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 27-MAR-2024, entry version 224. 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:8940146, PubMed:11294867, PubMed:12530537, PubMed:15053742, CC PubMed:14764453, PubMed:15364913, PubMed:26858303). Interacts (via C- CC terminal cytosolic domain) with GGA1 and GGA2 (via N-terminal VHS CC domain) (PubMed:11821067, PubMed:17855360, PubMed:30679749, CC PubMed:20015111). Interacts with PACS1 (PubMed:17855360, CC PubMed:17646382). 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=4; IntAct=EBI-1171329, EBI-447141; CC Q92673; Q9UJY4: GGA2; NbExp=5; 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=4; 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:21994944, PubMed:21385844, 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:9157966, PubMed:16174740, PubMed:21147781). Most abundant in CC the cerebellum, cerebral cortex and occipital pole; low levels in the CC putamen and thalamus (PubMed:9157966, PubMed:16174740). 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:9157966, PubMed:8940146). {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_003096.1; NM_003105.5. 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; 153. DR DIP; DIP-41229N; -. DR IntAct; Q92673; 73. 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; 44 sites, 15 N-linked glycans (9 sites), 4 O-linked glycans (9 sites). DR iPTMnet; Q92673; -. DR PhosphoSitePlus; Q92673; -. DR SwissPalm; Q92673; -. DR BioMuta; SORL1; -. DR DMDM; 296452912; -. DR EPD; Q92673; -. DR jPOST; Q92673; -. DR MassIVE; Q92673; -. DR MaxQB; Q92673; -. DR PaxDb; 9606-ENSP00000260197; -. DR PeptideAtlas; Q92673; -. DR ProteomicsDB; 75402; -. DR Pumba; Q92673; -. DR ABCD; Q92673; 1 sequenced antibody. DR Antibodypedia; 32786; 303 antibodies from 38 providers. DR DNASU; 6653; -. DR Ensembl; ENST00000260197.12; ENSP00000260197.6; ENSG00000137642.13. 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 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 neXtProt; NX_Q92673; -. DR NIAGADS; ENSG00000137642; -. DR OpenTargets; ENSG00000137642; -. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 238616; NON RARE IN EUROPE: Alzheimer disease. DR PharmGKB; PA36022; -. 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; 5840at2759; -. DR PhylomeDB; Q92673; -. DR TreeFam; TF324918; -. DR PathwayCommons; Q92673; -. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; Q92673; -. DR SIGNOR; Q92673; -. 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:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. 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: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:0051604; P:protein maturation; 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 CDD; cd00063; FN3; 5. DR CDD; cd00112; LDLa; 11. 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; 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; IPR015943; WD40/YVTN_repeat-like_dom_sf. DR PANTHER; PTHR12106; SORTILIN RELATED; 1. DR PANTHER; PTHR12106:SF20; SORTILIN-RELATED RECEPTOR; 1. DR Pfam; PF00041; fn3; 3. 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 Genevisible; Q92673; HS. 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 Receptor; Reference proteome; Repeat; Secreted; Signal; Transmembrane; KW 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 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 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 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 FT C-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 //