:response to desipramine; IEA:Ensembl. DR GO; GO:0070555; P:response to interleukin-1; IDA:UniProtKB. DR GO; GO:0010040; P:response to iron(II) ion; IDA:UniProtKB. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0032026; P:response to magnesium ion; IDA:UniProtKB. DR GO; GO:0034341; P:response to type II interferon; IDA:UniProtKB. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0035493; P:SNARE complex assembly; IDA:UniProtKB. DR GO; GO:0097435; P:supramolecular fiber organization; TAS:UniProtKB. DR GO; GO:0050808; P:synapse organization; IBA:GO_Central. DR GO; GO:0048488; P:synaptic vesicle endocytosis; ISS:UniProtKB. DR GO; GO:0016079; P:synaptic vesicle exocytosis; IDA:UniProtKB. DR GO; GO:0016082; P:synaptic vesicle priming; IMP:UniProtKB. DR GO; GO:0048489; P:synaptic vesicle transport; IEA:Ensembl. DR DisProt; DP00070; -. DR FunFam; 1.10.287.700:FF:000001; Alpha-synuclein; 1. DR Gene3D; 1.10.287.700; Helix hairpin bin; 1. DR IDEAL; IID00302; -. DR InterPro; IPR001058; Synuclein. DR InterPro; IPR002460; Synuclein_alpha. DR PANTHER; PTHR13820:SF5; ALPHA-SYNUCLEIN; 1. DR PANTHER; PTHR13820; SYNUCLEIN; 1. DR Pfam; PF01387; Synuclein; 1. DR PRINTS; PR01212; ASYNUCLEIN. DR PRINTS; PR01211; SYNUCLEIN. DR SUPFAM; SSF118375; Synuclein; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Alzheimer disease; KW Amyloid; Cell projection; Copper; Cytoplasm; Direct protein sequencing; KW Disease variant; Membrane; Metal-binding; Neurodegeneration; Nucleus; KW Parkinson disease; Parkinsonism; Phosphoprotein; Proteomics identification; KW Reference proteome; Repeat; Secreted; Synapse; Ubl conjugation. FT CHAIN 1..140 FT /note="Alpha-synuclein" FT /id="PRO_0000184022" FT REPEAT 20..30 FT /note="1" FT REPEAT 31..41 FT /note="2" FT REPEAT 42..56 FT /note="3; approximate" FT REPEAT 57..67 FT /note="4" FT REGION 20..67 FT /note="4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V- FT X(4)" FT REGION 100..140 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 111..140 FT /note="Interaction with SERF1A" FT /evidence="ECO:0000269|PubMed:22854022" FT COMPBIAS 112..140 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 2 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT BINDING 50 FT /ligand="Cu cation" FT /ligand_id="ChEBI:CHEBI:23378" FT /evidence="ECO:0000305" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:22407793" FT MOD_RES 87 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:10617630" FT MOD_RES 125 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:11162638, FT ECO:0000269|PubMed:12893833" FT MOD_RES 129 FT /note="Phosphoserine; by BARK1, PLK2, CK2, CK1 and GRK5" FT /evidence="ECO:0000269|PubMed:10617630, FT ECO:0000269|PubMed:11813001, ECO:0000269|PubMed:24936070" FT VAR_SEQ 41..54 FT /note="Missing (in isoform 2-5)" FT /evidence="ECO:0000303|PubMed:7601450" FT /id="VSP_006363" FT VAR_SEQ 103..130 FT /note="Missing (in isoform 2-4)" FT /evidence="ECO:0000303|PubMed:7601450, FT ECO:0000303|PubMed:7802671" FT /id="VSP_006364" FT VARIANT 30 FT /note="A -> P (in PARK1; no effect on oligomerization; FT dbSNP:rs104893878)" FT /evidence="ECO:0000269|PubMed:25561023, FT ECO:0000269|PubMed:9462735" FT /id="VAR_007957" FT VARIANT 46 FT /note="E -> K (in PARK1 and DLB; significant increase in FT binding to negatively charged phospholipid liposomes; FT increases oligomerization; dbSNP:rs104893875)" FT /evidence="ECO:0000269|PubMed:14755719, FT ECO:0000269|PubMed:15498564, ECO:0000269|PubMed:25561023" FT /id="VAR_022703" FT VARIANT 50 FT /note="H -> Q (in PARK1; no effect on protein structure; no FT effect on phosphorylation of the protein; no effect on FT membrane- and lipid-binding; increases oligomerization; FT increases fibril formation; increases secretion of the FT protein; impairs copper-binding; dbSNP:rs201106962)" FT /evidence="ECO:0000269|PubMed:23427326, FT ECO:0000269|PubMed:23457019, ECO:0000269|PubMed:24936070, FT ECO:0000269|PubMed:25561023" FT /id="VAR_070171" FT VARIANT 53 FT /note="A -> T (in PARK1; no effect on osmotic stress- FT induced phosphorylation; increases oligomerization; FT dbSNP:rs104893877)" FT /evidence="ECO:0000269|PubMed:12893833, FT ECO:0000269|PubMed:25561023, ECO:0000269|PubMed:9197268" FT /id="VAR_007454" FT MUTAGEN 2 FT /note="D->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 35 FT /note="E->K: No effect on oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 39 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 50 FT /note="H->A: Impairs copper-binding." FT /evidence="ECO:0000269|PubMed:21319811" FT MUTAGEN 57 FT /note="E->K: Increases oligomerization." FT /evidence="ECO:0000269|PubMed:25561023" FT MUTAGEN 67..71 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 71..82 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76..77 FT /note="Missing: Impairs polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 76 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT MUTAGEN 77 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 78 FT /note="Missing: Does not affect polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 85..94 FT /note="Missing: Reduces polymerization into amyloid FT fibrils." FT /evidence="ECO:0000269|PubMed:19722699" FT MUTAGEN 125 FT /note="Y->F: Abolishes osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 133 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT MUTAGEN 136 FT /note="Y->F: No effect on osmotic stress-induced FT phosphorylation." FT /evidence="ECO:0000269|PubMed:12893833" FT HELIX 3..11 FT /evidence="ECO:0007829|PDB:3Q25" FT STRAND 16..18 FT /evidence="ECO:0007829|PDB:7YK8" FT HELIX 21..32 FT /evidence="ECO:0007829|PDB:3Q26" FT STRAND 34..36 FT /evidence="ECO:0007829|PDB:8A4L" FT STRAND 38..40 FT /evidence="ECO:0007829|PDB:7V48" FT HELIX 41..44 FT /evidence="ECO:0007829|PDB:3Q27" FT STRAND 45..49 FT /evidence="ECO:0007829|PDB:8PJO" FT STRAND 52..55 FT /evidence="ECO:0007829|PDB:8JJV" FT STRAND 57..59 FT /evidence="ECO:0007829|PDB:8RQM" FT STRAND 60..63 FT /evidence="ECO:0007829|PDB:9FYP" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:3Q28" FT STRAND 70..72 FT /evidence="ECO:0007829|PDB:7YNP" FT STRAND 73..83 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 84..86 FT /evidence="ECO:0007829|PDB:8AEX" FT STRAND 88..96 FT /evidence="ECO:0007829|PDB:9EUU" FT STRAND 110..113 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 120..122 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 124..126 FT /evidence="ECO:0007829|PDB:1XQ8" FT TURN 133..136 FT /evidence="ECO:0007829|PDB:2N0A" SQ SEQUENCE 140 AA; 14460 MW; 6BB2F12128931663 CRC64; MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP DNEAYEMPSE EGYQDYEPEA //