SORL_HUMAN
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 03-AUG-2022, entry version 215.
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}.
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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 PDBsum; 2DM4; -.
DR PDBsum; 3G2S; -.
DR PDBsum; 3G2T; -.
DR PDBsum; 3WSX; -.
DR PDBsum; 3WSY; -.
DR PDBsum; 3WSZ; -.
DR AlphaFoldDB; Q92673; -.
DR BMRB; Q92673; -.
DR SMR; Q92673; -.
DR BioGRID; 112536; 148.
DR DIP; DIP-41229N; -.
DR IntAct; Q92673; 72.
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 GlyGen; Q92673; 43 sites, 15 N-linked glycans (9 sites), 3 O-linked glycans (8 sites).
DR iPTMnet; Q92673; -.
DR PhosphoSitePlus; Q92673; -.
DR BioMuta; SORL1; -.
DR DMDM; 296452912; -.
DR EPD; Q92673; -.
DR jPOST; Q92673; -.
DR MassIVE; Q92673; -.
DR MaxQB; Q92673; -.
DR PaxDb; Q92673; -.
DR PeptideAtlas; Q92673; -.
DR PRIDE; Q92673; -.
DR ProteomicsDB; 75402; -.
DR ABCD; Q92673; 1 sequenced antibody.
DR Antibodypedia; 32786; 265 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 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; 1046610at2759; -.
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; 15 hits in 1071 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 204 other tissues.
DR ExpressionAtlas; Q92673; baseline and differential.
DR Genevisible; Q92673; HS.
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:0016021; C:integral component of membrane; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
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: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:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0002024; P:diet induced thermogenesis; ISS:UniProtKB.
DR GO; GO:0038020; P:insulin receptor recycling; IDA:UniProtKB.
DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; IDA:Alzheimers_University_of_Toronto.
DR GO; GO:1902960; P:negative regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process; IDA:Alzheimers_University_of_Toronto.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; ISS:UniProtKB.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; ISS:Alzheimers_University_of_Toronto.
DR GO; GO:1902963; P:negative regulation of metalloendopeptidase activity involved in amyloid precursor protein catabolic process; IMP:Alzheimers_University_of_Toronto.
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:1901215; P:negative regulation of neuron death; ISS:Alzheimers_University_of_Toronto.
DR GO; GO:0032091; P:negative regulation of protein binding; IDA:Alzheimers_University_of_Toronto.
DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IMP:Alzheimers_University_of_Toronto.
DR GO; GO:1902948; P:negative regulation of tau-protein kinase activity; ISS: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:1902771; P:positive regulation of choline O-acetyltransferase activity; ISS:Alzheimers_University_of_Toronto.
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; 2.120.10.30; -; 1.
DR Gene3D; 2.130.10.10; -; 1.
DR Gene3D; 2.60.40.10; -; 3.
DR Gene3D; 4.10.400.10; -; 11.
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 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; SSF49265; 3.
DR SUPFAM; SSF57424; SSF57424; 11.
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.
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; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:22472873"
FT /id="VAR_070012"
FT VARIANT 511
FT /note="G -> R (in AD; unknown pathological significance;
FT loss of interaction with APP amyloid-beta peptides, hence
FT reduced 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; unknown pathological 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; unknown pathological 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; unknown pathological 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 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 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 492..495
FT /evidence="ECO:0007829|PDB:3WSX"
FT STRAND 504..510
FT /evidence="ECO:0007829|PDB:3WSX"
FT STRAND 519..525
FT /evidence="ECO:0007829|PDB:3WSX"
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 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
